Phase II trial of niraparib for BRCA-mutated biliary tract, pancreatic and other gastrointestinal cancers: NIR-B.

Due to the widespread use of cancer genetic testing in gastrointestinal cancer, the BRCA1/2 genetic mutation has been identified in biliary tract cancer as well as pancreatic cancer. Niraparib is a poly(ADP-ribose) polymerase (PARP) inhibitor, and PARP inhibitors exert their cytotoxicity against cancer cells in the context of homologous recombination deficiency, such as BRCA mutations, via the mechanism of synthetic lethality. The aim of this phase II NIR-B trial is to evaluate the efficacy and safety of niraparib for patients with unresectable advanced or recurrent biliary tract cancer, pancreatic cancer or other gastrointestinal cancers with germline or somatic BRCA1/2 mutations revealed by genetic testing. The primary end point is an investigator-assessed objective response rate in each cohort.Clinical Trial Registration: jRCT2011200023 (ClinicalTrials.gov).

A clinical study to confirm the efficacy and safety of niraparib for people with advanced biliary tract, pancreatic and other abdominal cancers with the BRCA genetic mutation: the NIR-B trial.BRCA gene is involved in repairing DNA injury and plays an important role in cancer growth. Cells with a mutation in the BRCA gene cannot repair DNA using a method called homologous recombination repair. Niraparib is part of a class of drugs called 'PARP inhibitors' that inhibit enzymes called 'PARP' involved in repairing DNA injury, and has shown efficacy against cancers with BRCA gene mutations. BRCA gene mutations are infrequent but have been found in a variety of cancers. The NIR-B trial is a clinical trial to evaluate the efficacy and safety of niraparib for people with advanced biliary tract, pancreatic and other abdominal cancers with BRCA gene mutations.

Clinical significance of circulating-tumour DNA analysis by metastatic sites in pancreatic cancer.

BACKGROUND: Liquid biopsy is an alternative to tissue specimens for tumour genotyping. However, the frequency of genomic alterations with low circulating-tumour DNA (ctDNA) shedding is shown in pancreatic ductal adenocarcinoma (PDAC). We, therefore, investigated the prevalence of KRAS mutations and ctDNA fraction by the metastatic site in patients with PDAC. METHODS: This study enrolled previously treated PDAC patients from a plasma genomic profiling study; ctDNA analysis was performed using Guardant360 at disease progression before initiating subsequent treatment. RESULTS: In 512 patients with PDAC, KRAS mutations were detected in 57%. The frequency of KRAS mutation in ctDNA differed depending on the metastatic organ; among patients with single-organ metastasis (n = 296), KRAS mutation detection rate was significantly higher in patients with metastasis to the liver (78%). In addition, the median maximum variant allele frequency (VAF) was higher with metastasis to the liver (1.9%) than with metastasis to the lungs, lymph nodes, peritoneum or with locally advanced disease (0.2%, 0.4%, 0.2% and 0.3%, respectively). CONCLUSION: The prevalence of KRAS mutations and maximum VAF were higher in patients with metastasis to the liver than in those with metastasis to other sites. This study indicated the clinical utility of ctDNA analysis, especially in PDAC with liver metastases.

Efficacy of chemotherapy for patients with metastatic or recurrent pancreatic adenosquamous carcinoma: A multicenter retrospective analysis.

BACKGROUND/OBJECTIVES: Pancreatic adenosquamous carcinoma (PASC) is a rare variant of pancreatic ductal adenocarcinoma (PDAC). The usual treatment for metastatic or recurrent PASC is systemic chemotherapy in accordance with the PDAC treatment strategy. This study aimed to investigate the efficacy of chemotherapy, especially the benefit of recent combination therapies, in patients with metastatic or recurrent PASC. METHODS: We conducted a multicenter retrospective analysis of 116 patients with metastatic or recurrent PASC treated with first-line chemotherapy between April 2001 and December 2017 at 24 Japanese institutions. RESULTS: Combination chemotherapies included gemcitabine + nab-paclitaxel (GnP, n = 28), fluorouracil/leucovorin + irinotecan + oxaliplatin (FFX, n = 10), gemcitabine + S-1 (GS, n = 10), and others (n = 9). Monotherapies included gemcitabine (n = 51) and S-1 (n = 8). The median overall survival (OS) was 6.5, 7.3, and 4.3 months for the whole cohort, the combination therapy group, and the monotherapy group, respectively. Multivariate analysis indicated that combination therapy showed a better trend in OS than monotherapy (hazard ratio = 0.68; 95% confidence interval, 0.38-1.20). GnP or FFX were selected in 58.7% of patients after FFX was approved in Japan, and revealed a median OS, median progression-free survival, and objective response rate of 7.3 months, 2.8 months, and 26.9% in GnP and 7.2 months, 2.3 months, and 20.0% in FFX respectively. CONCLUSIONS: This study suggests that combination therapy may be more effective than monotherapy. GnP and FFX showed similar and clinically meaningful efficacy for patients with metastatic or recurrent PASC.

In vitro and in vivo pharmacological profile of OPC-61815, a water-soluble phosphate ester pro-drug of tolvaptan.

Tolvaptan is an orally active vasopressin V2 receptor antagonist and used for the treatment of volume overload in some disease as an aquaretic. Tolvaptan sodium phosphate (OPC-61815) is a pro-drug of tolvaptan that was designed to improve water solubility and enable intravenous use. The conversion of OPC-61815 to tolvaptan was evaluated for in vitro and in vivo pharmacokinetic studies. The pharmacodynamics of OPC-61815 were evaluated for in vitro receptor binding affinity, in vivo aquaretic and anti-edematous action. The solubility of OPC-61815 in water at 25 °C was 72.4 mg/mL and more than 100,000 times the solubility of tolvaptan. OPC-61815 was hydrolyzed to tolvaptan by human tissue S9 fractions and main enzyme of hydrolysis was alkaline phosphatase. After intravenous administration of OPC-61815 to rats and dogs, tolvaptan was detected in plasma within 5 min and the bioavailability of tolvaptan was 57.7% and 50.9%, respectively. Binding affinity of OPC-61815 for the human V2 receptor was 1/14 weaker than that of tolvaptan. OPC-61815 exerted dose-dependent aquaretic action in rats and dogs and a corresponding anti-edematous action in rat edema models. These results suggest that OPC-61815, a water-soluble phosphate ester pro-drug of tolvaptan, is an effective aquaretic by converting to tolvaptan after intravenous administration.

Endoscopic duodenal stent placement versus gastrojejunostomy for unresectable pancreatic cancer patients with duodenal stenosis before introduction of initial chemotherapy (GASPACHO study): a multicenter retrospective study.

BACKGROUND: Endoscopic duodenal stent placement is an alternative technique to gastrojejunostomy for gastric outlet obstruction due to pancreatic cancer. We compared the efficacy of endoscopic duodenal stent placement with that of gastrojejunostomy for treating patients with pancreatic cancer who are candidates for intensive combination chemotherapies as the first line of treatment. METHODS: This retrospective observational study included 100 patients from 18 institutions in Japan. Inclusion criteria were as follows: (1) cytologically or histologically confirmed adenocarcinoma of the pancreas, (2) good performance status, (3) gastric outlet obstruction scoring system score of 0-1 and (4) no history of treatment for pancreatic cancer. RESULTS: There was no significant difference in the background characteristics of patients in the endoscopic duodenal stent placement (n = 57) and gastrojejunostomy (n = 43) groups. The median overall survival in the endoscopic duodenal stent placement and gastrojejunostomy groups was 5.9 and 6.0 months, respectively. Clinical success was achieved in 93 cases; the median time to food intake resumption was significantly shorter in the endoscopic duodenal stent placement group (median: 3 days, n = 54) than in the gastrojejunostomy group (median: 5 days, n = 43). Chemotherapy was introduced in 63% of the patients in both groups after endoscopic duodenal stent placement or gastrojejunostomy. Chemotherapy was started earlier in the endoscopic duodenal stent placement group (median: 14 days) than in the gastrojejunostomy (median: 32 days) group. CONCLUSIONS: Endoscopic duodenal stent placement showed similar or better clinical outcomes than gastrojejunostomy. Thus, it might be a promising option in patients with good performance status.

Risk stratification and prognostic factors in patients with unresectable undifferentiated carcinoma of the pancreas.

BACKGROUND: Undifferentiated carcinoma (UC) of the pancreas has been considered a highly aggressive malignancy. However, only a few studies have systematically described the clinical course of UC patients. The aim of this study was to clarify the prognosis and construct a prognostic model for patients with unresectable UC. METHODS: This study was conducted at 17 institutions in Japan, and a total of 55 patients were analyzed. RESULTS: The median overall survival (OS) of patients with unresectable UC was 3.95 months. In the multivariate Cox proportional hazards (CPH) model, age ≥65 years, Eastern Cooperative Oncology Group performance status (ECOG PS) ≥2, and C-reactive protein (CRP) >10 mg/L were independent prognostic factors for OS (age ≥65 years: hazard ratio [HR], 2.732; 95% confidence interval [CI], 1.353-5.515; ECOG PS ≥ 2: HR, 7.866; 95% CI, 1.981-31.241; CRP >10 mg/L: HR, 1.956; 95% CI, 1.013-3.775). Based on the ß coefficients from the CPH model, the prognostic scores were defined as follows: age ≥65 years (3 points), ECOG PS ≥ 2 (6 points), and CRP >10 ml/L (2 points). The final prognostic model was the sum of the points. The derived prognostic model stratified patients into high-risk (score ≥4) and low-risk (score 0-3) groups, with significant differences in OS (1.45 vs. 8.19 months, respectively; p < 0.001). CONCLUSIONS: The prognostic model stratified patients into high-risk and low-risk groups. These findings suggest that this model can serve as a tool for patient information and decision-making with regard to the therapeutic strategy for UC.

Pharmacokinetics and metabolism of brexpiprazole, a novel serotonin-dopamine activity modulator and its main metabolite in rat, monkey and human.

The pharmacokinetics of brexpiprazole were investigated in the in vitro and in vivo.The total body clearance of brexpiprazole in rat and monkey was 2.32 and 0.326 L/h/kg, respectively, after intravenous administration, and oral availability was 13.6% and 31.0%, respectively. Dose-dependent exposures were observed at dose ranges between 1-30 mg/kg in the rat and 0.1-3 mg/kg in the monkey.Brexpiprazole distributed widely to body tissues, and Vd,z were 2.81 and 1.82 L/kg in rat and monkey, respectively. The serum protein binding of brexpiprazole was 99% or more in animals and human. Uniform distribution character among the species was suggested by a traditional animal scale-up method.A common main metabolite, DM-3411 was found in animals and humans in the metabolic reactions with the liver S9 fraction. CYP3A4 and CYP2D6 were predominantly involved in the metabolism.The affinity of DM-3411 for D2 receptors was lower than that of brexpiprazole, and neither DM-3411 nor any metabolites with affinity other than M3 were detected in the brain, demonstrating that brexpiprazole is only involved in the pharmacological effects.Overall, brexpiprazole has a simple pharmacokinetic profile with good metabolic stability, linear kinetics, and no remarkable species differences with regard to metabolism and tissue distribution.

In vitro evaluations for pharmacokinetic drug-drug interactions of a novel serotonin-dopamine activity modulator, brexpiprazole.

Brexpiprazole, a serotonin-dopamine activity modulator, is indicated for the treatment of schizophrenia and also adjunctive therapy to antidepressants for the treatment of Major Depressive Disorder. To determine the drug-drug interaction risk for cytochrome P450, and SLC and ABC transporters, brexpiprazole and its metabolite, DM-3411 were assessed in this in vitro investigation.Brexpiprazole exhibited weak inhibitory effects (IC50 >13 µmol/L) on CYP2C9, CYP2C19, CYP2D6 and CYP3A4 activities, but had moderate inhibitor activity on CYP2B6 (IC50 8.19 µmol/L). The ratio of systemic unbound concentration (3.8 nmol/L) to the Ki value was sufficiently low. DM-3411 had comparable inhibitory potentials with brexpiprazole only for CYP2D6 and CYP3A4. The mRNA expressions of CYP1A2, CYP2B6 and CYP3A4 were not changed by the exposure of brexpiprazole to human hepatocytes.Brexpiprazole and DM-3411 exhibited weak or no inhibitory effects for hepatic and renal transporters (OATPs, OATs, OCTs, MATE1, and BSEP), except for MATE-2K (0.156 µmol/L of DM-3411), even for which the ratio to systemic unbound concentration (5.3 nmol/L) was sufficiently low.Brexpiprazole effected the functions of P-gp and BCRP with IC50 values of 6.31 and 1.16 µmol/L, respectively, however, the pharmacokinetic alteration was not observed in the clinical concomitant study on P-gp and BCRP substrates.These in vitro data suggest that brexpiprazole is unlikely to cause clinically relevant drug interactions resulting from the effects on CYPs or transporters mediating the absorption, metabolism, and/or disposition of co-administered drugs.

[A case of obstructive jaundice and duodenal stenosis caused by vaginal cancer and retroperitoneal metastasis].

A 76-year-old woman with a history of radiation therapy for vaginal cancer was referred to our hospital because of fever and hepatobiliary dysfunction. Computed tomography showed stenosis of the lower bile duct and edema-like changes in the duodenum from the descending to transverse parts. Endoscopic biliary stenting was performed according to the rendezvous method. Squamous cell carcinoma, similar to vaginal cancer, was found on pathological examination of the duodenum. We accordingly diagnosed obstructive jaundice and duodenal stenosis caused by vaginal cancer and retroperitoneal metastasis. To the best of our knowledge, other such cases have not been reported.

A Phase II Trial of Everolimus in Patients with Advanced Pancreatic Neuroendocrine Carcinoma Refractory or Intolerant to Platinum-Containing Chemotherapy (NECTOR Trial).

BACKGROUND: Platinum-containing regimens are widely used as first-line chemotherapy for unresectable pancreatic neuroendocrine carcinoma (NEC), but second-line chemotherapies have yet to be established. OBJECTIVES: We evaluated the safety and efficacy of everolimus in patients with pancreatic NEC refractory or intolerant to platinum-containing chemotherapy. METHODS: This study was a prospective, multicenter, phase II trial in patients with pancreatic NEC after platinum-containing chemotherapy. Everolimus treatment was continued until disease progression or intolerable toxicity was observed. The primary endpoint was progression-free survival (PFS). RESULTS: Participants comprised 25 patients. Median age was 63 years, median PFS was 1.2 months (95% confidence interval [CI] 0.9-3.1 months), median overall survival was 7.5 months (95% CI 3.1-13.5 months), overall response rate was 0%, and disease control rate was 39.1%. Common grade 3/4 adverse events were hyperglycemia (20%), thrombocytopenia (16%), and anemia (16%). CONCLUSION: The efficacy of everolimus was limited in patients with unresectable pancreatic NEC.

Surgery for Pancreatic Neuroendocrine Tumor G3 and Carcinoma G3 Should be Considered Separately.

BACKGROUND: The role of surgery in pancreatic neuroendocrine neoplasm grade 3 (pNEN-G3) treatment remains unclear. We aimed to clarify the role of surgery for pNEN-G3, which has recently been reclassified as pancreatic neuroendocrine tumor-G3 (pNET-G3) and pancreatic neuroendocrine carcinoma-G3 (pNEC-G3), with and without metastases, respectively. METHODS: We analyzed a subgroup of patients from the Japanese pancreatic NEC study, a Japanese multicenter case-series study of pNEN-G3. Pathologists subclassified 67 patients as having pNET-G3 or pNEC-G3 based on morphological features. We compared the overall survival (OS) rates among patients who were grouped according to whether they had undergone tumor-targeted surgery for tumors without (SwoM) or with (SwM) metastases, or non-surgical procedures (NS). RESULTS: Data from 21 patients with pNET-G3 (SwoM, n = 6; SwM, n = 5; NS, n = 10) and 46 patients with pNEC-G3 (SwoM, n = 8; SwM, n = 5; NS, n = 33) were analyzed. OS of patients with pNET-G3 was significantly longer after SwoM and SwM than with NS (p = 0.018 and p = 0.022). In contrast, OS did not significantly differ between either SwoM or SwM and NS (p = 0.093 and p = 0.489) among patients with pNEC-G3. CONCLUSION: The role of surgery should be considered separately for pNET-G3 and pNEC-G3. Although SwoM and SwM can be considered for pNET-G3, caution is advised before considering SwM and SwoM for pNEC-G3.

Randomized phase II/III clinical trial of elpamotide for patients with advanced pancreatic cancer: PEGASUS-PC Study.

Gemcitabine is a key drug for the treatment of pancreatic cancer; however, with its limitation in clinical benefits, the development of another potent therapeutic is necessary. Vascular endothelial growth factor receptor 2 is an essential target for tumor angiogenesis, and we have conducted a phase I clinical trial using gemcitabine and vascular endothelial growth factor receptor 2 peptide (elpamotide). Based on the promising results of this phase I trial, a multicenter, randomized, placebo-controlled, double-blind phase II/III clinical trial has been carried out for pancreatic cancer. The eligibility criteria included locally advanced or metastatic pancreatic cancer. Patients were assigned to either the Active group (elpamotide + gemcitabine) or Placebo group (placebo + gemcitabine) in a 2:1 ratio by the dynamic allocation method. The primary endpoint was overall survival. The Harrington-Fleming test was applied to the statistical analysis in this study to evaluate the time-lagged effect of immunotherapy appropriately. A total of 153 patients (Active group, n = 100; Placebo group, n = 53) were included in the analysis. No statistically significant differences were found between the two groups in the prolongation of overall survival (Harrington-Fleming P-value, 0.918; log-rank P-value, 0.897; hazard ratio, 0.87, 95% confidence interval [CI], 0.486-1.557). Median survival time was 8.36 months (95% CI, 7.46-10.18) for the Active group and 8.54 months (95% CI, 7.33-10.84) for the Placebo group. The toxicity observed in both groups was manageable. Combination therapy of elpamotide with gemcitabine was well tolerated. Despite the lack of benefit in overall survival, subgroup analysis suggested that the patients who experienced severe injection site reaction, such as ulceration and erosion, might have better survival.

Zinc Deficiency as a General Feature of Cancer: a Review of the Literature.

Trace elements are minerals that are present in very low concentrations in the human body and yet are crucial for a wide range of physiological functions. Zinc, the second most abundant trace element, is obtained primarily from the diet. After being taken up in the intestine, zinc is distributed to various target organs, where it plays key roles in processes such as immunity, protein folding, apoptosis, and antioxidant activity. Given the important role of zinc in a wide range of enzymatic reactions and physiological processes, zinc deficiency has been identified in a variety of diseases, notably cancer. In recent years, multiple meta-analyses and reviews looking at zinc levels in individual cancer types have been published, as have a plethora of primary studies demonstrating a link between low zinc levels and specific types of cancer. In this review, we summarize recent evidence implicating low zinc concentrations in serum or tissues as a characteristic in a wide range of cancers. We also discuss preliminary findings indicating that zinc level measurement could ultimately become a useful clinical tool for cancer diagnosis and predicting outcomes in patients with cancer. Finally, we suggest future directions for further elucidating the role of zinc deficiency in cancer development and progression.

Impact of Reduced Acidic Earwax pH and Earwax-Determinant Genotypes in Acquired Middle Ear Cholesteatoma.

OBJECTIVE: The development of acquired middle ear cholesteatoma is associated with a single nucleotide polymorphism, 538G>A, in the human adenosine triphosphate-binding cassette transporter C11 (ABCC11) gene, which is a determinant of the earwax morphotype, such as wet- and dry-type earwax; however, the mechanism underlying this association is unclear. We focused on the earwax pH and aimed to elucidate the mechanism between ABCC11 genotypes and acquired middle ear cholesteatoma. STUDY DESIGN: Prospective observational study. SETTING: Single-center, academic hospital. METHODS: We recruited 40 patients with acquired middle ear cholesteatoma who underwent surgery and 115 controls with no history of middle ear cholesteatoma. We assessed the earwax pH and ABCC11 genotypes in all participants. Clinical information was collected from the patients with cholesteatoma. RESULTS: The earwax pH was significantly less acidic in patients with cholesteatoma and those carrying wet earwax genotypes (ABCC11 538G/G or 538G/A) than in the controls and those carrying the dry earwax genotype (ABCC11 538A/A), respectively. Furthermore, earwax pH was significantly positively correlated with high preoperative cholesteatoma stages in the patients with cholesteatoma. CONCLUSION: Our results show that the less acidic earwax pH was significantly related to the development and progression of acquired middle ear cholesteatoma. The less acidic earwax pH may play an important role in the mechanism underlying the association between acquired middle ear cholesteatoma and the ABCC11 gene at site 538.

[Multiple pyogenic liver abscesses with the decline in neutrophil phagocytic function: a case report].

A 51-year-old man presenting with fever, weight loss and general fatigue was diagnosed with jaundice and liver tumors and admitted to our hospital for further investigation and treatment. We diagnosed multiple pyogenic liver abscesses, obstructive jaundice, and silent syphilis. The patient was successfully treated with endoscopic biliary stenting, endoscopic nasobiliary drainage, percutaneous transhepatic abscess drainage, and, most effectively, transcatheter regional hepatic arterial infusion with antibiotics. We speculated that the decline in neutrophil phagocytic function may concern to occur the pyogenic liver abscess.

Serum zinc levels in cancer patients are low and difficult to elevate when complicated by liver cirrhosis: A retrospective study.

In this study, we analyzed blood zinc concentration in patients with various cancer types and the degree of improvement in relation to the underlying disease following treatment with zinc preparations. Serum zinc levels of 530 cancer patients whose blood zinc levels were measured at our hospital from 2016 to 2021 were retrospectively examined in accordance with the primary disease. Changes in zinc levels were analyzed in 155 patients whose zinc levels had been measured on 2 or more occasions in accordance with whether they had received zinc preparations. In addition, the concentration course of zinc before and after zinc formulation administration in 73 patients was examined in accordance with the presence or absence of liver cirrhosis complications. Mean serum zinc levels were below normal in all carcinomas measured, and zinc levels were significantly lower in cirrhosis-hepatocarcinoma cases than in other primary disease cases. Furthermore, serum zinc levels in patients who did not receive zinc preparations decreased significantly over time. In patients who received zinc preparations, the elevated levels of zinc after treatment were significantly lower in patients with cirrhosis than in those without cirrhosis. There was a weak inverse correlation between pre-dose zinc concentration and increased zinc concentration in patients with cirrhosis. In the analysis of covariance, the presence of liver cirrhosis was predominantly correlated with elevated zinc per dose. In summary, serum zinc levels in cancer patients are low and especially low in cancer patients with liver cirrhosis compared with those without cirrhosis after the administration of zinc preparations.

FIGHT-102: A phase 1 study of pemigatinib in Japanese patients with advanced malignancies.

BACKGROUND: FIGHT-102 was a phase 1, dose-escalation, dose-expansion study of pemigatinib in Japanese patients with advanced solid tumors. Here, we report safety, tolerability, and preliminary efficacy of pemigatinib from FIGHT-102. METHODS: Patients (≥20 years old) self-administered oral pemigatinib 9, 13.5, or 18 mg QD on intermittent dosing (Part 1) or 13.5 mg QD intermittent or continuous dosing (Part 2). A dosing cycle was 21 days (2 weeks on/1 week off or 21 continuous days). Primary endpoint was safety. Secondary endpoints were pharmacokinetics, pharmacodynamics, and preliminary efficacy. RESULTS: Forty-four patients (Part 1, n = 14; Part 2, n = 30) were enrolled; most common tumors, cholangiocarcinoma, n = 8; esophageal, n = 6; 26 patients had confirmed FGF/FGFR alterations (Part 1, n = 3; Part 2, n = 23); 70.5% had ≥3 prior systemic therapies. Maximum tolerated dose was not identified. The recommended phase 2 dosage was determined to be 13.5 mg QD. Most common treatment-emergent adverse events (TEAEs) were hyperphosphatemia (81.8%), dysgeusia (45.5%), stomatitis (43.2%), and alopecia (38.6%); most frequent Grade ≥3 TEAEs were anemia and decreased appetite (9.1% each). In Part 1, no patient achieved partial response (PR) or complete response, and 7 (50.0%) patients had stable disease (SD). In Part 2, 5 (16.7%) patients achieved PR (one each with cholangiocarcinoma, gall bladder cancer, breast cancer, urothelial tract/bladder cancer, and sweat gland carcinoma) and 6 (20%) had SD. Median duration of response was 9.56 months (95% CI: 4.17, 14.95). CONCLUSIONS: Pemigatinib demonstrated manageable adverse events, consistent pharmacokinetics and pharmacodynamics profiles, and preliminary efficacy in Japanese patients with advanced solid tumors.

MicroRNAs associated with postoperative outcomes in patients with limited stage neuroendocrine carcinoma of the esophagus.

Esophageal neuroendocrine carcinoma (E-NEC) is an aggressive disease with a poor prognosis. The present study aimed to assess the role of surgery in the treatment of patients with resectable E-NEC, and identify a microRNA (miRNA/miR) signature in association with positive postoperative outcomes. Between February 2017 and August 2019, 36 patients with E-NEC who underwent curative surgery at the Japan Neuroendocrine Tumor Society partner hospitals were enrolled in the study. A total of 16 (44.4%) patients achieved disease-free survival (non-relapse group), whereas 20 (55.6%) patients developed tumor relapse (relapse group) during the median follow-up time of 36.5 months (range, 1-242) after surgery with a 5-year overall survival rate of 100 and 10.8%, respectively (P<0.01). No clinicopathological parameters, such as histological type or TNM staging, were associated with tumor relapse. Microarray analysis of 2,630 miRNAs in 11 patients with sufficient quality RNA revealed 12 miRNAs (miR-1260a, -1260b, -1246, -4284, -612, -1249-3p, -296-5p, -575, -6805-3p, -12136, -6822-5p and -4454) that were differentially expressed between the relapse (n=6) and non-relapse (n=5) groups. Furthermore, the top three miRNAs (miR-1246, -1260a and -1260b) were associated with overall survival (P<0.01). These results demonstrated that surgery-based multidisciplinary treatment is effective in a distinct subpopulation of limited stage E-NEC. A specific miRNA gene set is suggested to be associated with treatment outcome.

A randomised phase II study of modified FOLFIRINOX versus gemcitabine plus nab-paclitaxel for locally advanced pancreatic cancer (JCOG1407).

AIM: We compared the efficacy of modified 5-fluorouracil, leucovorin, irinotecan, and oxaliplatin (mFOLFIRINOX) with that of gemcitabine plus nab-paclitaxel (GnP) for locally advanced pancreatic cancer (LAPC). METHODS: Patients with untreated LAPC were randomly assigned (1:1) to receive mFOLFIRINOX or GnP. One-year overall survival (OS) was the primary endpoint. The major secondary end-points included progression-free survival (PFS), response rate (RR), carbohydrate antigen 19-9 (CA19-9) response, and adverse events. The sample size was 124 patients to select a more effective regimen with a minimum probability of 0.85 and to examine the null hypothesis of the 1-year OS <53%. RESULTS: Of the 126 patients enrolled from 29 institutions, 125 were deemed eligible. The 1-year OS was 77.4% (95% CI, 64.9-86.0) and 82.5% (95% CI, 70.7-89.9) in the mFOLFIRINOX and GnP arms, respectively. The median PFS was 11.2 (95% CI, 9.9-15.9) and 9.4 months (95% CI, 7.4-12.8) in the mFOLFIRINOX and GnP arms, respectively. The RR and CA19-9 response rate were 30.9% (95% CI, 19.1-44.8) and 57.1% (95% CI, 41.0-72.3) and 42.1% (95% CI 29.1-55.9) and 85.0% (95% CI, 70.2-94.3) in the mFOLFIRINOX and GnP arms, respectively. Grade 3-4 diarrhoea and anorexia were predominant in the mFOLFIRINOX arm. CONCLUSION: GnP was considered the candidate for a subsequent phase III trial because of its better RR, CA19-9 response, and mild gastrointestinal toxicities. Both regimens displayed higher efficacy in the 1-year survival than in the historical data of gemcitabine monotherapy.

Loss of adipose tissue or skeletal muscle during first-line gemcitabine/nab-paclitaxel therapy is associated with worse survival after second-line therapy of advanced pancreatic cancer.

AIM: Progression of cachexia indicated by decreased body weight and composition is associated with poor survival of advanced pancreatic cancer (APC). There are limited data concerning the prognostic effect of cachexia on second-line chemotherapy (L2). We aimed to assess the impact of cachexia progression during first-line therapy (L1) on survival after L2. METHODS: We reviewed patients with gemcitabine/nab-paclitaxel (GEM/nabPTX)-refractory APC who underwent L2 with modified FOLFIRINOX or S-1 between 2015 and 2019 in our institution. We determined clinicopathological data including body composition parameters: subcutaneous fat area (SFA), visceral fat area (VFA), and skeletal muscle index (SMI). Correlations of changes in these parameters, as well as their effect on overall survival after L2 (OS2), were examined. RESULTS: Median rates of change in SMI, SFA, and VFA were 0.19%, -4.17%, and -18.39%, respectively, in 59 patients during L1. Although there was moderate correlation in rate of change between SFA and VFA, there was no correlation between SMI and other parameters. We defined loss of SFA, VFA, and SMI as decreases greater than 8.5%, 34.1%, and 8.7%, respectively. Median OS2 of patients with loss in any of these parameters was significantly shorter than in patients without loss (3.83 vs. 8.73 months). Multivariate analysis revealed that loss in any parameters, performance status, and C-reactive protein/albumin ratio were independent negative prognostic factors. CONCLUSION: Loss of adipose tissue or skeletal muscle during L1 had a considerable impact on OS2 in APC refractory to GEM/nabPTX.