A multicenter retrospective observational NAPOLEON2 study of nanoliposomal irinotecan with fluorouracil and folinic acid in patients with unresectable pancreatic cancer.

Nanoliposomal irinotecan with fluorouracil and folinic acid (NFF) is a standard regimen after gemcitabine-based therapy for patients with unresectable or recurrent pancreatic cancer. However, there are limited clinical data on its efficacy and safety in the real-world. We therefore initiated a retrospective and prospective observational study (NAPOLEON-2). The results of the retrospective part were reported herein. In this retrospective study, we evaluated 161 consecutive patients who received NFF as second-or-later-line regimen. The main endpoint was overall survival (OS), and the other endpoints were response rate, disease control rate, progression-free survival (PFS), dose intensity, and adverse events (AEs). The median age was 67 years (range, 38-85 years). The median OS and PFS were 8.1 and 3.4 months, respectively. The objective response and disease control rates were 5% and 52%, respectively. The median relative dose intensity was 81.6% for nanoliposomal irinotecan and 82.9% for fluorouracil. Grade 3 or 4 hematological and nonhematological AEs occurred in 47 and 42 patients, respectively. Common grade 3 or 4 AEs included neutropenia (24%), anorexia (12%), and leukocytopenia (12%). Subanalysis of patients treated with second-line and third-or-later-line demonstrated no statistical significant difference in OS (7.6 months vs. 9.1 months, respectively; hazard ratio, 0.92; 95% confidence interval, 0.64-1.35; p = 0.68). In conclusion, NFF has acceptable efficacy and safety profile even in real-world clinical settings. The prospective study is in progress to validate these findings.

Next-Generation Sequencing Analysis of Pancreatic Cancer Using Residual Liquid Cytology Specimens from Endoscopic Ultrasound-Guided Fine-Needle Biopsy: A Prospective Comparative Study with Tissue Specimens.

This study evaluated the feasibility and clinical utility of liquid-based cytology (LBC) specimens via endoscopic ultrasound-guided fine-needle biopsy (EUS-FNB) for next-generation sequencing (NGS) of pancreatic cancer (PC). We prospectively evaluated the performance of DNA extraction and NGS using EUS-FNB samples obtained from PC. Thirty-three consecutive patients with PC who underwent EUS-FNB at our hospital were enrolled. DNA samples were obtained from 96.8% of the patients. When stratified with a variant allele frequency (VAF) > 10% tumor burden, the NGS success rate was 76.7% (n = 23) in formalin-fixed paraffin-embedded (FFPE), 83.3% (n = 25) in LBC, and 76.7% (n = 23) in frozen samples. The overall NGS success rate was 86.7% (n = 26) using FFPE, LBC, or frozen samples. The detection rates for the main mutated genes were as follows: 86.7% for KRAS, 73.3% for TP53, 66.7% for CDKN2A, 36.7% for SMAD4, and 16.7% for ARID1A. LBC had the highest median value of VAF (23.5%) for KRAS and TP53. PC mutation analysis using NGS was successfully performed using LBC compared with FFPE and frozen samples. This approach provides an alternative and affordable source of molecular testing materials.

Multicenter Retrospective Analysis of Original versus Modified FOLFIRINOX in Metastatic Pancreatic Cancer: Results of the NAPOLEON Study.

INTRODUCTION: Original FOLFIRINOX (oFFX) is more toxic than other regimens for patients with metastatic pancreatic cancer (mPC); therefore, a modified FFX (mFFX) regimen with a reduced dosage has been used in Japanese clinical practice. However, very few studies have compared these two regimens. METHODS: This study was conducted as part of a multicenter retrospective study of 318 patients with mPC across 14 centers in Japan (NAPOLEON study). To control for potential bias and confounders, we conducted a propensity score-adjusted analysis of patient characteristics and clinical outcomes. RESULTS: oFFX and mFFX were administered to 48 and 54 patients. More patients with younger age and poorer performance status were included in the oFFX group. The overall survival (OS; median, 11.6 vs. 11.3 months; hazard ratio [HR], 0.91; 95% confidence interval [CI], 0.60-1.40; p = 0.67), progression-free survival (PFS) (median, 6.3 vs. 5.7 months; HR, 0.85; 95% CI, 0.56-1.28; p = 0.44), and overall response rate (29 vs. 26%, p = 0.71) were not significantly different for the oFFX and mFFX groups. Thrombopenia and liver dysfunction were significantly more frequent with oFFX than with mFFX. The median received dose intensity of CPT-11 was higher with oFFX than with mFFX (299 vs. 270 mg/m2/week, p < 0.01). The propensity score-adjusted analysis revealed no statistically significant differences in OS and PFS between the two groups. CONCLUSION: In our data, there was no significant difference in efficacy between mFFX and oFFX, and mFFX has fewer adverse events.

Effects of immune checkpoint inhibitor therapy resumption in patients with malignant tumors after moderate-to-severe immune-related adverse events.

BACKGROUND AND AIMS: Immune checkpoint inhibitors (ICIs) are used to treat several cancers, but they sometimes induce immune-related adverse events (irAEs). Patients with irAEs often have improved antitumor responses, but discontinuation of ICIs after irAEs is considered necessary. Resuming the use of ICIs after irAEs is preferable, but few studies have investigated the safety of ICI resumption after irAEs. Therefore, we evaluated the factors associated with the recurrence of irAEs after ICI resumption to investigate the safety of this approach. METHODS: In this observational study, we enrolled patients treated with ICIs from September 2014 to March 2020 at our institution. Patient characteristics, ICIs, grades of irAEs, ICI discontinuation or resumption rates, and recurrence rates of irAEs after ICI therapy were analysed. RESULTS: Two-hundred eighty-seven patients were included in the present study, and 76 patients experienced grade 2 or higher irAEs. Forty-two patients underwent ICI resumption after recovering from irAEs, and 13 of them had a recurrence of irAEs. Among those 13 patients, six had a recurrence of the same irAE, and seven experienced other irAEs. Ten of the 13 patients had grade ≥2 irAEs, and none had fatal irAEs. In the grade 2 or higher irAE group, more patients had irAEs associated with multiple organs and of initial grade ≥2 than those in the grade 1 and no recurrent irAEs group. CONCLUSIONS: Patients with initial multisystemic irAEs and irAEs of grade ≥2 were more likely to experience relapse or develop new grade ≥2 irAEs after ICI resumption.

Gemcitabine Plus Nab-Paclitaxel Versus FOLFIRINOX in Locally Advanced, Unresectable Pancreatic Cancer: A Multicenter Observational Study (NAPOLEON Study).

OBJECTIVES: FOLFIRINOX (FFX, a combination of oxaliplatin, irinotecan, fluorouracil, and leucovorin) and gemcitabine plus nab-paclitaxel (GnP) have been used as standard, first-line treatments for advanced pancreatic cancer. However, no study has compared the efficacy of the 2 regimens. This study retrospectively compared the efficacy and safety of the 2 regimens in patients with locally advanced pancreatic cancer. METHODS: We reviewed the records of patients with locally advanced pancreatic cancer who started FFX or GnP as first-line chemotherapy as part of a multicenter retrospective study in patients with unresectable pancreatic cancer treated with FFX or GnP (NAPOLEON study). RESULTS: Sixteen of the 63 patients were treated with FFX, and the other 47 patients were treated with GnP between December 2013 and March 2017. There were no significant differences in median overall survival rate between the GnP (15.5 months) and FFX (14.3 months, P = 0.60) groups or median progression-free survival rate between the GnP (8.8 months) and FFX (8.1 months, P = 0.51) groups. Both treatments were generally well tolerated, although anorexia was more severe in the FFX group than in the GnP group. CONCLUSIONS: The effects of FFX and GnP were similar but resulted in different toxicities, which could guide agent choice.

A case of immunoglobulin G4-related sclerosing mesenteritis without other organ involvement.

A 64-year-old man presented to our hospital with abdominal pain and 4-5 episodes of watery diarrhea per day for 2 months. Abdominal ultrasound examination revealed a mass in the peritoneal cavity, and computed tomography showed a 13.4 cm mass in the mesentery and a 3 cm mass in the mesocolon. The patient underwent laparoscopic partial resection for diagnosis. Microscopically, abundant fibrosis and numerous immunoglobulin (Ig) G4-positive plasma cells were observed. The serum level of IgG4 was 665 mg/dl postoperatively. These findings suggested that the lesion was consistent with IgG4-related sclerosing mesenteritis. Oral steroids resulted in rapid disappearance of symptoms and a decrease in masses. Recently, sclerosing mesenteritis are reported as IgG4-related disease or mimicking IgG4-related disease but multiple lesions rarely occur in the same organ. We report a case of IgG4-related sclerosing mesenteritis with multiple lesions without involvement of other organs, such as the pancreas and salivary glands.

Analysis of factors affecting progression-free survival of first-line chemotherapy in older patients with advanced gastrointestinal cancer.

OBJECTIVES: Few studies have investigated factors influencing the efficacy of chemotherapy in older patients with cancer. This study aimed to evaluate the usefulness of G8, geriatric assessment (GA), and factors measured in general clinical practice for evaluating progression-free survival (PFS) of first-line palliative chemotherapy in older patients with advanced gastrointestinal cancer. MATERIALS AND METHODS: This was a prospective observational study of older patients (age ≥70 years) with advanced gastrointestinal cancer. The modified cut-off value of G8 was determined by referring to two or more abnormal GA conditions. The usefulness of baseline GA and G8 (conventional and modified cut-off value) was assessed according to the efficacy (PFS and disease control rate) of the administered first-line palliative chemotherapy. RESULTS: Overall, 93 patients were evaluated between March 2017 and February 2019. A modified G8 cut-off value of ≤12 had a sensitivity and specificity of 68.9% and 46.9%, respectively. PFS was significantly prolonged in the patients with G8 > 12, serum albumin ≥3.5 g/dl, and in whom grade ≥3 adverse events occurred. There was no significant difference in the PFS between monotherapy and combination therapy. GA was not useful for predicting PFS prolongation or the occurrence of serious adverse events in first-line treatment. CONCLUSION: Among older patients with advanced gastrointestinal cancer who receive first-line chemotherapy, a modified G8 cut-off value of 12 points, occurrence of grade 3 or higher adverse events, albumin levels, rather than age or performance status were predictors of PFS prolongation.

Prognostic significance of extracellular volume fraction with equilibrium contrast-enhanced computed tomography for pancreatic neuroendocrine neoplasms.

BACKGROUND: /Objectives: Identifying reliable pretreatment imaging biomarkers for pancreatic neuroendocrine neoplasm (PanNEN) is a key imperative. Extracellular volume (ECV) fraction quantified with equilibrium contrast-enhanced CT can be easily integrated into routine examinations. This study aimed to determine whether ECV fraction with equilibrium contrast-enhanced computed tomography (CECT) could predict long-term outcomes in patients with PanNEN. METHODS: This study was a retrospective observational study of 80 patients pathologically diagnosed with PanNEN at a single institution. ECV fraction of the primary lesion was calculated using region-of-interest measurement within PanNEN and the aorta on unenhanced and equilibrium CECT. The impact of clinical factors and tumor ECV fraction on progression-free survival (PFS) and overall survival (OS) was assessed with univariate and multivariate analyses using Cox proportional hazards models. The correlation between WHO classification and tumor ECV fraction was evaluated using Kendall rank correlation coefficients. RESULTS: PFS and OS rates were estimated as 93.4% and 94.6%, 78.7% and 86.2%, 78.7% and 77.0%, and 78.7% and 66.6% at 1, 3, 5, and 10 years, respectively. Multivariate analysis revealed that Union for International Cancer Control (UICC) stage (hazard ratio [HR] = 3.95, P = 0.003), WHO classification (HR = 12.27, P = 0.003), and tumor ECV fraction (HR = 11.93, P = 0.039) were independent predictors of PFS. Patient age (HR = 1.11, P < 0.001), UICC stage (HR = 3.14, P = 0.001), and tumor ECV fraction (HR = 5.27, P = 0.024) were independent significant variables for predicting OS. Tumor ECV fraction had a weak inverse relationship with WHO classification (P = 0.045, τ = -0.178). CONCLUSIONS: ECV fraction determined by equilibrium CECT and UICC stage may predict survival in patients with PanNEN.

[Factors associated with unemployment or job change due to the treatment of designated intractable diseases].

OBJECTIVES: Unemployment or job change due to treatment for a disease is affected by various factors such as disease type, degree of disability, and workplace patient support. This study aimed to clarify the factors affecting the unemployment/job-change rate among workers who had designated intractable diseases. METHODS: A questionnaire survey was administered to 3,210 designated patients with intractable diseases who underwent applications for renewal of medical care subsidies at the Hirakata City Public Health Center during fiscal year 2019 (July-December). Of these patients, 539 workers aged 20-59 years who were employed as regular workers, temporary contract worker/dispatched workers, and part-time workers when they became designated intractable diseases were subjects of the analysis. Unemployment/job-change due to the treatment for a designated intractable disease was treated as an event occurrence, while the absence of unemployment/job-change due to disease at the time of the survey were considered censored cases. The Kaplan-Meier method was used to determine the trend of the unemployment/job-change rate associated with the duration of work. The Cox proportional hazard model was used to examine the relationship between unemployment/job-change and factors such as gender, age at onset, disease groups, activities of daily living, types of employment, experienced workplace supports (e.g., reduced working hours and hourly paid leave), and existence of insoluble medical difficulties at the workplace. RESULTS: The unemployment/job-change rate due to treatment for designated intractable disease was 19.4%. Significantly independent factors of unemployment/job-change were the following: 50s at onset (compared to those in their 30s, HR = 2.55, 95% CI (1.21-5.37)), requiring outing assistance (compared to going out alone, 2.31 (1.13-4.71)), being a temporary contract worker/dispatched worker (compared to a regular worker, 2.66 (1.20-5.89)), existence of insoluble medical difficulties at workplace (4.15 (2.43-7.09)). Experienced workplace support was not a significant factor in preventing unemployment/job-change. CONCLUSIONS: Age at onset, degree of disability, form of employment, and existence of insoluble medical difficulties at the workplace were significantly associated with unemployment/job change due to treatment for designated intractable diseases. The relationship between workplace patient supports and unemployment/job-change was not clear, but to reduce medical difficulties in the workplace, workplace supports must be expanded. Given that workplace support is not an obligatory effort for employers, it is necessary to establish a system where employers can easily promote workplace support.

A case of gallbladder neuroendocrine carcinoma diagnosed preoperatively using somatostatin receptor scintigraphy.

Gallbladder neuroendocrine carcinoma (NEC) is a rare gallbladder tumor. The current report is a case of a patient preoperatively diagnosed with gallbladder NEC using somatostatin receptor scintigraphy (SRS). A 63-year-old man was admitted to our hospital by a family doctor after abdominal ultrasonography revealed thickened walls of the neck of his gallbladder. At Kagoshima University Hospital, CT and MRI of the abdomen and endoscopic ultrasonography confirmed the thickening of the walls of the neck of the gallbladder. However, it did not resemble a typical gallbladder cancer or tumor, such as a neuroendocrine tumor or malignant lymphoma. Positron emission tomography and SRS showed abnormal accumulation at the tumor site. Endoscopic retrograde cholangiopancreatography was performed, adenocarcinoma was suspected based on intra-gallbladder bile cytology, and a cholecystectomy with lymphadenectomy was performed. The postoperative pathological diagnosis was small cell NEC (pT3a, N0, M0, stage II). Immunohistochemistry indicated that the gallbladder tumor cells were positive for synaptophysin, chromogranin A, and cluster of differentiation (CD) 56, and negative for somatostatin receptors (SSTR) 2 and 5. Gene expression assays revealed the expression of all SSTR subtypes (SSTR1-5) in the tumor. Generally, NECs exhibit poor accumulation in SRS, however, the results of the current case suggest that SRS may be useful in the preoperative diagnosis of NEC.