Advances in molecular, genetic and immune signatures of gastric cancer: Are we ready to apply them in our patients' decision making?
ORCID number: Stavros Gkolfinopoulos (0000-0003-2470-8620); Demetris Papamichael (0000-0002-2643-5569); Konstantinos Papadimitriou (0000-0003-4500-4075); Panos Papanastasopoulos (0000-0003-4352-881X); Vassilios Vassiliou (0000-0002-1164-6531); Panteleimon Kountourakis (0000-0002-1134-6176).
Author contributions: Gkolfinopoulos S and Papamichael D participated in manuscript preparation and revision, approval of the final version; Papadimitriou K and Papanastasopoulos P participated in manuscript preparation, approval of the final version; Vassiliou V participated in manuscript preparation; Kountourakis P participated in conception and design of the review, manuscript preparation and revision, approval of the final version.
Conflict-of-interest statement: Dr. Kountourakis has nothing to disclose.
In the last few years we have witnessed a vast expansion of our knowledge regarding the molecular and genetic profile of gastric cancer. The molecular subtypes described have shed light on the pathogenesis of the disease, thus prompting the development of new therapeutic strategies and favoring a more individualized approach for treatment. Most of the clinical trials for so called targeted therapies could be considered, at best, partially successful. In addition, checkpoint inhibitors have recently been added to our armamentarium in later stages of the disease, and combinations with chemotherapy and targeted agents are currently under development. In view of the rapid advances of molecular oncology, a new challenge for the clinical oncologist arises: The appropriate patient selection for each new therapy, which can be made possible only through the implementation of predictive biomarkers in our therapy decision making.
Core tip: Despite recent advances in cancer therapeutics, the survival of gastric cancer patients with metastatic disease is dismal due to the complexity of the disease, the constant evolution of tumors and our still limited understanding of its biology. It is evident that a wide spectrum of prognostic and predictive biomarkers is needed in order to rationalize our decisions when managing patients with this specific tumor type and tailor our treatment to suit better the individual patient's unique needs.
Gastric cancer (GC) is the fifth most common type of cancer and the third most common cause of cancer-related mortality worldwide. Despite recent advances in cancer therapeutics, driven by the application of the findings of basic science in cancer genetics and host-tumor immune interactions, the prognosis of most patients with metastatic disease is dismal. Indeed, in GC we seem to lack clear molecular targets based on key regulatory genes or the aberrant expression of growth factor receptors. Furthermore, the universal rise of immunotherapeutic approaches in various tumor types has only recently been incorporated in GC. It is evident that a wide spectrum of prognostic and predictive biomarkers is needed in order to rationalize our decisions when managing patients with this specific tumor type and tailor our treatment to suit better the individual patient's unique needs.
Our understanding in GC genetics was greatly expanded in 2014, when four main molecular subtypes of the disease were recognized in the context of the Cancer Genome Atlas (TCGA) project. Further efforts were undertaken in order to relate molecular subtypes with the known histological subtypes that Lauren had proposed roughly half a century ago as well as with the location of the primary tumor and prognosis. These efforts were met with moderate success, since it is now widely accepted that there is an important degree of overlap. Various basic studies and clinical trials followed, aiming to discover a clinically meaningful way of utilizing the findings of the TCGA project. Unfortunately, thus far, the results have fallen short of the initial high expectations, although some success has been noted in subgroups of patients across trials that exhibited unique molecular characteristics. In 2015, another major molecular classification was proposed, this time from the Asian Cancer Research Group (ACRG), which shares similarities with TCGA yet has enough differences to be considered completely distinct (Table 1). The novelty with the ACRG was that the molecular subtypes discovered were associated with clinical outcomes. A short review and comparison of both classification systems will be presented, followed by a brief and non-exhaustive analysis of the most important clinical trials employing target or immunotherapeutic strategies in this expanding area of oncology.
Table 1 Molecular subtypes of gastric cancer according to the Cancer Genome Atlas and Asian Cancer Research Group.
TCGA: Cancer Genome Atlas; ACRG: Asian Cancer Research Group; CIN: Chrosomal instability; MSI-Η: Microsatellite-high; GS: Genomically stable; EBV: Epstein-Barr virus; MSS: Microsatellite stable; TP53: Tumor protein p53; EMT: Epithelial-mesenchymal transition.
The first and most comprehensive molecular characterization of gastric adenocarcinoma was reported by the TCGA Network. In this study, 295 (therapy naive) primary gastric adenocarcinoma samples were characterized using six different molecular platforms, including array-based somatic copy number analysis, whole-exome sequencing, array-based DNA methylation profiling, messenger RNA sequencing, microRNA sequencing, and reverse-phase protein array. No survival or racial differences were found among patients from each subgroup. As mentioned before, there were four main subtypes discovered, which can roughly be categorized in the following groups.
The following two subtypes are less likely to respond to immunotherapeutic strategies per se. Rather, combination approaches are probably required in order to attain a response using immunotherapy, such as adding chemotherapy to checkpoint inhibition or dual checkpoint inhibition. However, in cases with marked T-cells infiltration, we might expect that the checkpoints are probably up-regulated, and thus immunotherapy might still work. Apart from immunotherapy, targeted therapy with tyrosine kinase inhibitors (TKI) may prove to be another option in select subgroups of patients that carry specific driver mutations.
Chromosomal instability (50% of samples): The majority of the tumors analyzed in the project have fallen in this category. This subtype is found more frequently in the gastroesophageal junction (GEJ)/cardia (65%), is of intestinal histology, and affects mainly older (> 70 yo) individuals. Genetically, it is characterized by marked aneuploidy and high frequency of TP53 mutations (73%). Consequently, it features a high number of focal amplification of receptor tyrosine kinases, most importantly VEGFA, EGFR (10%), ERBB2 (24%), ERBB3 (8%), and c-Met (8%) as well as amplification of genes encoding cell cycle mediators, such as CCNE1, CCND1, and CDK6. These genetic aberrations contribute to making it the ideal candidate for application of targeted treatment, especially TKI inhibitors and monoclonal antibodies.
Genomically stable (20% of samples): The trademark characteristics of this subtype are diploidy and somatic mutations in CDH1 (37%), which is also the gene that is mutated in hereditary diffuse GC syndrome. Further common genetic aberrations are either RHOA mutations or CLDN18-ARHGAP rearrangements, both discovered in approximately 30% of tumors and usually mutually exclusive. All those mutations lead to disrupted intercellular cohesion and enhanced invasiveness, thus it is no surprise that most (73%) of these tumors belong to the diffuse histological variant. Most patients are of younger age (median 59 years), and there is no gender predominance. The inherent relative lack of immunogenicity and targetable driver mutations may lead to increased difficulty in applying individualized treatment in this subtype. Perhaps this is the single molecular subtype in TCGA classification where classic cytotoxic chemotherapy will continue to retain the primary role in treatment.
The other two subtypes are characterized by extensive infiltration of PD-L1(+) immune cells, which are dispersed throughout the tumor instead of being located in the invasive margin, as is common with other malignancies. It is speculated that the patients who exhibit response to checkpoint inhibitors will belong to this particular subgroup, although this has not yet been proven.
Microsatellite-high (21% of samples): The second most common subtype in the TCGA classification is characterized by extensive DNA methylation and multiple somatic mutations. These types of tumors are diagnosed at an older age (median age 72 years), with a slightly higher preponderance in female patients (56%). The various and dispersed mutations across the genome are mostly a consequence of MLH1 promoter hypermethylation. Other important genes, with potentially targetable products, which are found mutated, are PIK3CA, EGFR, ERBB2, and ERBB3.
The extensively mutated genetic material of these tumors creates an opportunity for immune system-oriented strategies. Indeed, the high amount of neoantigens, often presented in MSI-high tumors, elicit an immune response, manifested through extensive PD-L1 expression, which in this subtype reaches 33% and 45% on tumor and immune cells, respectively[13,14].
Epstein-Barr virus-positive (9% of samples): This subtype, whose main characteristic is the high Epstein-Barr virus (EBV) burden, was found to occur predominantly in the gastric fundus or body (62%), and is more common in men (81%). In TCGA, a recurrent amplification of 9p24.1 genetic locus is described, which is the site of genes JAK2, CD274, and PDCD1LG2. The first accounts for the aberrant activation of the JAK-STAT pathway, while the latter two encode PD-L1 and PD-L2, respectively. The 9p amplifications are found in at least 15% of EBV (+) tumors and lead to enhanced neoepitope presentation. It is also characterized by extreme DNA hypermethylation, most notably of the CDKN2A promoter, which leads to complete lack of p16 (p16INK4A) protein. It also features recurrent PIK3CA (80%), ARID1A (55%), and BCOR (23%) mutations. These molecular alterations characterizing this particular subtype hint at the therapeutic potential of JAK inhibition, PI3K/MTOR inhibition and immunotherapeutic approaches.
The ACRG analyzed 300 GC samples using gene expression, genome-wide copy number microarray and targeted sequencing. Partially overlapping with the TCGA classification and sharing some similarities but also exhibiting enough differences to be categorized as a completely distinct classification, four molecular subtypes are described. In this case, the foundations of this molecular classification are based on the basis of MSI status, TP53 function, and epithelial-mesenchymal transition (EMT). In this classification the subtypes were associated with relevant clinical outcomes and revealed survival differences that were validated in independent cohorts.
This subtype is characterized by the highest rate of TP53 mutations (60%). Also, it features a greater aneuploidy and recurrent focal amplifications in MDM2, ROBO2, GATA6, MYC. ERBB2, EGFR, CCNE1, and CCND1.
Compared to the rest, this subtype is characterized by a higher prevalence of EBV infection. In addition to exhibiting an active TP53 pathway, it is associated with APC, ARID1A, KRAS, PI3KCA, and SMAD4 mutations.
This subtype occurred frequently in the antrum (75%), was mostly (> 60%) of intestinal-type histology, and was diagnosed more frequently at early stages (I or II), thus exhibiting the best overall survival. Genetically, it was associated with the presence of hypermutation, especially in genes encoding KRAS (23.3%), the PI3K-PTEN-mTOR pathway (42%), ARID1A (44.2%), ERBB2 (16.3%), ERBB3 (14%), and ALK (16.3%).
This subtype was associated with diffuse type histology, as it was expected considering that it features aberrations in genes responsible for cell adhesion and motility. It presents at a significantly younger age with most of the patients diagnosed at advanced stages (III/IV). Consequently, it carries the worst overall prognosis and a higher chance of recurrence. It is also characterized by higher rates of peritoneal spread, which can also be attributed to the above mentioned genetic changes[6,15].
It is evident that, when comparing the two classifications, certain similarities exist between the different subtypes. Apart from the obvious association between the MSI subtypes in both classifications, it can be argued that roughly the equivalent of the genomically stable (GS) subtype in the ACRG classification is the microsatellite stable/epithelial-mesenchymal transition (MSS/EMT) subtype, while analogies exist between the EBV and chromosomal instability (CIN) subtypes on one hand, and MSS/TP53+ and MSS/TP53- on the other, respectively. However, as has been stated previously, there are certain major differences. For instance, while in the TCGA classification, EBV is a distinct subtype; ACRG EBV-infected tumors represent a part of the spectrum of the wider MSS/TP53+ subtype, which, moreover, is not characterized by hypermethylation or hypermutation. Another important difference is that in ACRG classification, CDH1 and RHOA mutations did not occur as frequently in the MSS/EMT as in its approximately equivalent GS subtype. It can be argued that these differences, among others, point also to the genetic heterogeneity of GC between different populations of different ethnic backgrounds, suggesting potentially different pathogenetic mechanisms for this disease in different parts of the globe.
HER2 inhibition: HER2 protein in GC is overexpressed mainly as a result of gene amplification. Its overexpression results in increased cell proliferation via its main target pathways, namely PI3K/Akt/mTOR and the RAS/MAPK. Consequently, its blockade may potentially halt tumor progression, at least temporarily, until an alternative pathway is switched-on driving resistance.
HER2 amplification is mainly a characteristic of GEJ tumors (15%-32%) rather than distal ones (10%-15%). Also, the exact location of the protein in the cell differs, depending on the level of differentiation of the tumor. Well-differentiated tumors express the protein in the cell surface, whereas it is located mainly in the cytoplasm in poorly differentiated cancer cells. HER2 targeting has been implemented in various lines of therapy, with both monoclonal antibodies and TKIs with variable success (Table 2).
Table 2 Main targeted agents evaluated in metastatic gastric cancer.
Biologic target Targeted agent Name/type of trial Line of therapy Study arms Results Ref.
ECX: Epirubicin-Cisplatin-Capecitabine; Ril: Rilutumumab; XP: Cisplatin-Capecitabine; Cet: Cetuximab; EOX: Epirubicin - Oxaliplatin - Capecitabine; Pani: Panitumumab; FP: Cisplatin - 5Fu; H: Herceptin; Pert: Pertuzumab; Pac w: Paclitaxel weekly; Lap: Lapatinib; TDM-1: Trastuzumab emtansine; Bev: Bevacizumab; Ram: Ramucirumab; Apa: Apatinib; OS: Overall survival; PFS: Progression free survival; ORR: Overall response rate.
Trastuzumab, a chimeric monoclonal antibody targeting the domain IV of HER2, has gained approval in first-line therapy when combined with fluopyrimidine/cisplatin chemotherapy doublet, after the positive results of the phase III ToGA trial. A subset analysis of this trial has indicated that the provided survival benefit is narrowed only to the group of patients where HER2 is clearly overexpressed, as manifested by combined immunohistochemistry (IHC) (+2) and fluorescent in situ hybridization (FISH) positivity, or IHC (+3) positivity. As a result, Trastuzumab should be administered to a specific subset of patients fulfilling the criteria mentioned above.
In an attempt to replicate the positive results of CLEOPATRA, where another HER2-targeting monoclonal antibody Pertuzumab gained approval in the treatment of advanced breast cancer, the phase III JACOB trial was initiated. In this trial, Pertuzumab was combined with chemotherapy doublet and Trastuzumab in stage IV treatment-naive GC patients. Although the mOS was numerically superior in the Pertuzumab arm by 3.3 mo, with a 16% reduction in the risk of death, the trial missed statistical significance only just barely (P = 0.0565). Furthermore, as opposed to the ToGA trial, the majority of subgroups were consistent with the overall analysis. The combination therapy also resulted in more incidents of diarrhea and hypokalemia.
Another attempt at HER2 inhibition in first line was the phase III TRIO-013/LOGIC trial, where, in a selected population of HER2 positive patients, the addition of Lapatinib, a small intracellular TKI of ERBB1 and ERBB2, was evaluated on whether it would improve the survival benefit derived by Oxaliplatin/Capecitabine doublet chemotherapy. Unfortunately, the trial failed to demonstrate a statistically significant survival benefit. However, it did raise the question of the accuracy of the current method of appreciating HER2 positivity, since the observed clinical benefit closely correlated with the degree of gene amplification as well as with HER2 protein levels, implying that implementing a different scoring system where HER2 over-expressing tumors are defined by an IHC score of more than 3 (IHC) or 2 (FISH) values, may be more precise.
Lapatinib was also evaluated in the second line in the phase III Asian TyTAN trial, where it was added to weekly Paclitaxel. It is interesting to note that the trial was performed in an unselected population, with 31% demonstrating weak (IHC: 1+) or none at all HER2 positivity. No survival benefit was noted in the study population, although in the subgroup with strong HER2 positivity (IHC: 3+), median survival improved to 14 mo vs 7.6 mo (P = 0.0176).
Another negative phase III trial compared a monoclonal antibody used in HER2(+) breast cancer, Trastuzumab Emtansine (TDM-1), and taxane monotherapy in HER2(+) patients (GATSBY trial). However, as in the TyTAN trial, HER2 expression was evaluated in archived samples, not taking into account the clonal heterogeneity and the possibility of tumoral evolution that may have occurred from the first to second line chemotherapy setting.
An attractive hypothesis regarding the etiology of the negative results of the above mentioned trials, apart from using archival samples, is the downregulation of HER2(+) tumors as a result of our targeting the HER2 protein in the first line setting. It is possible that HER2-directed therapies should be implemented preferably in the beginning of the treatment algorithm, with continuation or switch to another HER2 targeting agent, beyond progression, remaining an option for the select few who retain HER2 positivity. However, this is currently hypothesis-generating and should be confirmed within a clinical trial.
Inhibition of angiogenesis: Neoangiogenesis has an established role in GC pathogenesis, mainly through vascular endothelial growth factor (VEGF)/VEGFR2 signaling, as there is evidence that VEGF serum levels correlate with increased stage and worse prognosis. In animal models, VEGFR2 inhibition led to angiogenesis impairment and tumor regression.
Based on these data, targeting this pathway, either the receptor or the ligand, with monoclonal antibodies and TKIs has been studied in various clinical trials. In this case, targeting VEGFA with Bevacizumab in combination with traditional chemotherapy in first line has not provided a substantial survival benefit in a phase III trial, although results showed a significant improvement in progression free survival (PFS) (6.7 mo vs 5.3 mo) and overall response rate (46% vs 37.4%).
On the contrary, targeting the receptor has been more effective. In the phase III REGARD trial, Ramucirumab, a monoclonal antibody blocking VEGFR2 demonstrated superior survival over placebo in second line. Also, the same drug, when combined with a taxane in second line, also led to a statistically significant survival benefit of 2.2 mo. The attempt to expand the use of Ramucirumab in first line in combination with FOLFOX in a phase II trial did not produce the required results. However, there is another ongoing phase III trial of Ramucirumab combined with Cisplatin and a fluoropyrimidine in HER2 negative patients in first line (RAINFALL; NCT02314117) that may clarify its efficacy in this setting.
Inhibiting angiogenesis with TKIs also has a role in the management of advanced GC. Apatinib, a multikinase inhibitor mainly targeting VEGFR2, significantly improved OS over placebo in a phase III trial in patients with heavily pretreated advanced GC, which led to its regulatory approval as monotherapy beyond second line. Also, Regorafenib, another multikinase inhibitor targeting, among others, VEGFR2, is currently being tested in the same setting in a phase III trial after successfully achieving its primary endpoint of superior PFS in a relevant phase II trial[31,32]. Sorafenib resulted in disease stabilization and moderately good PFS in chemo-refractory patients in first- and second-line, but its addition to chemotherapy did not provide adequately encouraging results to justify a phase III trial[33-36]. Therefore, it appears that inhibition of angiogenesis has a definite role in advanced GC. Still, there are only hints regarding the potential predictive biomarkers that would help in individualizing its use. For instance, the two less immunogenic subtypes in the TCGA classification, namely the CIN and GS, were associated with VEGFA gene amplification and elevated expression of angiogenesis-related pathways, respectively, providing some clues regarding the importance of angiogenic pathways as a driving force of progression in tumors with these molecular signatures. It must also be noted that the positive results with angiogenesis inhibition have been produced in the later lines of treatment, which may imply that in the early stages of GC progression, angiogenesis has a less substantial role, while it is more predominant in later stages of the natural course of the disease. Lastly, it is important to note that targeting the receptor rather than the ligand seems to be the appropriate strategy, a phenomenon for which we have not yet reached a clear and robust explanation but may prove crucial for future anti-angiogenic strategies.
EGFR inhibition: Epidermal growth factor receptor (EGFR) or Erb-B1 is a transmembrane receptor found overexpressed in 30% of GC, while the EGFR gene is amplified in nearly 5%. Increased EGFR signaling has been correlated with higher stage, poorly differentiated tumors, and increased invasiveness[38-40]. In preclinical models, Cetuximab, a chimeric anti-EGFR antibody, induces antibody-dependent cell-mediated cytotoxicity (ADCC). Phase II trials with Cetuximab, Panitumumab, or Erlotinib combined with cytotoxics have yielded responses ranging between 41% and 65%, while second line Gefitinib or Erlotinib monotherapy has provided less impressive results, with responses between 9% and 11%, limited mostly to proximal GC[42-47].
These data have prompted testing of anti-EGFR targeting in phase III trials. However, both EXPAND and REAL3 phase III trials testing Cetuximab and Panitumumab in combination with Cisplatin-Capecitabine and EOX, respectively, did not show any PFS or OS benefit. Again, this may be attributed to poor patient selection, since the study population was not evaluated for EGFR expression or gene amplification[48,49]. The potential importance of this parameter has been made clear in at least two studies: in the phase II study combining FOLFOX with Cetuximab, where the patients that exhibited greater than four EGFR gene copies demonstrated increased OS, and also in the TRANS-COG, where the subset of EGFR-amplified patients derived a statistically significant survival benefit with the addition of Gefitinib (HR = 0.19; P = 0.007)[50,51].
This appears to have been taken into account in a phase III trial of second-line Nimotuzumab with Irinotecan (NCT01813253), which is currently recruiting patients that harbor EGFR-overexpressing (IHC: +2/3) tumors.
PI3K/Akt/mTOR inhibition: Resistance to targeted therapies often appears as a result of activation of downstream effectors by alternative molecular pathways. The PI3K/Akt/mTOR pathway in GC may become constitutively activated either through mutations in the PI3K gene, which occurs most often in EBV(+) and MSI tumors, or through inactivation of PTEN gene, the main negative regulator of the pathway, which is mostly found in the MSI subtype[3,53].
Targeting this pathway with an mTOR inhibitor, Everolimus, has produced encouraging results in a phase II trial, producing a median PFS of 2.7 mo and OS of 10.1 mo. However, the phase III GRANITE-1 trial that compared Everolimus to placebo in an unselected patient population, as second- or third-line therapy, failed to demonstrate any survival benefit. Once again, the study population was unselected for PI3K pathway activation. Impairment of Akt function via allosteric inhibition in a phase II study of the small molecule MK-2206, in unselected patients, did not produce any positive results either.
The above findings, rather than just annulling the findings of basic science, may be viewed as a further indication for the need of appropriate patient selection. PI3k/Akt/mTOR inhibition may still have a role where activation of this pathway is indeed the driver of cancer progression.
MET inhibition: The MET proto-oncogene encodes the c-MET receptor tyrosine kinase that has a crucial role in cell proliferation, angiogenesis, and migration. Its canonical activation pathway is via binding of its ligand, hepatocyte growth factor (HGF), but the activation can result independently of the binding through gene amplification or somatic mutation. The MET gene has been found amplified in 4%-10% of GC, while its protein product has been found overexpressed by IHC in up to 70%. The implications of this deviation between gene amplification and protein overexpression have been made evident in the MET-targeted clinical trials.
All phase II and III trials that included patients based on MET overexpression via IHC provided negative results. A probable explanation is the vague definition of MET positivity by IHC. In the phase III RILOMET study, the addition of Rilutumumab, an HGF-targeting monoclonal antibody, to triplet chemotherapy (ECX) proved detrimental. The study was terminated prematurely because of increased risk of death in the investigational arm. The main targeted agents evaluated in various clinical settings in GC are presented in Table 2.
A possible way in which tumors survive complete elimination from cytotoxic chemotherapy is the presence of cancer stem cells. Cancer "stemness" is frequently manifested through the activation of the STAT3 pathway, which induces the transcription of Nanog and Myc genes. The rationale for investigating this pathway in GC after failure of previous therapies in a large phase III trial (BRIGHTER) was provided by encouraging response and disease control data from phase I and II trials, where the small molecule BBI608 (Napabucasin) was combined with Paclitaxel This trial is ongoing, however, interim analysis indicated diminished possibility of achieving the primary endpoint of OS[59,60].
Poly (ADP-ribose) polymerase (PARP) is essential in correcting single-strand DNA breaks induced by cytotoxic agents. Inhibition of PARP has provided significant benefit in the subgroup of patients with breast and ovarian cancer that already exhibit a certain level of defect in the DNA repair mechanism, such as loss of function of BRCA1/2 genes. Since BRCA1/2 mutations in GC are rare, this strategy was implemented in tumors that are characterized by other defects in the repair pathway, like in the ATM gene, a quality termed "BRCAness"[61,62]. Preclinical and early clinical trials on tumors with ATM deficiency and TP53 mutations were completed with significant success. However, the phase III GOLD trial failed to reveal a statistically significant, according to predetermined criteria, survival benefit in patients treated with Olaparib and Paclitaxel. This failure might once again be attributed to poor patient selection, since the study population was not selected based on TP53 mutations, while furthermore only 18% of patients were ATM negative.
Andecaliximab, previously known as GS-5745, is a monoclonal antibody that targets matrix metalloproteinase (MMP) 9, an extracellular enzyme involved in matrix remodeling, angiogenesis, tumor growth, and metastasis. Encouraging results from the phase I study, where it was combined with FOLFOX in patients both treatment naive and pretreated, have secured its evaluation in a phase III trial (NCT02545504), where it is tested in first line in the same combination. The trial has completed accrual, and results are awaited. It is important to note that this strategy, if successful, has the potential to be implemented in a wide spectrum of patients with GC, without the need for a predictive biomarker. Also, since MMP inhibition affects the collagenous stroma of the tumor, not only will it clear the path for the chemotherapy drugs to reach cancer cells, but also it will enhance tumor immunogenicity, with obvious implications for a potential combination with immunotherapy.
Immunotherapy, mainly through the form of checkpoint inhibitors, has over the last few years been added to the armamentarium of various cancer therapeutic approaches, with serial approvals for the treatment of a wide spectrum of solid and hematologic malignancies. Unfortunately, the only single predictive biomarker we currently have at our disposal is PD-L1, which is far from being the most efficient in the field. Indeed, patients without PD-L1 expression can still respond, while others who express the biomarker do not derive benefit. In GC, contrary to melanoma or lung cancer, PD-L1 is expressed mostly in myeloid-derived immune cells and not in tumor cells. The presence of MSI, as manifested through IHC or polymerase chain reaction (PCR), is considered predictive for response to immunotherapy, while other approaches, such as IFN-γ signature and immunoscore, have not yet been incorporated to clinical practice.
There is adequate evidence supporting the implementation of immunotherapy in GC management, both preclinical and clinical. Firstly, there seems to be an association between PD-L1 and disease burden and, consequently, to limited survival. In addition, according to the data from TCGA, as previously mentioned, elevated PD-L1 expression has been noted in the EBV(+) GC subtype, which correlates with the significant amount of the neoantigens produced as an effect of viral infection, as well as of amplification of 9p24. Furthermore, it is well established that MSI-high tumors also mount a robust immune response, which predicts for clinical outcome and benefit of immune checkpoint blockade[67-69]. Clinical trials thus far have focused on checkpoint inhibitors, especially anti-PD-1/anti-PD-L1 and anti-CTLA4 antibodies, with the best results having been produced by the former.
The first trial to test an anti-PD1 inhibitor in advanced disease was the Keynote-12, where the safety and activity of Pembrolizumab in this setting was assessed. Only patients with PD-L1 positive tumors were enrolled. PD-L1 positivity was deemed as membrane staining in ≥ 1% of cells, or alternatively as the presence of a distinctive PD-L1 positive pattern at the interface between neoplastic cells and their adjacent stroma. In this trial, no association between PD-L1 levels and response was observed. The results were similar to other trials of anti-PD-1 in various solid malignancies, with a response rate of 22% (95%CI: 10-39) and manageable toxicity profile, prompting the initiation of two large phase III trials. The Keynote-061 is evaluating Pembrolizumab vs Paclitaxel in the second line. In the first-line setting, Keynote-062 has three arms comparing pembrolizumab as monotherapy and platinum/5-FU combination with or without pembrolizumab. Finally, following the most recent trend of combining immunotherapy with targeted therapies or chemotherapy, two multicenter phase IB/II studies are ongoing, determining activity and safety of Pembrolizumab in combination with anti-HER2 agents in patients with HER2 positive GC (NCT02901301 and NCT02689284)[73,74]. Their results are eagerly awaited.
Continuing with PD-1/PD-L1 inhibition, Nivolumab, another anti-PD-1 agent, was the first to gain approval in the third line setting, following the positive results of the pivotal phase III trial ONO-4538/BMS-936558 (ATTRACTION 2). This trial, which employed an all-Asian study population, showed a statistically significant, albeit numerically small, survival benefit for Nivolumab over placebo in heavily pretreated patients with advanced/metastatic GC or GEJC. Median OS was 5.3 mo vs 4.1 mo (HR = 0.63, P < 0.0001,) and mPFS was 1.61 mo vs 1.45 mo (HR = 0.60, P < 0.0001) in the Nivolumab (n = 330) and placebo arms (n = 163), respectively. This resulted in the Food and Drug Administration (FDA) approval of Nivolumab for GC or GEJC, in third line or beyond, irrespective of PD-L1 expression.
Finally, in the field of PD-1/PD-L1 axis inhibition, another promising agent is the anti-PD-L1 Avelumab, which has provided promising clinical activity in unselected patients, treated as first-line maintenance or second-line after progression, in the phase Ib trial JAVELIN. In this trial, patients were randomized after treatment with a first-line chemotherapy-based regimen by progression status: patients achieving disease control received Avelumab as switch maintenance, while those with progressive disease received the drug as second line. An acceptable safety profile, which was the primary endpoint of the trial, was demonstrated. Overall response rate was 9.0% and 9.7% in the two subgroups, respectively. Following these positive results, two randomized phase III trials were developed: JAVELIN Gastric 100, testing Avelumab as switch maintenance in the first line setting, and JAVELIN Gastric 300, in the third line[77,78]. Unfortunately, it was recently announced that JAVELIN Gastric 300, comparing single-agent Avelumab with physician's choice of chemotherapy, did not meet its primary endpoint of superior overall survival. The other phase III trial is still ongoing.
Less encouraging has been the use of anti-CTLA4 inhibitors. Firstly, regarding Ipilimumab, the Phase IItrial (NCT01585987) that compared the drug to placebo in the second line was stopped prematurely when it became evident that the final analysis would procure no PFS benefit. Also, no responses were reported with Tremelimumab, another anti-CTLA-4 inhibitor in the same setting. It should also be noted that higher toxicity was observed in these trials, as compared to anti-PD-1/PD-L1 blockade. These differences might be attributed to the different targeting of these two classes of checkpoint inhibitors. While those targeting the PD-1 axis have an immediate effect in the tumor microenvironment, the anti-CTLA-4 modulates the immune response mainly in the lymph nodes.
In an attempt to enhance the activity of anti-CTLA-4 agents, combination treatment with anti-PD-1 was tested. The CheckMate-32 was a phase I/II trial with three arms: 160 pretreated patients were randomized to receive either Nivolumab monotherapy in the dose of 3 mg/kg, or Nivolumab plus Ipilimumab in the doses of 3-1 mg/kg in the second arm or 1-3 mg/kg in the third arm of the study. In all three arms, notable responses were observed, with an overall disease-control rate of 38%. The responses differed between PD-L1-positive (≥ 1%) and PD-L1-negative (< 1%) tumors, reaching 27% and 12%, respectively. The highest overall response rate (26%) and overall survival (6.9 mo) were observed in arm 3 (Nivolumab 1 mg/kg and Ipilimumab 3 mg/kg), which prompted the launch of a phase III trial. The ongoing CheckMate-649 investigates Nivolumab plus Ipilimumab vs FOLFOX/XELOX in the first line, and a subgroup analysis regarding PD-L1 expression has already been planned.
Conclusively, immunotherapy could have a role in GC management, although, as in the management of other cancers, better predictive biomarkers are required. Moreover, it remains to be seen whether there is rationale for combining immunotherapy with targeted therapies and/or chemotherapy.
Even though most clinical trials investigating targeted agents have not produced the desired results so far, their failures might be attributed mostly to erroneous study planning and unscrupulous patient selection. The value of recognizing distinct molecular cancerous pathways goes far beyond mere classification purposes, and shall be better appreciated when these results could be applied in everyday practice with the purpose of providing clinically meaningful outcomes for our patients. Unfortunately, it is still unclear whether the clinical benefits of implementing next-generation sequencing and targeted therapies in the clinic will outweigh the economic burden of such a practice. Perhaps a way to tackle this issue is to create a panel of the main molecular and immune signatures of implemented pathways in order to categorize appropriately the patients in distinct prognostic and predictive subgroups. The results of the TCGA and ACRG classifications, among others, may provide the basis of such a molecular/immune signature panel that remains to be validated prospectively in large clinical trials providing the basis for rational stratification and design.
Health economics concerns aside, if our goal is to optimize outcomes for our GC patients, we probably need to implement these new molecular signatures in our daily practice. Due to the complexity of the disease, the constant evolution of tumors, and our still limited understanding of its biology, our mission to provide the best therapy to our patients is extremely difficult and challenging. However, through targeting tumorigenic drivers and awakening the immune system through immune-oriented strategies, it might be possible that we will at least be able to achieve the goal of life prolongation, while, at the same time, effectively alleviate cancer-related symptoms. A potential, hopefully not overly idealized, glimpse to the future of managing this disease, entails its multidisciplinary management by a variety of experts from diverse scientific backgrounds, towards an individualized approach for each unique patient.


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Of course YouTube just isn't the only source of video content material within the internet. Your interest surrounded by music and videos has no restrictions? Neither has our app! by https://www.audacityteam.org/ of FLVTO you may convert music from numerous video-internet hosting sites together with Vimeo, Dailymotion, Metacafe, facebook, and lots of more. simply paste the URL and convert your video into a excessive-high quality MP4 procession in your desktop in seconds.
To allow transport of overlapping WebVTT cues in MP4 tracks, WebVTT cues are break up happening non-overlapping cues and gathered now samples, as defined below. MP4 Parsers give usually hoedown the rear consumption so that the transport in MP4 is clear to the applying. extra usually, the carriage has been designed such that the WebVTT content material after exchange/export in an MP4 is similar, together with feedback and text content material that's not valid in keeping with the syntax but processable through a conformant WebVTT parser.
You can heave and any iTunes suitable motion pictures indoors iTunes, if it would not profession be sure to put it the place it says "Library". mp3gain believe you want particular codecs to have the ability to watch WMV video iTunes. however so far as I keep in mind it might probably fun .mov and .mp4 films with none problem.


text:
Q: MySQL IF in SELECT, replace the letter 'A' on 'AAA' How to display the list of employers, so that if the name is found the letter 'A' the system has replaced this name on 'AAA' ?

A: As @shmosel said you can use the REPLACE function along with an UPDATE
UPDATE [yourtablename]
SET [yourfieldname] = REPLACE([yourfieldname], 'text to find', 'text to replace with')
WHERE [yourfieldname] LIKE '%text to find%'

redpajama_set_name: RedPajamaStackExchange


Late Pleistocene to Holocene sea surface temperature development in the NW-Pacific and its marginal seas.
Max, Lars, Riethdorf, Jan-Rainer, Tiedemann, Ralf, Nürnberg, Dirk and Abelmann, Andrea (2011) Late Pleistocene to Holocene sea surface temperature development in the NW-Pacific and its marginal seas. [Poster] In: AGU Fall Meeting 2011. , 05.12.-09.12.2011, San Francisco, California, USA .
The subarctic N-Pacific acts as terminus of the modern ocean circulation with water masses highly enriched in dissolved nutrients and carbon dioxide. Today a permanent halocline results in strong upper-ocean stratification, which hampers the atmospheric-oceanic gas exchange and the supply of nutrients into the photic zone. Past changes in sea surface conditions in the subarctic Pacific are proposed to impact climate but are less well known than in the N-Atlantic. The onset and timing of past oceanographic changes are suggested to be driven by changes in oceanic circulation and/or atmospheric teleconnections.
Here, we present a suite of sediment records from the continental slope off Kamchatka (NW-Pacific), the western Bering Sea and the Sea of Okhotsk. All cores were obtained well above the shallow carbonate compensation depth (CCD) and provide sufficient material for detailed late Pleistocene to Holocene reconstructions of past changes in oceanographic conditions. The stratigraphy is based on high-resolution X-ray fluorescence scans (XRF) together with spectrophotographic measurements (color b*), which were aligned to the NGRIP oxygen isotope record and further confirmed by AMS 14C ages. Alkenone measurements were applied to reconstruct sea surface temperatures (SST) by use of the Uk'37 index (Müller et al., 1998). Our SST reconstructions span the last ∼15 ka BP. Prior alkenone concentrations were below the detection limit and thus indicate the absence of coccolithophoride blooms during the last glacial. After ∼14.7 ka BP the SST records in the NW-Pacific and western Bering Sea indicate an early increase in SST (Bolling/Allerod), followed by a cold spell at ∼12.8 ka BP (Younger Dryas) and the onset of warm Holocene climate conditions around ∼10.7 ka BP. During the early Holocene the SST increased by up to 4°C. This pronounced warming is interpreted as amplified stratification of the upper water column, which is paralleled by laminae formation at the sea floor. The SST record, derived from the Sea of Okhotsk, shows a slightly different pattern and indicates a more gradual warming towards the Holocene. Finally, a drop in SST by ca. 2°C is observed towards the middle Holocene, which also challenges the proposed idea of a SST seesaw pattern between the N-Atlantic and N-Pacific (Kim et al., 2004).
Kim, J.-H., Rimbu, N., Lorenz, S.J., Lohmann, G., Nam, S.-I., Schouten, S., Rühlemann, C. & Schneider, R.R. (2004): North Pacific and North Atlantic sea-surface temperature variability during the Holocene. – Quaternary Science Reviews 23, 2141-2154.
Müller, P.J., G. Kirst, G. Ruhland, I. von Storch & A. Rosell-Melé, (1998): Calibration of the alkenone paleotemperature index (UK'37) based on core-tops from the eastern South Atlantic and the global ocean (60 degrees N - 60 degrees S) – Geochimica Et Cosmochimica Acta 62, 1757-1772.


text:
Christina Paxson Elected Board Chair of the Association of American Universities
Christina H. Paxson, president of Brown University in Providence, Rhode Island, was elected chair of the board of directors of the Association of American Universities.
Founded in 1900, the Association of American Universities is composed of 65 of America's leading research universities dedicated to transforming lives through education, research, and innovation. AAU member universities collectively help shape policy for higher education, science, and innovation; promote best practices in undergraduate and graduate education; and strengthen the contributions of leading research universities to American society. The 65 member institutions receive about three fifths of all federal research grant funds.
"This is a moment of significant disruption in higher education, and engagement with federal lawmakers and policymakers regarding the impact of research, education, and scholarship is increasing in critical importance," Dr. Paxson said. "I look forward to working to further the ability of research institutions to drive discovery that finds cures, saves lives, and fuels innovation that drives economic growth across the country."
Dr. Paxson has served as Brown University's nineteenth president and a professor of economics and public policy since July 1, 2012. Previously, she was dean of the Princeton School of International and Public Affairs and a professor of economics and public affairs at Princeton University. Dr. Paxson joined the faculty at Princeton in 1986 and was promoted to full professor in 1997. Her research focuses on health, economic development, and public policy.
President Paxson became a fellow of the American Academy of Arts and Sciences in 2017 and has previously served as vice chair of the AAU board. She has served as vice president of the American Economic Association, is a member of the Council on Foreign Relations, and is vice chair of the Federal Reserve Bank of Boston's board of directors.
Dr. Paxson is a graduate of Swarthmore College in Pennsylvania. She earned a master's degree and a Ph.D. in economics from Columbia University.
Tags: Brown University • Columbia Uniersity • Princeton University • Swarthmore College

redpajama_set_name: RedPajamaCommonCrawl


How we use engagement on social media to gain hundreds of real, authentic followers and turn them into customers.
The purpose is right there in the title, "Social" Media. As a business or an individual, you're on social media because you want to build and maintain relationships, keep in touch with friends and family, and create an online community that supports you and is engaged in what's happening in your life.
For a personal account, that's natural. You're commenting on baby photos, sharing details about your recent vacation, and finding old friends from high school. You like, you comment, and you interact. So how do you check those "social" boxes as a business?
Let's be clear, I'm not telling you to shift all of your personal stuff over to your business page. "Personal" and "social" can often get blurred and that needs to be managed closely to walk the line of professional, but relatable. Occasionally you might drop a photo of your granddaughter wearing company apparel, but primarily, we want to keep the personal stuff at arm's length. What I'm telling you is to do all of the liking, commenting, and engaging that a person would, and do it intentionally.
Being social as a business is all about engagement, and engagement that feels real. Let's start with Instagram. We all know that Instagram is about modern content, great photos, and getting that like from our followers. There is so much more to succeeding on Instagram than just posting photos.
When was the last time you liked and commented on other photos as your business account? It should happen every day and if that's too much, at least a good chunk of time right after you make a post. Like the posts of businesses and people in your feed, like the recent posts of your followers, comment on posts of people who like your posts, and just keep liking and commenting. If I wasn't clear there, I want you to engage with just about every post you see on Instagram, but not just what appears in your feed.
Let's talk a bit more about what to like/comment on and how to find those posts. The obvious place to start is your feed. When you're scrolling through Instagram, you're seeing primarily posts from the accounts you follow and a scattering of ads and boosted posts from other accounts. Like 'em all, and I really mean it.
The trickier part is making sure you like the posts not only of the people you follow, but the people that follow you. Just go to your account, click on Followers, and click through that list. You can follow them back or you can just go to their page, like 1-3 of their posts, and move to the next person. This is a huge step in making sure your post gets seen by your followers. Scratch their back and they will scratch yours.
The final step in liking everything in sight is finding new accounts that you don't follow, and that don't follow you. This is where hashtags come in handy. Now, I'm not going to dive into the use of hashtags to promote your posts, but if you want more info on when and how to use hashtags on social media, let me know in the comments and we'll be sure to cover that in another post. For now, I'm just going to talk about using hashtags to find new accounts and posts to engage with.
Did you know you can follow a hashtag? If you search a hashtag relevant to your business like #vtbusiness or #marketing or #toystore or #bedandbreakfast you will see the posts that have been tagged with that hashtag. You can actually "follow" that tag the same way you would an account and then any post using that hashtag will appear in your feed. This is a huge way to diversify what accounts you're seeing and interacting with.
If there's a hashtag that's related to your business or in a segment you want to get more followers from, just search the hashtag, like a ton of posts, and go about your day. No need to follow every hashtag, it's just a good way to find new accounts and build new relationships. You never want to get stuck where your account is only being seen by the same people every day. That's not going to help you grow.
Let's step away from Instagram and talk about Facebook. This is a huge one, and most likely the primary social media platform for your business. Facebook has exploded for businesses and with options to boost posts and buy ads for such low prices, it's an incredible place to put some focus. Now, buying ads and boosting posts is huge, but we're talking about the "social" part here. If you want some more info on Facebook boosting, leave a comment or give us a call because man, we love boosting things on Facebook.
So, back to the "social" part of Facebook. No offense to MySpace and platforms of yester-year, but Facebook really defined social media and propelled its consuming role in our culture and business models that we see today. It has replaced websites for some businesses (not recommended but hey, if it's working for you keep at it) and is one of the first places people search for info on businesses.
You know Facebook is important, so how do you embrace being "social". Facebook is the same tune, different story. You need to be commenting, liking, and engaging, but not quite in the same way as on Instagram. There's certainly some room to like the posts of other pages on Facebook, but your big focus should be on maintaining engagement on your own posts and page. That means replying to every comment you get on your posts and responding to any messages that comes your way.
Let's start with replying to comments on your posts. Social media platforms all have crazy algorithms that control who sees your posts, when they see them, and how many people see them. It's not all as natural and organic as you'd like, but in the most basic way possible, the more comments and likes you get on a post, the more people Facebook (and Instagram for that matter) is going to show your posts to. One way to make the most of those comments: like and reply.
Facebook comments can be questions about your businesses, general feedback like "looks great" or even negative comments and experiences. Reply to them all and do it in a way that looks real. It used to be pretty common for businesses to reply with a canned response like "send us a message and we'll talk about it privately". That is not what we want to do in the year of 2019. People want transparency and moving a conversation to your messages makes it look like you have something to hide. If it's a simple "thank you", an answer to their question, directing them to your website, or responding to an issue or concern, do it publicly, respectfully, and promptly. In summary, if you get a comment, reply to it.
Next up on Facebook, let's talk about messages. Now, people can DM (direct message) you on Instagram as well, but it's much more common on Facebook and it's a bit more involved. Facebook has all kinds of badges it will add to your page if you're doing well with the "social" part and having the "fast responder" badge is definitely something you want. Facebook will expose you if you only reply to half of your messages and it will lessen the likelihood of potential customers and clients reaching out to you if they see that you typically don't respond promptly.
We can't all be glued to our Facebook pages, so what do we do? Let's talk about "auto-responders". If anyone messages your business page, you should have an auto-responder that lets them know you're busy and you'll be with them soon. A quick, "Thanks for reaching out, give us a few minutes and we'll be back to chat" helps the customer feel valued and adds an extra dose of patience while they wait for you to actually get to them. The auto-responder looks just like a message, so make sure it is vague enough to make sense no matter what their message said. Oh and don't worry, if they send multiple messages before you get to them, the auto-responder knows what's happening and will not keep sending over and over again. Facebook is pretty smart like that.
Ok, let's hit one last tip before we go and this one is a bit of a dirty little secret. It's something that needs to be done delicately, but you know, sometimes you gotta do what you gotta do to get the attention your business deserves. Here's what I'm talking about: Comment on other people's ads and boosted posts from your business page.
I know, it's sneaky, and you don't want it to look like you're trying to snag business away from your competitors so be careful how and when you do this, how often you do this, and what kind of comment you leave. But listen, that post or ad has been boosted. It's going to be seen by hundreds, thousands, millions, who knows how many eyes, and you didn't pay a dime of it. Let's just piggy-back on that and get some views for free, right?
See the difference? On the bigger businesses, you can be bold and your comment can directly talk to other people in the comments who might see the post. For a smaller business, comment as though you're talking to the company do not under any circumstances write something that suggests you're trying to steal their business. It's a tricky one, but it can be a useful way to get your business name in front of new eyes and build some local connections.
Here's what I want you to remember. Social media needs to be "social" and that comes from interacting and engaging. This builds loyalty, increases the likelihood of people engaging with your content repeatedly, and will give you a great boost in word-of-mouth. It's really not all about just keeping people happy. Engagement is how social media platforms quantify the value of your posts and your account. They look at how many people interact with you, but they also really care about who you interact with.
If you want to succeed on social media, you absolutely must do more than just make posts. You need to engage and you need to make it a priority. I get it. Business owners are busy enough as it is and social media can feel like a never-ending burden. If you're not sure exactly who to engage with on social media, what to post, or you feel like you've tried everything and just can't figure it out, give us a call or drop us a line. We can build a schedule, train you in more detail, or just take it off your plate completely.


Tummo (Tib. གཏུམ་མོ་, Wyl. gtum mo), or chandali (Skt. caṇḍāli) is the practice of inner heat', one of the Six Yogas of Naropa, and the 'root of the path', according to Dilgo Khyentse Rinpoche.
Lama Thubten Yeshe, The Bliss of Inner Fire, Wisdom Publications, 1998.
Tummo (Tibetan: gtum-mo; Sanskrit: caṇḍālī) is a Form of Yoga, found in the Six Yogas of Naropa, Lamdre, Kalachakra and Anuyoga teachings of Tibetan Vajrayana.
Tummo originally derives from Indian Vajrayana tradition, including the instruction of the Mahasiddha Krishnacarya and the Hevajra Tantra.
The purpose of tummo is to gain control over Body processes during the Completion stage of 'highest yoga Tantra' (Anuttarayoga Tantra) or Anuyoga.
Tummo (gTum mo in Wylie transliteration, also spelled Tumo, or Tum-mo; Sanskrit caṇḍālī) is a Tibetan word, literally meaning fierce woman.
Tummo is a Tibetan word for inner Fire.
Tummo may also be rendered in English approximating its phonemic enunciation as 'Dumo'.
The channels do not exist in the way they are visualized during Vajrayana practice.
For example, during a deity visualization, the physical human Body is visualized as completely hollow, made of Light and has no internal organs.
Furthermore different systems have different visualizations.
In actuality, the "center channel" (dbu ma or avadhuti) is the whole arterial system, or more specifically the aorta.
The two "side channels" are the venous system (roma or rasanā) and the spinal column and nervous system (rkyang ma or lalanā).
A chakra is any place in the Body where there are clusters of arteries, veins and nerves.
After familiarity in trul khor, there is the practice of tummo.
In the practice of tummo, the visualization of lower ends to the three channels is primarily used to focus Body awareness in the subnavel area.
Breath retention, mulabandha and Uddiyana bandha force vāyu (wind, air) and ojas into the arterial system.
The Heart rate slows, the karmic winds suspend and the venous blood returns less impurities into the blood stream.
Ojas itself has two stores within the Body -- the Heart and brain.
Thus there is the visualization of blazing and dripping.
When the vāyu moves very little, that is considered subtle Mind.
This is because the Mind is inexorably linked to the winds, or even considered synonymous with the winds.
Sutrayana has no comparable methods to reduce the movement of vāyu to a significant extent.
Most people simply allow the energy to churn in a cauldron of chaotic thoughts and emotions or dissipate the energy in a superficial pursuit of pleasure, but a yogi or yogini consciously accumulates and then directs it for specified purposes.
This energy generates warmth as it accumulates and becomes an inner Fire or inner heat (candālī) that [potentially] burns away the dross of Ignorance and ego-clinging.
Numerous non-buddhist Tantras of the Shakta and Shaiva traditions (generally termed Hindu by westerners) speak of Kundalini, which is generally described as a coiled energy at the base of the spine, at the first chakra.
Kundalini yoga in the Natha Sampradaya and Vajrayana in Tibetan Buddhism both take their origin from the Mahasiddhas who were active in India from the 8th century to the 12th century.
Kundalini yoga practices formed the core of the teachings of a number of these Mahasiddhas and are strongly represented in both Tibetan Buddhist practices and contemporary kundalini yoga practices.
Kundalini yoga was spoken of as "Candali yoga" by these Mahasiddhas and became known as gTummo rnal 'byor in Tibet.
Candali yoga was a key practice of the famous Tibetan yogin Milarepa.
rLung) states that historically: "The rLung practitioner (yogi) uses special colors of Clothes to improve the Power of the Tummo Fire."
The psychic heat Drod is produced by the space particles and the heat manifested from the friction of the wind element.
This is another fundamental element as it supports and gives Power to the Consciousness, like the Power of the Fire that can launch rockets to space.
The Power is called medrod or 'digestion Fire' in medicine and Tummo in yoga Tantra.
The heat (Fire) sustains Life and protects the Body/Mind.
The psychic Fire increases the Wisdom, burns the ignorant Mind of the brain and gives realization and Liberation from the darkness of unawareness.
That is why yoga describes Tummo as the aggressive Fire which ignites from below navel, pierces the chakras one by one and reaches the sky of the crown chakra.
The tummo burning arrow married with the celestial bride leads to enjoy the Life of transformation of Samsara.
They give birth to the son of awareness from the blissful garden of Vajrayogini.
An attempt to study the physiological effects of Tummo has been made by Benson and colleagues (Benson et al., 1982; Cromie, 2002) who studied Indo-Tibetan Yogis in the Himalayas and in India in the 1980s.
In the first experiment, in Upper Dharamsala (India), Benson et al. (1982) found that these subjects exhibited the capacity to increase the temperature of their fingers and toes by as much as 8.3°C.
In a 2002 experiment, conducted in Normandy (France), two Monks from the Buddhist tradition wore sensors that recorded changes in heat production and metabolism (Cromie, 2002) .
Tummo is a spiritual technique taught by Tibetan Lamas.
Tummo in Tibet is not translated as heat, but rather depicts Mystical technique, and the energy generated was not primarily to warm the Body of the practitioner, but to support the spiritual progress of the practitioner.
Tummo exoteric which grants the Body the ability to heal and subtle warmth. Esoteric Tummo which allows the Body to survive even in extreme cold, and the Mystic Tummo (Kriya Yoga) which gives warmth in spiritual achievements while living in this World.
Tummo esoteric (Chandali) is very well known and is mastered by many Tibetans who either gain it through one's own effort, or through initiation or Angkur from a Vajra Master.
While Tummo exoteric and mystic is not mastered by many people, even among Tibetan mystic, there are only several people who mastered the three kinds of Tummo.
With the flow of Tummo in oneself, all Body level, physical, Mental, emotional and intuition level will progress much faster.
With Tummo esoteric of course one can survive in extreme cold even without any single cloth like what happened at Lachi Kang (near Everest summit), Himalaya.
The Mastery of Tummo exoteric is very beneficial for the curement of various kind of ailments and illness on all levels, physical, Mental, emotional and spiritual.
It is very easy to use Tummo because it does not require Concentration at all and the Healing will happen automatically simultaneously at all levels of beingness.
A Tummo practitioner himself doesn't need to know and able to diagnose the patient's illness, this way it helps patients who feel embarrassed to speak of his/her illness.
Tummo mystic will surely cause Tummo practitioner to achieve Meditation perfection in very short time.
Sakya Tummo is a Tummo system that originated from Buddhism.
Therefore, this Sakya Tummo is of direct lineage: Sastra Vardhana - Your Name..
Different with other Tummo system in general, Sakya Tummo only gives angkur once, which is of Vajra Master grade.
Despite of that, the Sakya Tummo angkur is already comprised of all grades whole fully, mantras and mudras, and also Vajra Body protector, Vajra weapon and many others.
It is a Tummo system that is very integrated and is very powerful.
Sakya Tummo allows a Disciple to accelerate his/her spiritual advancement and inner Power in Healing others.
Inside human Body, there exist at least three kinds of energy.
Those three kind of energies are utilized optimally as Booster in Tummo technique.
Vayu, Living energi of the Universe that flows inside the Body.
Vayu is a wind element.
Prana, Pra means the first . Na means the smallest energy unit. This energy is obtained through breathing. It functions to move and maintain all physicalorgans.
Samana, This energy functions to help digestion process in disassociating nutrition from useless matters, which would result in bodily waste (feces).
Vyana, This energy helps dissipating prana and samana (ojas and tejas) to the whole Body.
Apana, Apana functions to push out wastes and any other unneeded materials out of the Body.
Udana, Udana pushes air out of the lungs and skin surface. Including pushing out the spirit out of the Body.
Ojas, Energy generated from drinking. This energy is of water element. Ojas is obtained from water that we drink, juicy fruits and fresh vegetables.
Tejas, Energy generated from Food. This energy is of Fire element. Usually comes from solid Food.
Sakya Tummo Angkur will also give harmonious adjustments with the Universe energy that will enter from your Crown Chakra, and arouse the Awakening of Kundalini energy(only to extent of Kundalini energy.
Kundalini is contained in 7 layers of concentric ball.
The rotation of this seventh layer will be accelerated) which will arouse from your Base Chakra, which will then be combined with Vayu, Ojas, and Tejas.
That is why Tummo is felt by some of its practitioners have stronger energy Power than Reiki.
Activation Source of Energy in Body like Bottom, Middle And Upper Tantien.
Activation all energy system of Body include Vayu, Ojas, Tejas and Tattva.
This page was last edited on 14 December 2015, at 13:35.


text:
The X factor cancelled after 17 years
by Andre Paine
July 29th 2021 at 11:00AM
The X factor has been cancelled after 17 years.
"There are no current plans for the next series of The X Factor at this stage," said an ITV spokesperson.
Simon Cowell created The X factor, which launched in 2004. It last aired in the UK in 2018 (won by Dalton Harris) and was replaced during 2019 by spin-off shows The X factor: Celebrity and The X factor: The Band.
It was confirmed last year that the show would be taking a break in 2020, but it has now been cancelled.
The X factor was produced by Cowell's Syco Entertainment along with Fremantle production company Thames.
Sony Music took control of the Syco music catalogue last year, while Cowell retained the TV brands including Britain's Got Talent. Successful recording acts who emerged from The X factor include Leona Lewis, Olly Murs, JLS, Alexandra Burke, One Direction, Little Mix and James Arthur.
Cowell is working on the launch of a musical quiz show Walk The Line for ITV.
Click here to read our 2017 cover feature on The X factor with Simon Cowell.
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I have just been to my first Magento conference a week ago and another great conference took place just a few days after, this time in Manchester. As there have already been some reviews I will try to focus on interesting points of each talk in this review.
The speaker lineup for this event was awesome and the fact that the company I work for – Space 48 were co-organizing the event were enough to make me book a 2.5 hour flight from Budapest (400 kilometres from where I live) to Manchester.
The city itself is very interesting and has it's unique atmosphere. The conference venue "The Comedy Store" was a good choice and it was not too far from my hotel, so I took a walk on a nice sunny day.
After hanging around with my colleagues from company, we headed to to the main room. Jon Wodall the Founder and Managing Director of Space 48 gave us a brief introduction after who Jonathan Bowers from UK Fast gave his talk and played a Kids Code Club video clip that everyone enjoyed.
After these introductory talks, the first one was a well known Magento community leader Vinai Kopp with his talk labeled – The Beautiful Magento Module. The title itself sounded promising to me and I was right, it was one of the most useful and informative talks. At start Vinai gave us some facts about Magento and explained some recognized principles in programming world. One group of of these principles was SOLID. The one principle from SOLID Vinai especially wanted to talk about was the Open-Closed principle that has it's implementation in Magento. Many interesting points were mentioned here, the most controversial ones were that you should not write too many comments, but a self explanatory code which doesn't need many comments and that you should actually use private methods in your modules (opposite to core Magento). At the end Vinai recommended the book Clean Code by Robert C. Martin.
The next talk was Scalable and highly available data in Magento by Alistair Stead. What I memorized the most is that actually more servers is worse if database is the bottleneck of your application. Some terms were introduced such as performance, scaling and redundancy. What I liked about these talk is that there were some concrete advice that could improve your Magento application in form of "8 steps to performance". Amongst these were adding MySQL indexes, caching, reducing write operations. The most interesting one in my opinion was "Only modify state on HTTP POST request" which is a simple rule that can lead to better performance and to better application organization in my opinion. Another thing I did not know is that MySQL actually can be upgraded with zero downtime. Turning off automatic security upgrades and allocating enough RAM were also useful points.
After a lunch which was great there were some lightning talks which lasted around 15 minutes each. The first one was Space 48 CTO Tony Brown with his talk Magento Cache Tags and Debugging. It was a nice story of fixing a real life problem and how loading model in a loop caused additional unnecessary cache tags to be added.
The next one was Extending Magento with Backbone.js by Yousef Cisco of Ampersand company. This talks was mostly about Backbone.js and how Yousef and his team implemented it on a real project. There are some benefits from moving your logic to client side and one of these is making Varnish caching easier. Another feature that was presented was a bundle product configurator that worked on client side as well.
One of the talks that gained much interest was Separation of Code and State by Rick Steckles. Apparently, Rick and his team have developed a mechanism which provides the ability to have different sample data over various application phases (development, staging, production) with standardized configuration. That data is kept in YAML files (similar to what EcomDev have done with fixtures for their testing framework) and that data is applied to different stages of application.
The talk announced as 4th talk was Why you shouldn't be a Magento developer and it was supposed to be held by Matt O'Connor. As he couldn't make it, Dave Hitchen jumped in and his talk was named the opposite Why I want to be a Magento developer. He explained us why he chose Magento and he compared it with a few other platforms. The things he liked the most about Magento were modularity and extensibility. At the end Dave asked the audience for some advice and everyone gave him support.
Panel discussion was up next. Ben Marks, Vinai Kopp and Alistair Stead came up to the stage with Tony Brown moderating the discussion. There were questions from Twitter that were previously asked as well as questions from the audience. Some of them were about version control, enterprise and community Magento versions, composer and loads of other stuff and it was very interesting to hear from Magento community leaders on these topics.
One of the most anticipated talks was Magento on HHVM by Daniel Sloof. I mentioned Daniel in my Meet Magento Switzerland review where I found out that he has been contributing to HHVM project mostly by submitting patches that were fixing stuff that prevented Magento from working on that engine. After some basic introduction, Daniel explained the sorting problem which was especially important for Magento. It seems that PHP Zend Engine and HHVM have different behaviour when it comes to sorting, so Zend Engine native sorting had to be turned on for Magento to work. Currently both Community and Enterprise versions of Magento pass the Magento Test Automation Framework with near 100%. It's important to note that other caching extensions don't get in the way of HHVM so it wouldn't be a problem to use them. At the end there were a few words about Hack language which is basically a PHP statically typed language made also by Facebook. One interesting project was HipHopIndexer that takes only indexing part of Magento to HHVM.
The Final talk by the name How's things was given by Ben Marks. It was roughly the same concept as in Zurich conference with audience getting the updates on different Magento related topics. Amongst these were founding an Advisory Board, improving Github usage on Magento 2, fixing Magento Connect which were all set to be done in near future. Magento documentation will also be on Github so everyone will be able to contribute.
Jon Woodall gave the closing talk and we went to Ark Bar where the after party was held.
Sounds like a lot of fun, sad that I couldn't attend.
As a (mostly) frontend Magento developer, I am very interested in the RWD movements in the community, and the increasing number of talks about moving otherwise "dynamically generated" parts of Magento onto the client side for even more interaction (eg: passing data to the client for Backbone.js models). It's exciting to see the quality of design principles that have long powered the backend of Magento now being introduced to the frontend.


text:
Périgny è un comune francese di 2.293 abitanti situato nel dipartimento della Valle della Marna nella regione dell'Île-de-France.

Società

Evoluzione demografica

Note

Altri progetti

Collegamenti esterni

Perigny

redpajama_set_name: RedPajamaWikipedia


March 27, 2019 | You can, man.
On this week's show we discussed basic car repair and maintenance that you should really know how to do. These basic skills will provide you with a solid foundation on your DIY auto repair journey. Don't wait until you're stranded on the side of the road with a flat tire not knowing what to do. Get out there and try it out! If you've never tackled something on this list, don't you worry. A plethora of how-to's videos are just a YouTube search away. This episode is your friendly kick in the pants to make sure you're up to speed on basic car repair and maintenance know-how.


text:
'It's A Scandal' — Inside The Fight To Hold The Military Accountable For Medical Malpractice
"I feel like my life has been stolen from me because people failed to do their job," said Army Sgt....
By James Clark November 16, 2018
Army Sgt. 1st Class Richard Stayskal felt like he was falling apart.
A physically fit Green Beret, Stayskal first noticed something wrong with his body in March 2017 while training at the Army's Special Forces Dive School in Key West, Florida. Unable to keep up with his elite training — a red flag for the athletic 37-year-old combat veteran — he was sent home to Fort Bragg, North Carolina.
By April, Stayskal began to wheeze and had difficulty breathing when lying on his back; other times, his body would go numb, and his vision blurry. In May, he visited the emergency room twice, once on base at Womack Army Medical Center and a week later out in town. Then, in early June, he began coughing up blood — a teaspoon at first, but it was more by the day.
Answers as to why his health was on the decline proved elusive. The best guess from base doctors was walking pneumonia and allergies. Repeated calls to insurance providers at TriCare and doctors at Womack to have his appointment with a specialist moved up — to find out why breathing would make him wheeze and cough, then bleed — yielded no results.
Fed up, he turned to his unit for help and his commander intervened, landing him a consultation with a civilian pulmonologist by the end of June. Days later, he went in for a biopsy which uncovered a non-small cell adenocarcinoma. As he awoke from the surgery, Stayskal overheard the doctor telling his wife he had lung cancer.
It could have been caught five months earlier.
"I feel like my life has been stolen from me because people failed to do their job."
Before Stayskal headed to dive school in Florida, a CT scan during a routine health screening at Womack Army Medical Center on Jan. 27, 2017, showed a mass on his right lung. It's unclear why, but the tumor wasn't spotted. Then, when Stayskal was rushed to the base hospital emergency room on May 15, 2017 the attending doctors did a "retrospective reread" of that January scan, and suspecting something was amiss, recommended he meet with a pulmonologist. Stayskal was not made aware of their concerns, or that the mass appeared on the January CT scan.
A spokesperson for Womack Army Medical Center declined to comment to Task & Purpose.
Doctors' notes from Stayaskal's January physical, and mid-May emergency room visit, along with a timeline of events, were provided to Task & Purpose by attorneys from Whistleblower Law Firm, who are representing the soldier in an upcoming malpractice case. Additionally, a radiologist consulted by the law firm claimed that the alleged misdiagnosis occurred at a critical time, and that had the cancer been caught in January, it could have been treated more easily.
The cancer is now stage IV and has metastasized to Stayskal's pelvis, spinal bones, lymph nodes, liver, and spleen. Doctors estimate he may only have a year to live.
"I feel like my life has been stolen from me because people failed to do their job," Stayskal told Task & Purpose.
"Somebody sentenced me to an early death, and they could have prolonged it a lot longer. I'm being taken from my children, my two daughters, and my wife. I'm being taken from the plans I had for the next 15 years in the military, everything."
Richard Stayskal during his Special Forces deployment to Baghdad, Iraq in November 2009. Photo courtesy of Richard Stayskal.
Stayskal and his attorneys intend to file a federal civil lawsuit in the coming months with the U.S District Court in the Eastern District of North Carolina, where they'll have a chance to submit evidence to support their claim that the cancer diagnosis was missed, and raise their allegations of medical malpractice.
But that may be as far as it goes.
It's a near-certainty that the case will be dismissed before it ever gets to trial, for one reason: Because the alleged misdiagnosis occurred while Stayskal was in the military, he and his family are barred from suing the Department of Defense for medical malpractice due to an obscure 68-year-old legal rule known as the Feres Doctrine.
But lawsuits like Stayskal's — including a recent petition submitted to the Supreme Court in another case — raise significant questions about what are acceptable risks of military service that go well-beyond injury and death on the battlefield.
The Feres Doctrine was established in 1950 by the Supreme Court in Feres vs. United States, a case involving the Federal Tort Claims Act that allows citizens to sue the government for negligence or wrongdoing. In Feres, the Court dismissed a lawsuit brought by the widow of Army Lt. Rudolph Feres, who died in 1947 when his barracks caught fire due to a defective heating system, ruling that the federal government could not be held liable "for injuries to members of the armed forces arising from activities incident to military service."
In layman's terms, the Feres Doctrine prohibits troops and their families from suing the military for injury or death brought on by their service.
The reasoning behind Feres is two-fold: A system for compensating military personnel and their families for injury or death already exists in the form of disability compensation and life insurance payments; and opening the military to lawsuits might invite second-guessing of command decisions in civilian courts.
In the decades since the rule was established, it has been applied to a wide range of instances — from training mishaps, to sexual assault, and medical malpractice.
"What it has boiled down to over the years is where the care provided was, to use the term, 'incident to military service,' you're not covered under Feres," Brewster Rawls, a malpractice attorney and president of Rawls Law Group, told Task & Purpose. "That has been consistently applied in malpractice cases as being basically, if you're on active duty and you're treated in a military hospital, through a military healthcare provider, tough luck."
The Feres Doctrine is an interpretation of the Federal Tort Claims Act, and as a Supreme Court precedent "has the force of law, but it is how the law has been interpreted, not how Congress wrote the law," Rawls said.
Ultimately, that means Feres can only be changed in two ways: Through Congress, in the form of an amendment to the Federal Tort Claims Act; or through a Supreme Court decision to overturn the 1950 ruling.
It's difficult to say for sure exactly how many service members or military families have claims that run afoul of the Feres Doctrine, since the suits aren't always taken up by attorneys.
That's because Feres cases are near-impossible to win.
"The vast majority of the cases never even go to the first level of the system because most lawyers, you're gonna look at it and say 'I'm really sorry, this is unfair, but I can't take it," Rawls told Task & Purpose.
Which is what Natalie Khawam, one of the attorneys representing Stayskal, said she heard from other lawyers when they began looking into his case, adding that "the cases that are known as impossible and un-winnable are the most important cases to fight for."
After Stayskal found out he had lung cancer, he said he was in "disbelief." But when he learned that it could have been caught during his Jan. 27, 2017 health screening, he became "angry, devastated, upset, heartbroken," Stayskal said. "Lots of emotions."
"I just don't believe that this should be left alone, and allowed to continue to happen to soldiers, sailors, airmen, whatever — it shouldn't happen to anyone, in the civilian world or the military," Stayskal, who deployed overseas multiple times between his years in the Corps and the Army, told Task & Purpose.
A career soldier, he left the Marines in 2005 after a four-year enlistment as an infantryman and joined the Army a year later to pursue a career in special operations — inspired by the life-saving medical care of a Special Forces medic after he was shot in Iraq.
Richard Stayskal and his wife Megan at the hospital on Oct. 23, 2017 after a lobectomy. Photo courtesy of Richard Stayskal
"I went to everybody on post, people I've respected and known for years, and the general answer was there's nothing you can do," Stayskal said, adding that he filed a complaint with the director of Womack Army Medical Center in July 2017. When asked about the July complaint, a spokesman for the medical center referred Task & Purpose to the Army Claims Service at Fort Meade, Maryland, which did not respond to repeated requests for comment.
Desperate, Stayskal sought legal representation from Whistleblower Law Firm in October 2017.
"The more I learned about the Feres Doctrine — that it bars me from justice — it just didn't make sense to me," Stayskal, who is still on active duty in Army, told Task & Purpose. "Why am I not allowed to have this one right?"
Stayskal isn't the only one searching for an answer to that question.
In October 2003, after Air Force Staff Sgt. Dean Patrick Witt underwent a routine surgery for acute appendicitis, a series of errors — from moving Witt to the pediatric area, where undersized devices couldn't fit a grown adult, to nursing staff arguing and mistakenly administering a double dose of a "powerful stimulant," to improperly inserting a breathing tube — the airman was left with severe brain damage, The Los Angeles Times reported in 2008.
Three months later he was taken off life support, leaving behind a wife and two children. Despite the alleged mistakes, his family was barred from suing due to Feres. By 2011, Witt's case was submitted to the Supreme Court, but the court refused to hear it, declining without comment, Stars and Stripes reported in 2011.
When Carmelo Rodriguez went to his initial physical prior to joining the Marines in 1997, his doctor noted a melanoma on his back, but allegedly never informed him. Ten years later Rodriguez died of skin cancer, shortly after speaking with a CBS News crew who came to interview him for a story on medical malpractice, the organization reported in January 2008 — two months after his death.
By 2010, bills to overhaul the Feres Doctrine named for Rodriguez were introduced by both the House and Senate. The Senate measure died in the Judiciary Committee; the House measure was placed on the Union Calendar, and there it stayed. Neither were ever put to a vote.
And in March 2014, Lt. Rebekah Daniel, a Navy nurse stationed at Naval Hospital Bremerton in Washington, gave birth to a healthy baby girl at the facility where she worked. Four hours after the low-risk childbirth, she died. Her husband, Walter Daniel, filed a wrongful death suit in 2015, which was barred like the others.
"I understand that it's inherent in military service to accept some level of risk. However, the simple fact of giving birth to a child, in my opinion, that is not incident to service."
Still, Daniel brought the case before the 9th Circuit Court of Appeals, and though it upheld the lower court's ruling, Judge Michael Daly Hawkins wrote in his opinion: "If ever there were a case to carve out an exception to the Feres doctrine, this is it. But only the Supreme Court has the tools to do so."
On Oct. 11 of this year, Daniel and his attorneys filed a suit with the Supreme Court to attempt to do just that, as Task & Purpose previously reported.
Walter and Rebekah Daniel.Courtesy of Walter Daniel
"Look, we understand the risks of serving in the military," Daniel, who spent 18 years in the Coast Guard, said of he and his wife, both of whom came from multigenerational military families.
"I understand that it's inherent in military service to accept some level of risk," Daniel told Task & Purpose. "However, the simple fact of giving birth to a child, in my opinion, that is not incident to service."
"It's unacceptable, and it's worth the fight for justice."
Even so, a Supreme Court hearing is a long shot: Only about 80 of the 7,000 to 8,000 cases submitted each term are heard.
For decades, the Feres Doctrine has been roundly criticized by veterans advocates, lawmakers, and even judges — including the late Supreme Court Justice Antonin Scalia, who voiced his dissent in 1987:
"Feres was wrongly decided and heartily deserves the widespread, almost universal criticism it has received," Scalia wrote of Feres. The opinion stemmed from United States vs. Johnson, in which the Supreme Court barred the widow of a Coast Guard helicopter pilot from suing the government after her husband died in a crash during a rescue mission due to alleged negligence by federal air traffic controllers.
Among critics of Feres, the outrage over the doctrine stems from a double standard that allows one set of rules for civilians, and one for service members in cases where victims seek monetary damages.
For example, if a service member and a military dependent go to the same on-base hospital, receive the same treatment from a military doctor, and the same mistakes are made in each case, the law treats them very differently.
"The one who was on active duty cannot bring a claim under the Federal Tort Claims Act; the one who is a dependent, can," Eugene R. Fidell, who teaches military law at Yale Law School, told Task & Purpose.
"And so you have tremendously disparate outcomes based on the same professional shortcomings simply as a function of whether the victim of the malpractice is on active duty or not," said Fidell, who testified before Congress on the Feres Doctrine in 2009.
"That's the heart of the matter."
Critics of the Feres Doctrine have been willing to give ground when it pertains to combat operations or training, but there's a sense that the rule has been applied too broadly.
"We accept certain risks downrange, under undesirable circumstances," Stayskal told Task & Purpose. "But I wasn't in those circumstances."
"I was afforded TriCare and these other health benefits, well, they failed to take care of me when they said they would," he added. "I just don't think that should continue."
The legal rule isn't without its defenders. Though it's not a Department of Defense policy, the military has a vested interest in seeing the Feres Doctrine remain unchanged. The main argument: Changing Feres would cause more problems than it solves.
The Pentagon claims that reversing Feres would erode the military's current system of no-fault compensation, which provides disability payments to troops should they be injured in the course of their duties, Jessica Maxwell, a Pentagon spokesperson, told Task & Purpose in an email statement.
Though the government already offers compensation through the DoD's Disability Evaluation System, and the Veterans Benefits Administration, as well as a $400,000 Servicemembers' Group Life Insurance policy, those payments are rarely on par with what a plaintiff could receive through a successful lawsuit.
Additionally, the Pentagon argues that opening military care providers to lawsuits would lead to "defensive medicine practices" which Maxwell said could "compromise everyday medical decision making essential to military readiness."
Then there are the questions about who should have the right to sue.
If the Feres ruling were wholly reversed, then "an injured member or the family of a deceased member would be allowed to sue for certain injuries based on an allegation that some other military member or government employee was negligent," Maxwell said. "In contrast, military members injured or the families of members killed in combat or other military operations would have only the no-fault compensation system, even if the injury or death were due to friendly fire or there were some other issue of negligence by another military member."
"The combat injury or death would appear to be valued lower than an injury or death where a tort claim would be allowed," such as in the case of malpractice, Maxwell said. "Such an inequity toward members injured or killed in military operations could not be sustained."
But in the case of plaintiffs like Daniel and Stayskal, neither are seeking the wholesale reversal of the Feres Doctrine, just a change in the wording to allow suits in cases similar to theirs — where alleged malpractice occurred during routine operations at a stateside hospital, as opposed to mistakes made in a medical tent in a warzone.
"We accept certain risks downrange, under undesirable circumstances. But I wasn't in those circumstances."
As for the argument that these suits would create divisions between those who can sue and those who can't, or that it would somehow undermine good order and discipline, Stayskal rejects that line of reasoning.
"How many people do you see trying to sue anybody over losing a limb, or over being shot downrange?" asked the Green Beret, who was shot during a 2004 firefight in Ramadi, Iraq when he was in the Marines. "We understand those risks and that in a time of war, those circumstances are going to happen."
"When people ask me to do my job downrange on a combat deployment, they don't care what the answer is if I don't succeed," he continued. "But you're sitting here , asking to be checked over, making the appointments, and somebody just flat-out doesn't do their job?"
Another consequence of changing the legal rule could be expense. If Feres were changed, the federal government would have to shoulder the retroactive costs of previous malpractice cases, not to mention future ones.
To get a sense of cost, consider the Carmelo Rodriguez Military Medical Accountability Act of 2009 — the bill named for the Marine veteran who died of skin cancer after his melanoma was overlooked. Had the bill become law it would have cost the federal government roughly $2.7 billion over the next 10 years, according to a Congressional Budget Office estimate.
"Obviously, the government has to make sure the treasury is not drained as a result of malpractice claims by military personnel," Fidell said. "We're all taxpayers, we'd all bear that. Are there ways the government could alleviate that problem? Yes. For example, if it had better systems in place to make sure malpractice doesn't occur."
And though it may be counterintuitive, an initial influx of lawsuits, while costly, could play a role in that, Fidell told Task & Purpose.
"One purpose of malpractice litigation is to light a fire under medical providers to do the best possible job, or to do a job that meets reasonable professional standards, and that's a major incentive in American society," Fidell continued. "But the military medical system is outside that where the patient is an active-duty member."
Beyond balancing the competing pressures to amend a law many see as unfair, with the real-world costs of doing exactly that — there could be yet another reason efforts to change Feres have stalled: It's simply easier to maintain the status quo.
"Though occasionally justices have wrung their hands and said this is terrible, and members of Congress have had constituents banging on their door with really heart wrenching stories that are infuriating, that's not what gets the entire House or Senate leadership to spring into action," Fidell told Task & Purpose.
"It hasn't happened yet," Fidell added. "This is a conversation I have every two or three years with journalists. It's the same story. Somebody comes forward and gets the attention of someone in the blogosphere or the traditional media, and there's a little blip of interest, and then it fades."
"It's really a scandal."
As for Stayskal, the ordeal — from the alleged misdiagnosis, to his declining health and ongoing cancer treatment, and the upcoming legal battle against the Feres Doctrine — has taken a heavy toll.
"I don't even have the words sometimes to describe what my family and I are going through," Stayskal said.
Richard Stayskal at home with his daughters after his surgery in October 2017. Photo courtesy of Richard Stayskal
Stayskal has undergone three rounds of radiation, as well as surgery. He has lost weight, has trouble keeping food down, and is currently focused on reducing the pain — and maintaining his quality of life — as best he can.
"I take four pills a day," he said of medication he currently takes for chemotherapy. "Right now, the cancers are responding to the pills, so for all intents and purposes, I'm doing okay. There's pains here and there, it's hard to breathe, and I'm tired all of the time. I don't have much of a life anymore."
Stayskal's lawyers plan to file their suit with U.S District Court in the Eastern District of North Carolina before the new year, though they have until April 12, 2019 to do so.
"I would honestly like to be compensated for the atrocious acts committed upon me," Stayskal said. "We all know it's a hard day and age for one-person income and families, and now my wife is going to be forced to take on that role for something that they could have caught and fixed."
It's highly likely his suit will be barred, given the history of past Feres cases. Next, he and his lawyers will have a chance to raise their allegations and submit evidence, with the ultimate goal of strengthening a case for an appeal.
It's all part of the lengthy process necessary to get Stayskal his day in the nation's highest court.
But given the track record of previous malpractice claims that have run up against the Feres Doctrine, and failed Congressional efforts to see the rule changed, the chances for a victory in Stayskal's case are slim. More than that, it will take months, if not years.
And that is time he probably doesn't have.
James Clark View James Clark's articles
@JamesWClark
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