Pharmacogenomic study of gemcitabine efficacy in patients with metastatic pancreatic cancer: A multicenter, prospective, observational cohort study (GENESECT study).

BACKGROUND: Genetic polymorphisms of molecules are known to cause individual differences in the therapeutic efficacy of anticancer drugs. However, to date, germline mutations (but not somatic mutations) for anticancer drugs have not been adequately studied. The objective of this study was to investigate the association between germline polymorphisms of gemcitabine metabolic and transporter genes with carbohydrate antigen 19-9 (CA 19-9) response (decrease ≥50% from the pretreatment level at 8 weeks) and overall survival (OS) in patients with metastatic pancreatic cancer who receive gemcitabine-based chemotherapy. METHODS: This multicenter, prospective, observational study enrolled patients with metastatic pancreatic cancer patients who were receiving gemcitabine monotherapy or gemcitabine plus nanoparticle albumin-bound paclitaxel combination chemotherapy. Thirteen polymorphisms that may be involved in gemcitabine responsiveness were genotyped, and univariate and multivariate logistic regression analyses were used to determine the association of these genotypes with CA 19-9 response and OS. The significance level was set at 5%. RESULTS: In total, 180 patients from 11 hospitals in Japan were registered, and 159 patients whose CA 19-9 response could be assessed were included in the final analysis. Patients who had a CA 19-9 response had significantly longer OS (372 vs. 241 days; p = .007). RRM1 2464A>G and RRM2 175T>G polymorphisms suggested a weak association with CA 19-9 response and OS, but it was not statistically significant. COX-2 -765G>C polymorphism did not significantly correlate with CA 19-9 response but was significantly associated with OS (hazard ratio, 2.031; p = .019). CONCLUSIONS: Genetic polymorphisms from the pharmacokinetics of gemcitabine did not indicate a significant association with efficacy, but COX-2 polymorphisms involved in tumor cell proliferation might affect OS.

C-Reactive Protein/Albumin Ratio Is an Independent Risk Factor for Recurrence and Survival Following Curative Resection of Stage I-III Colorectal Cancer in Older Patients.

BACKGROUND: The number of older patients with cancer has increased, and colorectal cancer is expected to be affected by this trend. This study aimed to compare prognostic factors, including nutritional and inflammation-based indices, between patients aged ≥ 70 and < 70 years following curative resection of stage I-III colorectal cancer. PATIENTS AND METHODS: This study included 560 patients with stage I-III colorectal cancer who underwent curative resection between May 2010 and June 2018. A retrospective analysis was performed to identify prognosis-associated variables in patients aged ≥ 70 and < 70 years. RESULTS: Preoperative low body mass index, high C-reactive protein/albumin ratio, and comorbidities were mainly associated with poor prognosis in patients aged ≥ 70 years. Tumor factors were associated with a poor prognosis in patients aged < 70 years. The C-reactive protein/albumin ratio was independently associated with poor overall survival and recurrence-free survival in those aged ≥ 70 years. The time-dependent area under the curve for the C-reactive protein/albumin ratio was superior to those of other nutritional and inflammation-based indices in most postoperative observation periods in patients aged ≥ 70 years. CONCLUSIONS: Tumor factors were associated with a poor prognosis in patients aged < 70 years. In addition to lymph node metastasis, preoperative statuses were associated with poor prognosis in patients aged ≥ 70 years. Specifically, the preoperative C-reactive protein/albumin ratio was independently associated with long-term prognosis in patients aged ≥ 70 years with stage I-III colorectal cancer after curative resection.

Survival outcomes of patients with stage III colorectal cancer aged ≥ 80 years who underwent curative resection: the HiSCO-04 prospective cohort study.

BACKGROUND: The efficacy of adjuvant chemotherapy in elderly patients aged ≥ 80 years with stage III colorectal cancer remains unclear. In parallel with a multicenter prospective phase II trial evaluating the efficacy of uracil-tegafur and leucovorin as adjuvant chemotherapy (HiSCO-03), we conducted a prospective observational study of these patients to assess survival outcomes, including those ineligible for chemotherapy. METHODS: This multi-institutional prospective cohort study included 17 institutions in Hiroshima, Japan. Patients aged ≥ 80 years with stage III colorectal cancer who underwent curative resection were enrolled. The primary endpoint was 3-year disease-free survival, and the secondary endpoints were 3-year overall and relapse-free survival. Propensity score matching was used to assess the effects of adjuvant chemotherapy on survival outcomes. RESULTS: A total of 214 patients were analyzed between 2013 and 2018, including 99 males and 115 females with a median age of 84 years (range 80-101 years). Recurrence occurred in 58 patients and secondary cancers were observed in 17. The 3-year disease-free, overall, and relapse-free survival rates were 63.3%, 76.9%, and 62.9%, respectively. Adjuvant chemotherapy was administered to 65 patients with a completion rate of 52%. In a study of 80 patients that adjusted for background factors using propensity score matching, patients who completed the planned treatment showed improved disease-free survival (3-year disease-free survival: completed, 80.0%; not received, 65.5%; and discontinued, 56.3%; p = 0.029). CONCLUSIONS: Completion of adjuvant chemotherapy may improve the prognosis of patients with colorectal cancer aged ≥ 80 years, although the number of patients who would benefit from it is limited.

Long-Term Follow-up Data of a Multi-Institutional Phase-2 Study of S-1/oxaliplatin and Bevacizumab Therapy in Patients with Advanced Colorectal Cancer: The HiSCO-02 Study.

Oral fluoropyrimidines (FUs) have certain advantages over intravenous FUs, such as longer intervals between outpatient visits, no requirement for central venous port (CVP) implantation, and lower incidence of neutropenia. We previously reported the efficacy of S-1/oxaliplatin (SOX) with bevacizumab therapy as a first-line treatment for advanced colorectal cancer (CRC) in a prospective phase-II multi-institutional clinical trial (HiSCO-02 study). However, our prognostic data at the time lacked a sufficient observation period. Herein, we analyze the longer-term follow-up data, focusing on the status of eventual CVP implantation via an open-label, non-randomized, multicenter study. This study enrolled 55 patients (mean age, 64 years), of whom 43 died (41 of primary cancer). The median overall survival was 22.7 months (95% CI: 20.1-34.7 months). Post-treatment regimens after failure of first-line treatment were initiated in 43 patients; CPT11-based regimens were selected in most cases, and other oral FU combinations in nine. CVP was implanted in 35 patients prior to first-line treatment; eleven of the remaining 20 patients did not require CVP implantation. In conclusion, we report here the final prognostic update of the Phase II clinical trial examining the efficacy of SOX plus bevacizumab therapy, the results of which confirm the clinical efficacy of this regimen.

Association between social background and implementation of postoperative adjuvant chemotherapy for older patients undergoing curative resection of colorectal cancers, sub-analysis of the HiSCO-04 study.

PURPOSE: Adjuvant chemotherapy is recommended following colorectal cancer resection based on risk of recurrence. In older patients, treatment decisions should consider recurrence rates and tolerability, as well as functional prognosis, residual disease, and social factors. This study aims to investigate factors, including social background, influencing implementation of postoperative adjuvant chemotherapy in older patients undergoing curative resection for colorectal cancer. METHODS: This multi-institutional prospective cohort study included 15 institutions belonging to the Hiroshima Surgical study group for Clinical Oncology. We analyzed 159 older patients aged ≥ 80 years, who underwent curative resection for stage III colorectal cancer between December 2013 and June 2018, as sub-analysis of the HiSCO-04 study. RESULTS: In total, 62 (39.0%) patients underwent postoperative adjuvant chemotherapy. Four factors were significantly associated with its implementation: performance status < 2, Charlson Comorbidity Index < 2, prognostic nutritional index ≥ 40, and presence of a spouse or siblings as lifestyle supporters. No significant difference was found in the backgrounds between complete and incomplete postoperative adjuvant chemotherapy patients. CONCLUSION: Performance status, Charlson Comorbidity Index, nutritional status, and presence of a spouse or siblings as lifestyle supporters are possible factors influencing the implementation of postoperative adjuvant chemotherapy in older patients. To select appropriate treatment options, including postoperative adjuvant chemotherapy, it is essential to consider physical condition and comorbidities of older patients, thoroughly explain the situation to their families, and establish a support system to enhance understanding of the available treatment options.

Chemotherapy-induced neutropenia as a prognostic factor in patients with extensive-stage small cell lung cancer.

PURPOSE: Chemotherapy-induced neutropenia (CIN) is a dose-limiting factor for cytotoxic chemotherapy, but recently, it was suggested that CIN contributes to prolonged survival. In this study, we examined the association between severe CIN and survival and determined whether CIN affected survival in patients with extensive-stage small cell lung cancer (ES-SCLC). METHODS: The medical records from 214 patients with ES-SCLC treated with etoposide or irinotecan in combination with cisplatin (EP/IP) between 2012 and 2016 were collected and retrospectively analyzed. Landmark analysis was performed at the end of cycle 4, and the relationship between severe CIN and survival was determined by a log-rank test. In addition, a multivariate analysis using the COX proportional hazard model was performed to identify independent predictive factors. The Landmark analysis included 102 patients in the IP group and 47 patients in the EP group. RESULTS: No significant difference was found between grades 0-3 and grade 4 neutropenia and overall survival (OS) in the EP group (P = 0.57). Contrariwise, for the IP patients, the median OS was 444 days for grades 0-3 and 633 days for grade 4 neutropenia, which was significantly longer for patients who developed grade 4 neutropenia (P = 0.03). Multivariate analysis adjusted for potential factors revealed that the development of grade 4 CIN was identified as a significant predictor of longer OS (hazard ratio [HR], 0.50; 95% confidence interval (CI), 0.28-0.87, P = 0.015). CONCLUSION: The results indicated that the development of severe CIN with IP therapy is associated with prolonged OS.

[A Case of Advanced Esophageal Cancer with Esophago-Bronchial Fistula Closed by Pembrolizumab plus Chemotherapy Therapy].

We report a case of unresectable advanced esophageal cancer with an esophageal fistula that was treated with pembrolizumab plus CDDP plus 5-FU therapy and the fistula was closed. A 73-year-old male was diagnosed with cervical-upper thoracic esophageal cancer and esophago-bronchial fistula on CT and esophagogastroduodenoscopy. He underwent chemotherapy containing pembrolizumab. The fistula was closed after 4 cycles and oral intake became possible. Six months have passed since the first visit and chemotherapy is ongoing. The prognosis of esophago-bronchial fistula is extremely poor, and there is no established treatment, including fistula closure. Chemotherapy containing immune checkpoint inhibitors could considered to be expected not only for local control but also for long-term survival.

Adoptive immunotherapy overcomes genetic susceptibility to bloodstream infections due to fc-gamma receptor polymorphisms after liver transplantation.

Single nucleotide polymorphisms (SNPs) in FCGR3A can predict the susceptibility of liver transplant (LT) recipients to bloodstream infections (BSI) and clinical outcomes following living-donor LT (LDLT). Here, we retrospectively analyzed the relationship of adoptive immunotherapy with activated natural killer (NK) cells from perfusate effluents of liver allografts against BSI following LDLT. Higher BSI incidence and lower survival were observed in LT recipients with FcγRIIIa (158F/F or F/V) (n = 81) who did not receive adoptive immunotherapy (n = 55) than in those who did (n = 26) (BSI frequency, 36.4% vs. 11.5%; p = .033; log-rank p = .047). After matching patient background using propensity score, similar results were obtained (BSI ratio, 41.7% vs. 12.5%; p = .049; log-rank p = .039). The predominant BSI pathogens in patients who did and did not receive adoptive immunotherapy were gram-negative rods (n = 3, 100%) and gram-positive cocci (GPC) (n = 15, 65.2%), respectively. The proportion of NK cells administered to patients with BSI was significantly lower than that administered to patients without BSI (Number: 80.3 (29.9-239.2) × 106 cells vs. 37.1 (35.6-50.4) × 106 ; p = .033, percentage; 14.1 (13.3-17.8)% vs. 34.6 (16.5-47)%, p = .0078). Therefore, adoptive immunotherapy with NK cells was associated with the reduced post-transplant BSI related to GPCs due to FcγRIIIa SNP in LT recipients.

[Clinical Outcome of Robot-Assisted Distal Pancreatectomy in Our Institutional Introduction].

We evaluated the clinical outcome and assessed the safety of robot-assisted distal pancreatectomy(RADP)of early 5 cases in our institutional introduction. We followed the guidelines for introduction of robot-assisted pancreatectomy proposed by Japanese Society of Endoscopic Surgery. Patients' characteristics were 2 men and 3 women, 45-79(median 52) years old, and 3 patients with neuroendocrine neoplasm, 1 with intraductal papillary neoplasm and 1 with mucinous cystic neoplasm. Spleen-preserving RADP was performed in 2 cases. Clinical outcomes of 5 cases underwent RADP were, operation time was 308-437(median 330)minutes, blood loss was 5-270(median 100)mL and none received transfusion. Postoperative pancreatic fistula and postoperative complication more than Grade Ⅲa(Clavien-Dindo classification)were none. Postoperative hospital stay was 7-11(median 8)days. RADP in our institution was safely introduced by following the proposal of guidelines.

Efficacy of upfront hepatectomy without neoadjuvant chemotherapy for resectable colorectal liver metastasis.

BACKGROUND: Hepatectomy for resectable colorectal liver metastasis (CRLM) is recommended. However, the efficacy of upfront hepatectomy without neoadjuvant chemotherapy (NAC) is unclear due to the uncertainty of perioperative systemic chemotherapy. Moreover, it is crucial to predict the prognosis when considering perioperative chemotherapy. This study evaluated the impact of neoadjuvant chemotherapy on the prognosis of patients with resectable CRLM and assessed the usefulness of Beppu's nomogram for predicting prognosis. METHODS: This retrospective study identified 88 consecutive inpatients who underwent primary hepatic resection for CRLM; 58 received neoadjuvant chemotherapy and 30 underwent upfront surgery. Factors associated with recurrence-free survival were identified via univariate and multivariate analysis. Furthermore, propensity score analysis using inverse probability of treatment weighting (IPTW) was performed. RESULTS: On univariate analysis, poor recurrence-free survival was associated with multiple tumors, advanced primary tumor stage, vascular invasion by the primary tumor, a Beppu's nomogram score ≥ 6, and neoadjuvant chemotherapy. On multivariate analysis, a Beppu's nomogram score ≥ 6 and neoadjuvant chemotherapy were independent risk factors for recurrence. Neoadjuvant chemotherapy recipients had a higher incidence of lymph node metastasis and vascular invasion than non-recipients. Propensity score analysis revealed no significant difference in the recurrence-free survival rate between these groups. CONCLUSIONS: Our results show that upfront hepatectomy without neoadjuvant chemotherapy can be considered for resectable CRLM treatment. Beppu's nomogram score can be a tool for predicting the prognosis of patients with CRLM.

[Two Cases of Stevens-Johnson Syndrome after Nivolumab Therapy for Gastric Cancer].

Case 1: A 51-year-old man with advanced gastric cancer and peritoneal metastasis was referred to our hospital. He received fourth-line chemotherapy with nivolumab, but it became PD. Next, he received S-1 plus docetaxel therapy as fifth- line therapy. After 2 courses of S-1 plus docetaxel, erythema and blisters appeared on his limbs, with erosions of the oral mucosa and penis. We diagnosed Stevens-Johnson syndrome(SJS)based on the clinical and pathological findings. He received steroid treatment, but the cutaneous symptoms persisted; therefore, it was impossible to continue the chemotherapy because of the SJS. Case 2: A 75-year-old woman with recurrence of peritoneally disseminated gastric cancer received third-line chemotherapy with nivolumab. After 1 course of nivolumab, erythema appeared on her body and limbs, with erosion of the lips and oral mucosa. We diagnosed SJS based on the clinical findings. She received steroid treatment, but the cutaneous symptoms persisted; therefore, it was impossible to continue chemotherapy because of the SJS. It should be noted that the onset of serious irAEs, such as SJS, might make continuous chemotherapy difficult.

[Laparoscopic Left Hemicolectomy-It Is Confirmed That the Accessory Middle Colonic Artery Branched from the Splenic Artery Showed by Preoperative 3D-CT].

There is a wide variety of vessel types in the transverse colon region. Among them, it is very rare that the accessory middle colonic artery(A-MCA)is branched from the splenic artery. We found a transverse colon cancer. The dominant vessel of the cancer was the A-MCA branched from the splenic artery. This vessel type was confirmed by preoperative 3D-CT. We performed a laparoscopic left hemicolectomy for the cancer. In this study, we report a case of safe laparoscopic surgery in which we separate the A-MCA branched from the splenic artery using the preoperative 3D-CT image.

[Outcome of Repeated Surgical Resections of Hepatic and Pulmonary Metastases from Colorectal Cancer].

Previous reports have demonstrated that repeated surgical resections of resectable hepatic and pulmonary metastases from colorectal cancer contribute to a better prognosis. We retrospectively assessed the outcomes of 19 patients with colorectal cancer who underwent repeated resections of hepatic and pulmonary metastases between February 2007 and February 2017. The median observation period was 69.9 months, and 26 liver and 27 lung resections were performed. The cumulative 5-year survival rates after resection of the last metastasis was 75.1% and the median disease-free survival after resection of the last metastasis was 34.7 months. Although 7 patients showed recurrence and 4 patients died, 7 patients exhibited long-term survival. Univariate analysis revealed that simultaneous liver and lung metastases were significantly predictor of poor prognosis(p=0.039). Progress of the patients in the present study were comparable to those in previous reports. Therefore, we propose that repeated surgical resection of hepatic and pulmonary metastasis from colorectal cancer could improve patient prognosis. Further studies should examine to identify more accurate prognostic factor with large series.

[Effect on Prognosis of Immune-Related Adverse Events after Nivolumab Treatment in Gastric Cancer].

BACKGROUND: The clinical efficacy of nivolumab has been shown as a third-line treatment for advanced gastric cancer; however, nivolumab sometimes causes immune-related adverse events(irAEs). We retrospectively examined the clinical features and influence on treatment in cases of irAEs after nivolumab treatment. METHOD: We retrospectively examined 43 patients who received nivolumab treatment at our institution between October 2017 and December 2019. RESULT: The incidence of irAEs was 23.2%(10/43), and Grade 3 or higher irAEs included interstitial pneumonia, hypoadrenalism, Stevens- Johnson syndrome(SJS), and type 1 diabetes. Three patients showed long-term disease control after irAE onset. Meanwhile, SJS prevented patients from continuing treatment for gastric cancer. DISCUSSION: Nivolumab is effective in some patients with gastric cancer, while irAEs made subsequent treatment difficult. Trifluridine/tipiracil or irinotecan are also known to be effective as therapeutic drugs after third-line treatment for gastric cancer in addition to nivolumab; therefore, the choice of the third-line drug and management of irAEs owing to individual cases are considered desirable. CONCLUSION: Long-term efficacy is expected with nivolumab, but it may be necessary to recognize that the onset of serious irAEs might make subsequent treatment difficult.

[Total Pelvic Exenteration and Perineal Reconstruction with a Gracilis Myocutaneous Flap for Local Recurrence of Rectal Cancer].

The case involved a female in her 70s. Six years prior, she had undergone an abdominoperineal rectal resection for rectal cancer. Local recurrence was observed during follow-up so preoperative chemoradiotherapy was performed to shrink the tumor, followed by a total pelvic exenteration, bilateral ureterocutaneous fistula, and perineal reconstruction with a gracilis myocutaneous flap. She was discharged from hospital 39 days following surgery with no major complications. We herein report on a case of a good postoperative course due to surgery including a total pelvic exenteration and perineal reconstruction with a gracilis myocutaneous flap for postoperative local recurrence.

[A Case of Laparoscopic Abdominoperineal Resection of Anorectal Malignant Melanoma].

A 56-year-old woman with complaints of anal bleeding and pain visited our hospital, and an elastic soft mass was detected in the anal canal on digital examination.Colonoscopy showed a black Isp polypoid lesion with a black pit from the anal canal to the lower rectum(P-Rb).She was diagnosed with malignant melanoma based on colonoscopic biopsy.Tumor marker levels(CEA, CA19-9)were not increased.No distant metastasis was detected on abdominal CT.No direct invasion was detected on MRI of the pelvis.The patient underwent laparoscopic abdominoperineal resection and D2 lymph node dissection. Histopathology showed a malignant melanoma(pT4b, N0, M0, pStageⅡC).The patient received interferon therapy as adjuvant therapy.There is no sign of recurrence 2 years and 1 month after the surgery.Anorectal malignant melanoma is relatively rare, so establishment of therapy by the accumulation of cases is desired.

[Twenty-Five Cases of Locally Advanced Rectal Cancer That Underwent Laparoscopic Surgery after Preoperative Chemotherapy].

Several recent reports have described the administration of preoperative chemotherapy for locally advanced rectal cancer. In our hospital, preoperative chemotherapy based on oxaliplatin was administered for locally advanced rectal cancer with a tumor diameter of 5 cm or more and half semicircularity or more, and curative resection with laparoscopic surgery was performed after tumor shrinkage. We have experienced 25 cases that underwent preoperative chemotherapy for local advanced rectal cancer in our hospital from May 2012 to April 2016. No tumor increased in size during preoperative chemotherapy and there were no cases where R0 resection was impossible. In addition, no distant metastasis during chemotherapy was observed. Postoperative complications were observed in 3 cases(12%), and anastomotic leakage was observed in 1 case (4%), but conservative treatment was possible. Multidisciplinary treatment of preoperative chemotherapy and surgery should be considered as a therapeutic strategy for locally advanced rectal cancer, mainly in medical institutions without radiation treatment facilities.