On 16 August 2011, a 64-year-old male physician with no relevant co-morbidity was suspected for transversal colon cancer by colonoscopy. On 26 August 2011, seven likely secondary lesions were detected by abdominal ultrasound in different hepatic segments (the biggest lesion was 42 mm in the largest diameter) and 15 ng/mL was the serum CEA level. On 29 August 2011, he underwent hemicolectomy of the transversal colon, and adeno-carcinoma, G2/G4 was found in post-operative histology. pT3 N2a (6 regional lymph-nodes involved of 22 examined) M1 was the post-operative TNM classification. Kras was wild type. From 14 October 2011 to 20 July 2012, he received 1000 sqm/day capecitabine given orally and 130 mg/sqm oxaliplatin by i.v. infusion (the Xelox regimen) on days 1–14 every 21 days (one cycle) for six cycles, plus 5 mg/kg bevacizumab by i.v. infusion every two weeks followed by maintenance therapy with capecitabine and bevacizumab. His serum CEA level, which was 52 ng/mL at the beginning of chemotherapy, decreased to 25 ng/mL in July 2012, and the WB CT showed slight decreases in all hepatic metastases. On 11 September 2012, all detectable liver metastases were surgically removed following his demand and, in October 2012, his serum CEA level was in the normal range. In December 2012, a radiological assessment documented a suspected secondary lung nodule in addition to the recovery of metastatic liver disease; the serum CEA value was 5.9 ng/mL, which increased to 66 ng/mL in January 2013. From January to April 2013, he received seven cycles of 130 mg/sqm irinotecan by i.v. infusion and 500 mg/sqm cetuximab by i.v. infusion every two weeks. On 2 July 2013, he underwent surgical removal of the left liver lobe; contemporaneously, other secondary lesions were enucleated (overall, ten liver metastases were removed); post-operative histology confirmed the secondary origin of the liver lesions, while a subsequent abdominal MRI signaled three regions with necrotic features. WB positron emission tomography (PET) was negative for residual metastatic liver disease. On 28 February 2013 and 1 July 2013, the serum CEA level was in the normal range. On 21 August 2013, thoracic CT showed an increase in the previously detected nodule placed at the inferior left lung lobe, while liver ultra-sonography showed two small hypo-echogenic areas suspected to be surgical scars. On 29 August 2013, the patient underwent atypical resection of the inferior left lung lobe and post-operative histology confirmed that it was a secondary lesion compatible with primary colorectal cancer. The serum CEA level was 9 ng/mL at the end of September/beginning of October. On 24 October 2013, WB CT signaled a new focal liver lesion that was 57 mm in the largest diameter and a 16 mm nodule at the lower-basal region of the right lung: both were suspected for relapse. Following oncologic consultation, from November 2013 to January 2014, he received cycles with FOLFIRI plus cetuximab. In January 2014, the serum CEA level was in the normal range. In March 2014, he underwent surgical removal of the liver nodule and of the other two nodules in the right lung (one of them was a pleural lesion); they were all determined to be secondary lesions in the post-operative histology. He continued to receive the same FOLFIRI treatment for a total of six cycles until June 2014. In July 2014, WB CT showed multiple new bilateral lung nodules. On 19 September 2014, he accepted the invitation to be included in an experimental clinical trial that was recruiting previously treated patients who had progressed under cetuximab after an initial benefit. He was selected because of his high MET level, as assessed in a biologic sample; therefore, he was given 120 mg of tivantinib (a MET-inhibitor) orally twice daily and cetuximab until 25 October 2016, with an initial clinical-radiological partial response (PR) followed by a stable disease as documented by WB PET carried out on 27 May 2016. In addition, WB PET showed a likely metastatic lesion of the lateral eighth right rib; therefore, from 13 June 2016 to 17 June 2016, in addition to tivantinib and cetuximab, he underwent RT at the rib lesion (25 Gy as a total dose by five fractionated doses). During treatment with tivantinib plus cetuximab, the serum CEA value, which was measured every 2–3 months, was in the normal range until 21 September 2016, when it was found to be 12 ng/mL. On 04 November 2016, WB PET documented the progression of the secondary lesion of the eighth right rib. On 2 December 2016, the patient underwent palliative surgical removal of the lateral arch of the VIII rib; post-operative histology confirmed the metastatic origin of the rib lesion with infiltration of the surgical edges. On 27 December 2016, surgical intervention for soft rib tissue radicalization and the removal of the middle lobe of the right lung was carried out; post-operative histology confirmed the metastatic origin of the residual disease. On 15 February 2017, WB CT showed multiple bilateral suspected secondary pulmonary lesions; the biggest was 7 mm in the largest diameter in the right lung. On 15 February 2017, he was given regorafenib, which he interrupted on 23 May 2017 because of strong side effects and the rising serum CEA level. On 17 August 2017, WB CT documented the progression of the disease at the level of the previously treated eighth rib lesion and the appearance of two new suspected lung lesions on the thoracic wall and lower right lobe (29 × 13 mm), respectively. The remaining multiple bilateral pulmonary lesions, the biggest of which was 8 mm in the largest diameter, were substantially stable. On 15 September 2017, WB PET signaled at least four suspected lung lesions and pathological activity of the VII, VIII, and IX right ribs. On 21 September 2017 and 20 November 2017, serum CEA values were 11.2 and 96 ng/mL, respectively. In November 2017, he again started treatment with the Xelox regimen plus cetuximab. After two cycles, oxaliplatin was interrupted because of strong side effects and he continued with capecitabine and cetuximab. On 13 February 2018, the serum CEA value was 46.3 ng/mL. In March 2018, WB PET confirmed the progression of metastatic disease in the right lung and right chest wall; on 20 March 2018, following transient ChT interruption, the patient underwent surgical removal of the lower right pulmonary lobe, multiple resections of the residual left lung, and thoracotomy of the VII, VIII, and IX right ribs with subsequent plastic surgery of the thoracic wall. The control with WB CT, which was carried out soon after surgery, showed that one metastatic lesion remained on the right lobe, in addition to the multiple repetitions of the left lung lobe. He started with capecitabine and cetuximab therapy, which he continued until March 2019. Serum CEA values, which were 4.1, 4.5, 3.6, 4, and 5.1 ng/mL on 6 April 2018, 24 May 2018, 1 August 2018, 10 October 2018, and 27 October 2018, respectively, increased to 12 ng/mL in December 2018. WB CT carried out in January 2019 signaled three new hepatic repetitions, the largest of which was about 2 cm, and two of them were close to the hepatic and cava veins, respectively, while the multiple lung repetitions were stable. At the beginning of April 2019, he underwent surgical removal of the hepatic lesions. Yet another WB CT carried out soon after surgery showed the persistence of metastatic liver disease in addition to the stable multiple lung repetitions. At the beginning of July 2019, he entered an experimental protocol with temozolomide that was interrupted at the end of August after two cycles because of the unresponsive metastatic disease. On 16 August, the serum CEA value was 86 ng/mL. On 2 September, following an oncologic consultation, he was given tas-102 therapy, which is ongoing. Although this patient is not disease-free, he is doing well with 0-1 ECOG PS 98 months after primary surgery.\nThis patient underwent an uncommon number of surgical interventions (nine) and, during a prolonged time of post-operative monitoring, serum CEA was often in the normal range. Therefore, in this patient, surgery, in addition to a systemic treatment, likely allowed for the maintenance of an undetectable or detectable, but relatively low metastatic tumor burden. Five-year OS rates of 30%–43% were reported in patients who were submitted to complete pulmonary metastasectomy following hepatic resection for colorectal metastases at an earlier stage []. Similarly, a 30% five-year OS rate and a median OS ranging from 29 to 40.5 months was reported in a study [] in which 206 inoperable patients with pulmonary oligo-metastases were treated with stereotactic body radiotherapy (SBRT). In 118 (57%) of these 206 patients, colorectal carcinoma was the primary site of pulmonary oligo-metastases. Moreover, Marudanayagam et al. [] reported a 53% five-year OS after combined liver and lung resections for patients in which the pulmonary metastases developed more than six months after liver resection (metachronous group). However, 0% was the four-year OS for those in which, as in our patient, lung metastasis developed within six months after liver resection (synchronous group).
A 65-year-old male; was a heavy smoker from 15 or 16 to 42 years old and did not have relevant co-morbidities. When he was 58 years old, he underwent a left nephrectomy for the occasional detection of the absence of the left urinary duct. On 5 May 2010, he underwent subtotal esophagectomy with intra-thoracic esophago-plastic surgery; post-operative histology showed adeno-carcinoma of the esophageal–gastric junction, intestinal type by Lauren’s classification. pT2 N0 M0 was the post-operative TNM classification, and cells were HER2 negative. He did not receive any adjuvant therapy. This patient remained disease-free until September 2016, when he went to an emergency department because of heavy abdominal cramps. On this occasion, no pathological signs were ascertained by clinical-radiological assessment, and the patient was discharged without symptoms following anti-inflammatory and anti-spastic therapy. Two months later (in November), the same signs and sialorrhoea occurred; again, he went to the same emergency department, where WB CT showed pelvic ascites and mesenteric fat thickness with small nodules suspected for peritoneal metastases. This diagnosis was confirmed at the National Institute of Cancer in Milan, where the patient was sent for consultation. From 24 November 2016 to 1 February 2017, he received four cycles of 2000/sqm/day capecitabine given orally plus 130 mg/sqm oxaliplatin by i.v. infusion (the Xelox regimen) with complete response (CR); after that, on 1 April 2017, he started maintenance cyclic IT. This patient was disease-free at the last clinical-radiological assessment on 20 May 2019. To date, 35 months from the diagnosis of metastases, he is doing well.\nThe median OS of gastrointestinal cancer patients with moderate metastatic peritoneal ascites was reported to be 9.6 and 13.5 months [,].\nDuring IT in all four cases, the mean basal values of IL-2 increased. In patients 4 and 2, the difference was significant (** p = 0.046 and * p = 0.049, respectively) or close to significant (** p = 0.083). In patient 1, it was close to significant (* p = 0.061 and ** p = 0.083). The mean total number of lymphocytes decreased in two of the four cases. The difference was close to significant in patients 1 (* p = 0.076, ** p = 0.083) and 4 (* p = 0.079, ** p = 0.083). Accordingly, CD3+, CD4+, and NK basal values decreased during IT in three (75%) of the four examined patients. In particular, in contrast to NK, for which no significant difference occurred, the difference in CD3+ was significant (* p = 0.040) or close to significant (* p = 0.083) in patient 1 and close to significant (** p = 0.088) in patient 4. The difference in CD4+ was close to significant in both patients 1 (* p = 0.053, ** p = 0.083) and 3 (** p = 0.083). Basal VEGF, IL-12, and CD19+ values decreased in three (75%) patients. The difference in VEFG was close to significant (** p = 0.083) in patients 1 and 3. IL-12 was significant (* p = 0.040) or close to significant (** p = 0.083) in patient 2 and it was close to significant (** p = 0.083) in patient 1. In patients 1 (p = 0.063, ** p = 0.083) and 4 (* p = 0.071, ** p = 0.077), the difference in CD19+ was close to significant (). No significance was found for IL-6. An increase in three patients with only one close to significant was found for IL-10 and IL-2R. Conflicting results were obtained for CD8+; Treg; CD4+45RO; IL-1R; TNF alpha; TGF beta1; FGF; EGF; IGF1; and IL-1, IL-8, and CMP1 inflammatory cytokines (see ).