Factors Affecting Nonfunctioning Small Pancreatic Neuroendocrine Neoplasms and Proposed New Treatment Strategies.

BACKGROUND & AIMS: Despite previously reported treatment strategies for nonfunctioning small (≤20 mm) pancreatic neuroendocrine neoplasms (pNENs), uncertainties persist. We aimed to evaluate the surgically resected cases of nonfunctioning small pNENs (NF-spNENs) in a large Japanese cohort to elucidate an optimal treatment strategy for NF-spNENs. METHODS: In this Japanese multicenter study, data were retrospectively collected from patients who underwent pancreatectomy between January 1996 and December 2019, were pathologically diagnosed with pNEN, and were treated according to the World Health Organization 2019 classification. Overall, 1490 patients met the eligibility criteria, and 1014 were included in the analysis cohort. RESULTS: In the analysis cohort, 606 patients (59.8%) had NF-spNENs, with 82% classified as grade 1 (NET-G1) and 18% as grade 2 (NET-G2) or higher. The incidence of lymph node metastasis (N1) by grade was significantly higher in NET-G2 (G1: 3.1% vs G2: 15.0%). Independent factors contributing to N1 were NET-G2 or higher and tumor diameter ≥15 mm. The predictive ability of tumor size for N1 was high. Independent factors contributing to recurrence included multiple lesions, NET-G2 or higher, tumor diameter ≥15 mm, and N1. However, the independent factor contributing to survival was tumor grade (NET-G2 or higher). The appropriate timing for surgical resection of NET-G1 and NET-G2 or higher was when tumors were >20 and >10 mm, respectively. For neoplasms with unknown preoperative grades, tumor size >15 mm was considered appropriate. CONCLUSIONS: NF-spNENs are heterogeneous with varying levels of malignancy. Therefore, treatment strategies based on tumor size alone can be unreliable; personalized treatment strategies that consider tumor grading are preferable.

Efficacy of ramucirumab and subsequent nivolumab therapy in patients with advanced gastric cancer: A retrospective study.

Nivolumab monotherapy is a standard treatment of metastatic gastric cancer, and this type of cancer involves vascular endothelial growth factor (VEGF) signaling in the tumor immunological environment. The subgroup analysis of the ATTRACTION-2 trial revealed that prior treatment with ramucirumab (RAM), a VEGF inhibitor, affected the therapeutic effect of nivolumab. The present retrospective study aimed to review patients with metastatic gastric cancer who were treated with paclitaxel (PTX) and RAM followed by nivolumab. A total of 29 patients with metastatic gastric cancer were treated with PTX + RAM as second-line treatment, followed by nivolumab monotherapy as third-line treatment. The therapeutic efficacy of nivolumab was compared in 13 patients with progression-free survival (PFS) of <5 months and 16 patients with PFS ≥5 months after PTX + RAM therapy. The present study included 22 male and seven female patients, with a median age of 68 years (range, 45-82 years). Human epidermal growth factor receptor 2 positivity was observed in six patients. The disease control rate was 62.1%. The PFS and overall survival (OS) were 4.4 and 11.9 months, respectively. Patients with PFS ≥5 months after PTX + RAM therapy showed better outcome in both PFS (5.3 months vs. 2.8 months, P=0.039) and OS (6.9 months vs. 15.2 months, P=0.066) after nivolumab treatment than patients with PFS of <5 months after PTX + RAM therapy. However, no significant relationship was observed between the outcome of first-line treatment and nivolumab. The therapeutic effect of nivolumab was associated with prior PTX + RAM treatment in advanced gastric cancer.

Strangulated bowel obstruction caused by vaginal perforation due to vaginal cancer in a patient with chronic uterine prolapse.

A woman in her 90s with chronic uterine prolapse presented with abdominal pain and a vaginal mass. The patient had generalised peritonitis and a strangulated bowel obstruction originating from a perforated posterior vagina. We performed partial intestinal resection and a total hysterectomy, including excision of the perforation of the vaginal site and the adnexa. The patient died on postoperative day 8 due to worsening systemic sepsis. The pathological diagnosis revealed an invasive carcinoma in the perforated area of the vagina. Obstetric factors are the most frequent cause of female genital tract perforation, and chronic uterine prolapse is associated with this condition; however, vaginal cancer has never been reported as a cause of perforation. Therefore, close collaboration in gynaecology should be considered to investigate whether vaginal perforation and uterine prolapse are related to cancer.

A postoperative body weight increase is a novel risk factor for incisional hernia of midline abdominal incision after elective gastroenterological surgery.

PURPOSE: Midline abdominal incisions (MAIs) are widely used in both open and minimally invasive surgery. Incisional hernia (IH) accounts for most long-term postoperative wound complications. This study explored the risk factors for IH due to MAI in patients with clean-contaminated wounds after elective gastroenterological surgery. METHODS: The present study targeted patients enrolled in 2 randomized controlled trials to evaluate the efficacy of intraoperative interventions for incisional SSI prevention after gastroenterological surgery for clean-contaminated wounds. The patients were reassessed, and pre- and intraoperative variables and postoperative outcomes were collected. IH was defined as any abdominal wall gap, regardless of bulge, in the area of a postoperative scar that was perceptible or palpable on clinical examination or computed tomography according to the European Hernia Society guidelines. The risk factors for IH were identified using univariate and multivariate analyses. RESULTS: The study population included 1,281 patients, of whom 273 (21.3%) developed IH. Seventy-four (5.8%) patients developed incisional SSI. Multivariate logistic regression analysis revealed that female sex (odds ratio [OR], 1.39; 95% confidence interval [CI] 1.03-1.86, p = 0.031), high preoperative body mass index (OR, 1.81; 95% CI 1.19-2.77, p = 0.006), incisional SSI (OR, 2.29; 95% CI 1.34-3.93, p = 0.003), and postoperative body weight increase (OR, 1.49; 95% CI 1.09-2.04, p = 0.012) were independent risk factors for IH due to MAI in patients who underwent elective gastroenterological surgery. CONCLUSION: We identified postoperative body weight increase at one year as a novel risk factor for IH in patients with MAI after elective gastroenterological surgery.

Update of risk factors for surgical site infection in clean-contaminated wounds after gastroenterological surgery: An analysis of 1,878 participants enrolled in 2 recent randomized control trials for the prevention of surgical site infection.

BACKGROUND: Clean-contaminated wounds should be the main target for reducing the burden of harm caused by surgical site infection after gastroenterological surgery. METHODS: The present study targeted 1,973 patients enrolled in 2 randomized controlled trials to evaluate the efficacy of intraoperative interventions for incisional surgical site infection prevention after gastroenterological surgery with clean-contaminated wounds. Patients were reassessed, and preoperative and postoperative variables were collected. Risk factors for surgical site infection were identified by univariate and multivariate analyses. RESULTS: The study population included 1,878 patients, among whom 213 (11.3%) developed overall surgical site infection and 119 (6.3%) developed incisional surgical site infection. A multivariate analysis revealed that steroid or immunosuppressant use (odds ratio 3.03; 95% confidence interval 1.37-6.73, P = .0064), open surgery (odds ratio 1.77; 95% confidence interval 1.11-2.83, P = .0167), and long operative time (odds ratio 2.31; 95% confidence interval 1.5-3.56, P < .001) were independent risk factors for incisional surgical site infection. Steroid or immunosuppressant use (odds ratio 2.62; 95% confidence interval 1.29-5.33, P = .0078), open surgery (odds ratio 2.13; 95% confidence interval 1.44-3.16, P < .001), and long operative time (odds ratio 2.92; 95% confidence interval 2.08-4.10, P < .001) were also independent risk factors for overall surgical site infection in the multivariate analysis. Furthermore, a multivariate analysis revealed that a long operative time (odds ratio 3.21; 95% confidence interval 1.69-6.1, P = .00378) was an independent risk factor for incisional surgical site infection in patients who underwent laparoscopic surgery. CONCLUSION: Even under current measures for surgical site infection prevention, surgeons should continue to make efforts to appropriately expand the indication of laparoscopic surgery and to reduce operative times even when performing laparoscopic surgery.

A case of needle tract seeding that seemed to be caused by endoscopic ultrasound-guided fine-needle aspiration.

A 66-year-old man underwent a single endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) session and distal pancreatectomy for the pancreatic body adenocarcinoma measuring 12 mm in diameter. At 3 years after surgery, we diagnosed needle tract seeding (NTS) and performed total gastrectomy. NTS can occur with small tumors or after a single session of EUS-FNA.

Circulating tumor DNA in molecular assessment feasibly predicts early progression of pancreatic cancer that cannot be identified via initial imaging.

Molecular assessment using circulating tumor DNA (ctDNA) has not been well-defined. We recruited 61 pancreatic cancer (PC) patients who underwent initial computed tomography (CT) imaging study during first-line chemotherapy. Initial molecular assessment was performed using droplet digital PCR and defined as the change in KRAS-mutated ctDNA before and after treatments, which was classified into five categories: mNT, molecular negative; mCR, complete response; mPR, partial response; mSD, stable disease; mPD, progressive disease. Of 61 patients, 14 diagnosed with PD after initial CT imaging showed significantly worse therapeutic outcomes than 47 patients with disease control. In these 47 patients, initial molecular assessment exhibited significant differences in therapeutic outcomes between patients with and without ctDNA (mPD + mSD vs. mCR + mNT; 13.2 M vs. 21.7 M, P = 0.0029) but no difference between those with mPD and mSD + mCR + mNT, suggesting that the presence of ctDNA had more impact on the therapeutic outcomes than change in its number. Multivariate analysis revealed that it was the only independent prognostic factor (P = 0.0405). The presence of ctDNA in initial molecular assessment predicted early tumor progression and identified PC patients more likely to benefit from chemotherapy.

Aqueous Povidone-Iodine Versus Normal Saline For Intraoperative Wound Irrigation on The Incidence of Surgical Site Infection in Clean-Contaminated Wounds After Gastroenterological Surgery: A Single-Institute, Prospective, Blinded-Endpoint, Randomized Controlled Trial.

OBJECTIVE: This trial evaluated the superiority of intraoperative wound irrigation (IOWI) with aqueous povidone-iodine (PVP-I) compared with that with saline for reducing the incidence of surgical site infection (SSI). BACKGROUND: IOWI with aqueous PVP-I is recommended for the prevention of SSI by the World Health Organization and the Centers for Disease Control and Prevention, although the evidence level is low. METHODS: This single institute in Japan, prospective, randomized, blinded-endpoint trial was conducted to assess the superiority of IOWI with aqueous PVP-I in comparison with IOWI with saline for reducing the incidence of SSI in clean-contaminated wounds after gastroenterological surgery. Patients 20 years or older were assessed for eligibility, and the eligible participants were randomized at a 1:1 ratio using a computer-generated block randomization. In the study group, IOWI was performed for 1 minute with 40 mL of aqueous 10% PVP-I before skin closure. In the control group, the procedure was performed with 100 mL of saline. Participants, assessors, and analysts were masked to the treatment allocation. The primary outcome was the incidence of incisional SSI in the intention-to-treat set. RESULTS: Between June 2019 and March 2022, 941 patients were randomized to the study group (473 patients) or the control group (468 patients). The incidence of incisional SSI was 7.6% in the study group and 5.1% in the control group (risk difference 0.025, 95% CI -0.006 to 0.056; risk ratio 1.484, 95% CI 0.9 to 2.448; P =0.154). CONCLUSION: The current recommendation of IOWI with aqueous PVP-I should be reconsidered.

Implementation of intraoperative wound irrigation with aqueous 10% povidone-iodine and triclosan-coated sutures is not effective for reducing the incidence of incisional surgical site infection after major hepato-biliary-pancreatic surgery in patients with preoperative biliary drainage.

BACKGROUND/PURPOSE: Patients who receive preoperative biliary drainage (PBD) and biliary reconstruction are most at risk for incisional surgical site infection (SSI) in major hepatobiliary-pancreatic (HBP) surgery. METHODS: We evaluated 72 patients with PBD who underwent major HBP surgery and received intraoperative wound irrigation (IOWI) with saline and standard sutures between March 2014 and March 2017 (Cohort 1) and 63 patients with PBD who underwent major HBP surgery and received IOWI with aqueous 10% povidone-iodine and antibacterial sutures between June 2019 and February 2022 (Cohort 2). We compared the incidence of incisional SSI between the two cohorts. RESULTS: Twenty-seven (20.0%) of 135 patients developed incisional SSIs. The rate of current smoking was more frequent in patients who developed incisional SSIs than in those who did not (37.0% vs. 14.8%, p = .012). A total of 18 (25%) of 72 patients developed incisional SSI in Cohort 1, and nine (14.3%) of 63 developed incisional SSI in Cohort 2. Cohort 2 had a 10% lower incidence of incisional SSI than Cohort 1, a nonsignificant difference (p = .09). CONCLUSION: The implementation of IOWI with aqueous 10% PVP-I and antibacterial sutures failed to significantly reduce the incidence of incisional SSI in comparison to IOWI with saline and standard sutures in major HBP surgery.

A nationwide certification system to increase the safety of highly advanced hepatobiliary-pancreatic surgery.

BACKGROUND: To ensure that highly advanced hepatobiliary-pancreatic surgery (HBPS) is performed safely, the Japanese Society of Hepato-Biliary-Pancreatic Surgery (JSHBPS) board certification system for expert surgeons established a safety committee to monitor surgical safety. METHODS: We investigated postoperative mortality rates based on summary reports of numbers and outcomes of highly advanced HBPS submitted annually by the board-certified training institutions from 2012 to 2019. We also analyzed summary reports on mortality cases submitted by institutions with high 90-day post-HBPS mortality rates and recommended site visits and surveys as necessary. RESULTS: Highly advanced HBPS was performed in 121 518 patients during the 8-year period. Thirty-day mortality rates from 2012 to 2019 were 0.92%, 0.8%, 0.61%, 0.63%, 0.70%, 0.59%, 0.48%, and 0.52%, respectively (P < .001). Ninety-day mortality rates were 2.1%, 1.82%, 1.62%, 1.28%, 1.46%, 1.22%, 1.19%, and 0.98%, respectively (P < .001). Summary reports were submitted by 20 hospitals between 2015 and 2019. Mortality rates before and after the start of report submission and audit were 5.72% and 2.79%, respectively (odds ratio 0.690, 95% confidence interval 0.487-0.977; P = .037). CONCLUSIONS: Development of a system for designation of board-certified expert surgeons and safety management improved the mortality rate associated with highly advanced HBPS.

Liquid biopsy leads to a paradigm shift in the treatment of pancreatic cancer.

Pancreatic ductal adenocarcinoma (PDAC) is one of the most cancers. Its 5-year survival rate is very low. The recent induction of neoadjuvant chemotherapy and improvements in chemotherapy for patients with pancreatic cancer have resulted in improved survival outcomes. However, the prognosis of pancreatic cancer is still poor. To dramatically improve the prognosis, we need to develop more tools for early diagnosis, treatment selection, disease monitoring, and response rate evaluation. Recently, liquid biopsy (circulating free DNA, circulating tumor DNA, circulating tumor cells, exosomes, and microRNAs) has caught the attention of many researchers as a new biomarker that is minimally invasive, confers low-risk, and displays an overall state of the tumor. Thus, liquid biopsy does not employ the traditional difficulties of obtaining tumor samples from patients with advanced PDAC to investigate their molecular biological status. In addition, it allows for long-term monitoring of the molecular profile of tumor progression. These could help in identifying tumor-specific alterations that use the target structure for tailor-made therapy. Through this review, we highlighted the latest discoveries and advances in liquid biopsy technology in pancreatic cancer research and showed how it can be applied in clinical practice.

Enhancement of DNA hypomethylation alterations by gastric and bile acids promotes chromosomal instability in Barrett's epithelial cell line.

Gastric and bile acid reflux leads to chronic inflammation, resulting in methylation alterations in Barrett's esophagus (BE) together with chromosomal instability (CIN). We investigated DNA hypomethylation following acid exposure and confirmed its significance in BE-related carcinogenesis by inducing CIN in vitro. OACP4C, an esophageal cancer cell line, and CP-A, a non-dysplastic cell line originating from BE, were exposed to acidic conditions using deoxycholic acid. CP-A exhibited substantially increased DNA hypomethylation of alpha satellite sequences in the centromere region, as well as increased levels of alpha satellite transcripts, but no changes were observed in the long interspersed nucleotide element-1 sequences distributed throughout the entire genome. These changes were not clearly found in OACP4C. Copy number changes at specific chromosomes were identified in CP-A, along with an increased number of cells exhibiting abnormal segregations, whereas these changes were rarely observed in OACP4C. The changes were maintained after several cell divisions. These findings suggest that alpha satellites are likely targets of DNA hypomethylation induced by acid exposure. CP-A was more sensitive to acid exposure than OACP4C, indicating that acid-induced DNA hypomethylation is involved in cancer development rather than progression, which could be involved in the underlying mechanism of esophagogastric junction carcinoma development.

Mid-term Efficacy of Local Repair Using Modified Altemeier Technique for Stomal Prolapse: A Case Series.

INTRODUCTION:  Stomal prolapse (SP) is characterized by full-thickness protrusion of the bowel through the stoma site. The surgical procedures for SP include local repair, abdominal wall fixation, and stoma relocation. However, previous reports were mostly case reports or case series with a small number of patients and lacked long-term results. A modified Altemeier technique (MAT) has been used for the local repair of SP in our institution, and this study aimed to evaluate its mid-term efficacy. METHODS:  We reviewed patients who underwent MAT for SP between August 2013 and December 2020. The variables included patient characteristics, type of stoma, indications of stoma creation, the time interval from stoma creation to prolapse, site of prolapse, reasons for SP surgery, perioperative variables, complications during SP surgery, and length of follow-up. Recurrence of SP was defined as the need for change in stoma care or re-protrusion of the stoma by more than 5 cm in length. RESULTS:  Ten patients were included in this study. The median age at the time of SP surgery was 71.5 years. The indications of stoma creation included unresectable or recurrent intra-abdominal malignancies in four patients, diverting ileostomy with rectal cancer surgery in two, transverse colon cancer in one, gastric and rectal cancer in one, rectovaginal fistula in one, and non-occlusive mesenteric ischemia in one. The median interval from stoma creation to prolapse was 2.5 months. Six patients underwent elective SP surgery, and four patients underwent emergency surgery for incarcerated prolapse. The median operative time was 75.5 min. Postoperative complications that included transient mucosal ischemia and subcutaneous abscess occurred in one patient. There were four recurrences (40%), and the median time interval from surgery to recurrence was 4.5 months. Two patients underwent repeated MAT, one of whom underwent stomal reversal with laparotomy for re-recurrence. The median follow-up duration was 19 months. CONCLUSION:  MAT for SP is associated with a high recurrence rate in mid-term follow-up.

Indications and Outcomes of a Hybrid Method Combining Laparoscopic and Anterior Approaches for Inguinal Hernia Repair.

Introduction Surgery for complex inguinal hernia (IH) (recurrent IH or IH after radical prostatectomy (RP)) may be difficult because of the presumed scar or adhesion in the retropubic space. A hybrid method combining the laparoscopic and anterior approaches (HLAA) in a bidirectional surgical technique may be an option in complex IH cases. Methods Patients at our institution who underwent IH repair for complex IH using HLAA from April 2018 to November 2019 were included. We retrospectively evaluated the patient characteristics, IH diagnosis, intraoperative variables, complications, and hernia recurrence during the follow-up period. Results Twenty patients were involved in this study. Seven patients underwent hLAA for recurrent IH, whereas the remaining 13 underwent hLAA for IH after RP. Five patients had bilateral IH, all of whom had IH after RP. The type of IH was lateral in 21 patients, medial in six patients, and lateral and medial in two patients. Hernia repair was performed using a patch alone in two patients and a plug and patch in 18 patients. Seroma or hematoma was observed in five patients, and one patient experienced chronic pain. No hernia recurrence was observed during the median follow-up period of 24 months. Conclusion hLAA could facilitate precise diagnosis and intraoperative confirmation of repair for recurrent IH and IH after RP. The intraoperative findings and the cause of recurrence can be easily shared among surgeons in hLAA. Further investigations are necessary to determine the long-term efficacy of hLAA in a larger cohort.

Minimally invasive esophagectomy in the semi-prone position for corrosive esophagitis: a case report.

Treatment strategies for corrosive esophagitis include conservative treatment, such as balloon dilatation at the stenosis site, and surgical treatment. Esophagectomy for corrosive esophagitis is usually performed through the transthoracic or transhiatal approaches. Herein, we report a case of corrosive esophagitis treated with thoracoscopic esophagectomy with the patient in the semi-prone position. The patient was a 48-year-old woman who developed corrosive esophagitis due to accidental ingestion of an alkaline agent. Surgical intervention was required for esophageal stenosis. Therefore, thoracoscopic esophagectomy was performed with the patient in the semi-prone position with bilateral pulmonary ventilation. In our hospital, good operative outcomes have been obtained using thoracoscopic esophagectomy for esophageal cancer with the patient in the semi-prone position with bilateral pulmonary ventilation. This technique is also considered effective for the treatment of corrosive esophagitis.

Modified keyhole plus technique with partial release of posterior rectus sheath for parastomal hernia repair after ileal conduit.

Parastomal hernia (PH) is a common complication of ileal conduit diversions. The Sugarbaker technique has a lower recurrence rate than the keyhole (KH) technique and is typically preferred. However, it may not be feasible in some cases because of anatomical features including the length of the conduit and torsion of the ureter. An 80-year-old woman with complaints of abdominal distention was diagnosed with PH 5 years after radical cystectomy. Computed tomography revealed a 90 × 20-mm muscular layer defect on the cranial side of the ileal conduit. Therefore, we performed the KH technique with intracorporeal closure of the defect using a relief incision of the posterior rectus sheath, avoiding the possibility of torsion of the ureteral ileal anastomosis. No hernia recurrence was observed at postoperative 10 months. The proposed KH plus technique may be an effective method for PH after ileal conduit diversion, thus preventing urinary complications.

IκBζ regulates the development of nonalcoholic fatty liver disease through the attenuation of hepatic steatosis in mice.

IκBζ is a transcriptional regulator that augments inflammatory responses from the Toll-like receptor or interleukin signaling. These innate immune responses contribute to the progression of nonalcoholic fatty liver disease (NAFLD); however, the role of IκBζ in the pathogenesis of NAFLD remains elusive. We investigated whether IκBζ was involved in the progression of NAFLD in mice. We generated hepatocyte-specific IκBζ-deficient mice (Alb-Cre; Nfkbizfl/fl) by crossing Nfkbizfl/fl mice with Alb-Cre transgenic mice. NAFLD was induced by feeding the mice a choline-deficient, L-amino acid-defined, high-fat diet (CDAHFD). CDAHFD-induced IκBζ expression in the liver was observed in Nfkbizfl/fl mice, but not in Alb-Cre; Nfkbizfl/fl mice. Contrary to our initial expectation, IκBζ deletion in hepatocytes accelerated the progression of NAFLD after CDAHFD treatment. Although the increased expression of inflammatory cytokines and apoptosis-related proteins by CDAHFD remained unchanged between Nfkbizfl/fl and Alb-Cre; Nfkbizfl/fl mice, early-stage steatosis of the liver was significantly augmented in Alb-Cre; Nfkbizfl/fl mice. Overexpression of IκBζ in hepatocytes via the adeno-associated virus vector attenuated liver steatosis caused by the CDAHFD in wild-type C57BL/6 mice. This preventive effect of IκBζ overexpression on steatosis was not observed without transcriptional activity. Microarray analysis revealed a correlation between IκBζ expression and the changes of factors related to triglyceride biosynthesis and lipoprotein uptake. Our data suggest that hepatic IκBζ attenuates the progression of NAFLD possibly through the regulation of the factors related to triglyceride metabolism.

Risk factors associated with hypoglycemic events after total pancreatectomy: A nationwide multicenter prospective study in Japan.

BACKGROUND: The number of total pancreatectomy cases have increased worldwide, expanding the need for new insulin products and high-titer pancrelipases. However, the current data that is focused on hypoglycemic events after a total pancreatectomy from large nationwide series are still lacking. This study is aimed to assess the risk factors associated with hypoglycemic events after a total pancreatectomy. METHODS: Data were prospectively collected from 216 consecutive patients who underwent total pancreatectomies between August 2015 and December 2017 from 68 Japanese centers. Of the 216 patients, 166 with a follow-up period of 1 year were analyzed. The risk factors for hypoglycemic events at 6 and 12 months (postoperative months 6 and 12) were investigated based on the results of a nationwide multicenter prospective study. RESULTS: Of the 166 patients, 57 (34%) and 70 (42%) experienced moderate or severe hypoglycemic events or hypoglycemia unawareness on a monthly basis at postoperative months 6 and 12, respectively. Multivariate analysis revealed that body weight loss after surgery ≥0.3 kg and total cholesterol level ≤136 mg/dL at postoperative month 6, and glycated hemoglobin level ≤8.9% and rapid-acting insulin use at postoperative month 12 were independent risk factors for hypoglycemic events after a total pancreatectomy. There were different independent risk factors depending on the postoperative period. CONCLUSION: Patients with body weight loss after surgery, low total cholesterol level, strict glycemic control, and using rapid-acting insulin should be aware of the occurrence of hypoglycemic events after their total pancreatectomy. In order to prevent hypoglycemic events after a total pancreatectomy, we need to consider optimal nutritional and glycemic control according to the postoperative period.

Overexpression of satellite RNAs in heterochromatin induces chromosomal instability and reflects drug sensitivity in mouse cancer cells.

Overexpression of satellite RNAs in heterochromatin induces chromosomal instability (CIN) through the DNA damage response and cell cycle checkpoint activation. Although satellite RNAs may be therapeutic targets, the associated mechanisms underlying drug sensitivity are unknown. Here, we determined whether satellite RNAs reflect drug sensitivity to the topoisomerase I inhibitor camptothecin (CPT) via CIN induction. We constructed retroviral vectors expressing major satellite and control viruses, infected microsatellite stable mouse colon cancer cells (CT26) and MC38 cells harboring microsatellite instability, and assessed drug sensitivity after 48 h. Cells overexpressing satellite RNAs showed clear features of abnormal segregation, including micronuclei and anaphase bridging, and elevated levels of the DNA damage marker γH2AX relative to controls. Additionally, overexpression of satellite RNAs enhanced MC38 cell susceptibility to CPT [half-maximal inhibitory concentration: 0.814 µM (control) vs. 0.332 µM (MC38 cells with a major satellite), p = 0.003] but not that of CT26. These findings imply that MC38 cells, which are unlikely to harbor CIN, are more susceptible to CIN-induced CPT sensitivity than CT26 cells, which are characterized by CIN. Furthermore, CPT administration upregulated p53 levels but not those of p21, indicating that overexpression of major satellite transcripts likely induces CPT-responsive cell death rather than cellular senescence.

Prophylactic use of pegfilgrastim enables the management of severe neutropenia without dose delays in patients with metastatic colorectal cancer treated with TAS-102 plus bevacizumab.

Combined treatment with bevacizumab and trifluridine/tipiracil (TAS-102) leads to an increased chance of survival in patients with refractory metastatic colorectal cancer (mCRC); however, this treatment is associated with an increased frequency of severe neutropenia (number of neutrophils <1,000), which should ideally be managed without dose delays. The present study provided a retrospective review of 35 patients with mCRC, and aimed to elucidate the benefits of prophylactic pegfilgrastim for the treatment of severe neutropenia. Patients received TAS-102 (35 mg/m2) orally twice daily on days 1-5 and 8-12 of each 28-day treatment cycle, along with intravenous bevacizumab (5 mg/kg) on days 1 and 15. Moreover, the patients received 3.6 mg pegfilgrastim on day 15 of each cycle. The incidence of adverse events (AEs), disease control rate (DCR), progression-free survival (PFS) and overall survival (OS) were assessed. In the first and subsequent cycles, 23 and 12 patients, respectively, received pegfilgrastim. The most common AE experienced was grade 3/4 neutropenia (8 patients; 22.9%). Among these 8 patients, 6 (17.1%) and 3 (8.6%) exhibited neutropenia prior to receiving pegfilgrastim or following discontinuation of pegfilgrastim administration, respectively. Moreover, 1 individual among these 8 patients (2.9%) demonstrated grade 3 neutropenia both prior to receiving pegfilgrastim and following discontinuation of pegfilgrastim. A total of 2 patients (5.7%) exhibited grade 3 bone pain, which prevented sustainable administration of pegfilgrastim and resulted in grade 3 neutropenia. Dose delays and dose reduction of TAS-102 due to neutropenia were required in 5 (14.3%) and 2 (5.7%) patients, respectively, during the treatment period. None of the patients exhibited severe neutropenia during chemotherapy after pegfilgrastim administration, thereby preventing dose delays and dose reduction of TAS-102. The relative dose intensity was 96.8% (65.0-100.0%), and the DCR was 54.3%. The median PFS and median OS were 4.4 and 14.9 months, respectively. In conclusion, prophylactic pegfilgrastim may facilitate the management of severe neutropenia without dose delays in patients with mCRC treated with TAS-102 plus bevacizumab.