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Abstract Background Poor patient accrual can delay reporting of clinical trials and, consequently, the development of new treatments. For reducing the risk of additional resource requirements, a method for setting planned accrual periods with minimal deviation from the actual accrual periods is desirable. Risk factors for poor patient accrual and the appropriate method of estimating the required accrual period for timely completion of clinical trials were evaluated using the data of trials conducted by the Japan Clinical Oncology Group. Methods The study included 199 trials that started patient accrual between January 1, 1990, and June 30, 2021. The explanatory variables included factors that could be evaluated prior to trial commencement. We also evaluated whether the estimation methods for accrual pace could lead to completion within the planned accrual period. Results Approximately 23.6% of trials were completed within the planned accrual period. The risk factors for trial extension included planned accrual periods > 3 years (reference group: ≤ 3 years, odds ratio [OR] 0.37, 95% confidence interval [CI]: 0.15–0.92, P = 0.033) and stratified trial design (reference group: nonrandomized phase II trials, nonrandomized phase III trial [OR: 3.28, 95% CI: 0.99–10.9, P = 0.051], randomized phase II trial [OR: 3.91, 95% CI: 0.75–20.30, P = 0.105], and randomized phase III trial [OR: 9.29, 95% CI: 3.39–25.40, P

Abstract Background The da Vinci™ Surgical System, recognized as the leading surgical robotic platform globally, now faces competition from a growing number of new robotic surgical systems. With the expiration of key patents, innovative entrants have emerged, each offering unique features to address limitations and challenges in minimally invasive surgery. The hinotori™ Surgical Robot System (hinotori), developed in Japan and approved for clinical use in November 2022, represents one such entrant. This study demonstrates initial insights into the application of the hinotori in robot-assisted surgeries for patients with rectal neoplasms. Methods The present study, conducted at a single institution, retrospectively reviewed 28 patients with rectal neoplasms treated with the hinotori from November 2022 to March 2024. The surgical technique involved placing five ports, including one for an assistant, and performing either total or tumor-specific mesorectal excision using the double bipolar method (DBM). The DBM uses two bipolar instruments depending on the situation, typically Maryland bipolar forceps on the right and Fenestrated bipolar forceps on the left, to allow precise dissection, hemostasis, and lymph node dissection. Results The study group comprised 28 patients, half of whom were male. The median age was 62 years and the body mass index stood at 22.1 kg/m2. Distribution of clinical stages included eight at stage I, five at stage II, twelve at stage III, and three at stage IV. The majority, 26 patients (92.9%), underwent anterior resection using a double stapling technique. There were no intraoperative complications or conversions to other surgical approaches. The median operative time and cockpit time were 257 and 148 min, respectively. Blood loss was 15 mL. Postoperative complications were infrequent, with only one patient experiencing transient ileus. A median of 18 lymph nodes was retrieved, and no positive surgical margins were identified. Conclusions The introduction of the hinotori for rectal neoplasms appears to be safe and feasible, particularly when performed by experienced robotic surgeons. The double bipolar method enabled precise dissection and hemostasis, contributing to minimal blood loss and effective lymph node dissection.

Abstract Palbociclib combined with endocrine therapy is approved for treating patients with hormone-receptor-positive/human epidermal growth factor receptor 2-negative (HR+/HER2−) advanced breast cancer; however, data on palbociclib combined with tamoxifen are limited. We investigated the efficacy and safety of palbociclib–tamoxifen in patients with HR+/HER2− advanced breast cancer. This double-blind phase 3 study included 184 women who were randomly assigned 1:1 to receive palbociclib–tamoxifen or placebo–tamoxifen. Pre/perimenopausal women also received goserelin. The primary endpoint was investigator-assessed progression-free survival (PFS). Secondary endpoints included overall survival (OS) and safety. Median PFS was 24.4 months (95% confidence interval [CI], 13.1–32.4) with palbociclib–tamoxifen and 11.1 months (95% CI, 7.4–14.6) with placebo–tamoxifen (hazard ratio [HR], 0.60; 95% CI, 0.43–0.85; P = 0.002). Palbociclib–tamoxifen improved PFS in patients who were treated with first-line or second-line endocrine therapy and pre-, peri-, and postmenopausal patients. Though OS data are still immature (median not reached in both groups), an overall risk reduction of 27% (HR, 0.73; 95% CI, 0.44–1.21) with palbociclib–tamoxifen was observed at the time of PFS analysis. The most common grade 3/4 adverse event with palbociclib–tamoxifen was neutropenia (89.0% [none were febrile] versus 1.1% with placebo–tamoxifen). There were no deaths owing to adverse events in either group. Among patients with HR+/HER2− advanced breast cancer, palbociclib–tamoxifen resulted in significantly longer PFS than tamoxifen alone. Early OS data showed a trend favoring palbociclib–tamoxifen. Trial registration: ClinicalTrials.gov number, NCT03423199. Study registration date: February 06, 2018.

Background: Biomarkers to predict the recurrence risk are required to optimize perioperative treatment. Adjuvant chemotherapy for patients with human epidermal growth factor 2-positive (HER2-positive) early breast cancer is decided by pathological responses of neoadjuvant chemotherapy (NAC). However, whether pathological responses are appropriate biomarkers is unclear. Currently, there are several studies using minimal residual disease (MRD) as a predictor of prognosis in solid tumors. However, there is no standard method for detecting MRD. Objectives: This study aimed at prospectively evaluating the relationship between MRD detection and recurrence in Asian patients with HER2-positive early breast cancer. Design: Prospective, observational, single-group, and exploratory. This study will include 60 patients from 2 institutions in Japan and the Philippines. The invasive disease-free survival (IDFS) rates of the MRD-positive and MRD-negative groups are compared in patients with HER2-positive early breast cancer who undergo surgery after receiving NAC. Methods and analysis: Circulating tumor DNA (ctDNA) levels of patients will be evaluated 6 times: before NAC, after NAC, after surgery, and annually after surgery for 3 years. We will analyze the genetic profile of blood and tissue samples using the Todai OncoPanel (TOP) and the methylation level of DNA. The primary endpoint is IDFS. Secondary endpoints include overall survival (OS) and disease-free survival (DFS). Patient enrollment began in June 2022, and new participants are still being recruited. Ethics: This study has been approved by the National Cancer Center Hospital Certified Review Board in March 2022 and has been approved by the Research Ethics Board of the participating center. Discussion: Our findings will contribute to determining whether MRD detection using TOP is useful for predicting the recurrence of HER2-positive early breast cancer. If this is proven, MRD detected by TOP could be used in the future as a biomarker to assist in the de-/escalation of treatment strategies in the next interventional trial, thereby avoiding overtreatment in patients at low risk, and in the addition of intensive treatment modalities for those in patients at high risk.

Abstract Background This study aimed to investigate the effect of the use of new lithotomy stirrups-2 on the pressure dispersal on lower limbs, which may lead to the prevention of well-leg compartment syndrome (WLCS) and deep venous thrombosis (DVT), which are the most commonly associated adverse events with laparoscopic and robot-assisted rectal surgery. Methods A total of 30 healthy participants were included in this study. The pressure (mmHg) applied on various lower limb muscles when using conventional lithotomy stirrups-1 and new type stirrups-2 was recorded in various lithotomy positions; 1) neutral position, 2) Trendelenburg position (15°) with a 0° right inferior tilt, and 3) Trendelenburg position (15°) with a 10° right inferior tilt. Using a special sensor pad named Palm Q®, and the average values were compared between two types of stirrups. Results The use of new lithotomy stirrups-2 significantly reduced the pressure applied on the lower limb muscles in various lithotomy positions compared with the use of lithotomy stirrups-1. The most pressured lower limb muscle when using both lithotomy stirrups was the central soleus muscle, which is the most common site for the development of WLCS and DVT. In addition, when using the conventional lithotomy stirrups-1, the pressure was predominantly applied to the proximal soleus muscle; however, when using lithotomy stirrups-2, the pressure was shifted to the more distal soleus muscle. Conclusion These results suggest that the new lithotomy stirrups-2 is useful in reducing the pressure load on leg muscles, especially on the proximal to central soleus, and may reduce the incidence of WLCS and DVT after rectal surgery performed in the lithotomy position. Further clinical studies are needed to determine whether the use of lithotomy stirrups-2 prevents these complications in various clinical settings.

Abstract Background Hydrocele of the canal of Nuck (HCN) is a rare disease, and its indications for laparoscopic surgery are not well-established. Case presentation A 53-year-old woman was referred to our hospital due to an uncomfortable thumb-sized inguinal mass. Preoperative computed tomography scan and magnetic resonance imaging revealed a hydrocele extending from the abdominal cavity around the left deep inguinal ring via the inguinal canal to the subcutaneous space. The patient was diagnosed with HCN protruding into the abdominal cavity and extending to the subcutaneous space. Laparoscopy can easily access the hydrocele protruding into the abdominal cavity. Furthermore, laparoscopic hernioplasty can be superior to the anterior approach for females. Hence, laparoscopic surgery was performed. After transecting the round ligament of the uterus, a tense 3-cm hydrocele was dissected with it. In order to approach the hydrocele distal to the deep inguinal ring, the transversalis fascia was incised medially to the inferior epigastric vessels. The subcutaneously connected hydrocele was excised from the incision. Then, the enlarged deep inguinal ring was reinforced using a mesh with the laparoscopic transabdominal preperitoneal approach. The patient was discharged 2 days postoperatively. Laparoscopic resection can be more effective for a hydrocele protruding into the abdominal cavity as it facilitates an easy access to the hydrocele. Moreover, laparoscopic resection of a hydrocele extending from the inguinal canal to the subcutaneous space via a transversalis fascia incision can be safer, with low risk of injury to the inferior epigastric vessels. The incised transversalis fascia and the enlarged deep inguinal ring due to the HCN were simultaneously repaired with the laparoscopic transabdominal preperitoneal repair. There are two reports on laparoscopic resection via a transversalis fascia incision for HCNs located between the inguinal canal and the subcutaneous space, which does not require intraperitoneal hydrocelectomy. However, this is the first report on laparoscopic resection of large HCNs protruding into the abdominal cavity and extending beyond the inguinal canal into the subcutaneous space via intraperitoneal hydrocelectomy and a transversalis fascia incision. Conclusions Laparoscopic surgery with transversalis fascia incision can be useful for HCNs extending from the abdominal cavity to the subcutaneous space.

Abstract Background Although most duodenal carcinomas are pathological adenocarcinomas, a small number of cases have been reported of adenosquamous carcinoma, characterized by variable combinations of two malignant components: adenocarcinoma and squamous cell carcinoma. However, owing to the small number of cases of non-ampullary duodenal adenosquamous carcinoma, there have been no reported cases of emergency pancreaticoduodenectomy for gastrointestinal hemorrhage due to non-ampullary duodenal adenosquamous carcinoma. Case presentation A 66-year-old Japanese male presented to the referring hospital with a chief complaint of abdominal pain, diarrhea, and dark urine that had persisted for 1 month. The patient was referred to our hospital because of liver dysfunction on a blood examination. Laboratory results of the blood on the day of admission showed that total and direct bilirubin levels (12.0 mg/dl and 9.6 mg/dl) were markedly increased. An endoscopic retrograde biliary drainage tube was inserted for the treatment of obstructive jaundice, and imaging studies were continuously performed. Contrast-enhanced computed tomography and endoscopy revealed an ill-defined lesion involving the second portion of the duodenum, predominantly along the medial wall, and measuring 60 mm in diameter. No metastases were observed by positron emission tomography. Pancreaticoduodenectomy was planned based on the pathological findings of poorly differentiated adenocarcinoma. However, 2 days before the scheduled surgery, the patient experienced hemorrhagic shock with melena. Owing to poor hemostasis after endoscopic treatment and poor control of hemodynamic circulation despite blood transfusion, radiological embolization and hemostasis were attempted but were incomplete. An emergency pancreaticoduodenectomy was performed after embolizing the route from the gastroduodenal artery and pseudoaneurysm area to reduce bleeding. The operation was completed using an anterior approach without Kocherization or tunneling due to the huge tumor. The operation time was 4 h and 32 min, and blood loss was 595 mL The pathological diagnosis was adenosquamous carcinoma. The postoperative course was uneventful with 17 day hospital stay and the patient is currently well, with no signs of recurrence 9 months after surgery. Conclusions This report presents an extremely rare case of successful emergency pancreaticoduodenectomy for gastrointestinal hemorrhage caused by non-ampullary duodenal adenosquamous carcinoma.

Abstract Background REGATTA trial failed to demonstrate the survival benefit of reduction gastrectomy in patients with advanced gastric cancer with a single non‐curable factor. However, a significant interaction was found between the treatment effect and tumor location in the subset analysis. Additionally, the treatment effect appeared to be different between Japan and Korea. This supplementary analysis aimed to elucidate the effect of reduction surgery based on tumor location and country. Methods Multivariable Cox regression analyses in each subgroup were performed to estimate the hazard ratio (HRadj), including the following variables as explanatory variables: country, age, sex, incurable factor, cT, cN, primary tumor, performance status, histological type, and macroscopic type. Results Patients (95 in Japan and 80 in Korea) were randomized to chemotherapy alone (86 patients) or gastrectomy plus chemotherapy (89 patients). The subgroup analysis according to the country revealed a worse overall survival in gastrectomy plus chemotherapy arm in Japan (hazard ratio: 1.32, 95% confidence interval: 0.85–2.05), but not in Korea (hazard ratio: 0.85.95% confidence interval: 0.52–1.40). Overall survival was better in distal gastrectomy plus chemotherapy compared with chemotherapy alone (hazard ratio = 0.69, 95% confidence interval: 0.42–1.13), and worse in total gastrectomy plus chemotherapy compared with chemotherapy alone (hazard ratio = 1.34, 95% CI: 0.93–1.94), which was more remarkable in Korea than in Japan. Conclusions Primary chemotherapy is a standard of care for advanced gastric cancer; however, the survival benefits from reduction by distal gastrectomy remained controversial.

Summary: Background: BRAF V600 mutations are common in melanoma, thyroid, and non-small-cell lung cancers. Despite dabrafenib and trametinib being standard treatments for certain cancers, their efficacy across various solid tumours remains unelucidated. The BELIEVE trial assessed the efficacy of dabrafenib and trametinib in solid tumours with BRAF V600E/R or non-V600 BRAF mutations. Methods: Between October 1, 2019, and June 2022, at least 50 patients with measurable and seven without measurable diseases examined were enrolled in a subcohort of the BELIEVE trial (NCCH1901, jRCTs031190104). BRAF mutated solid tumour cases other than BRAF V600E mutated colorectal cancer, melanoma, and non-small cell lung cancer cases were included. Patients with solid tumours received dabrafenib (150 mg) twice daily and trametinib (2 mg) once daily until disease progression or intolerable toxicity was observed. The primary endpoint was overall response rate (ORR), and secondary endpoints included progression-free survival (PFS), 6-month PFS, and overall survival (OS). Bayesian analysis was performed using a prior distribution with a 30% expected response rate [Beta (0.6, 1.4)]. Findings: Fourty-seven patients with measurable disease, mainly with the BRAF V600E mutation (94%), and three others with non-V600E BRAF mutations (V600R, G466A, and N486_P490del) were enrolled. The primary sites included the thyroid gland, central nervous system, liver, bile ducts, colorectum, and pancreas. The confirmed ORR was 28.0%; the expected value of posterior distribution [Beta (14.6, 37.4)] was 28.1%, although the primary endpoint was achieved, not exceeding an unexpectedly high response rate of 60% obtained using Bayesian analysis. The disease control rate (DCR) was 84.0%. The median PFS was 6.5 months (95% confidence interval [CI]; 4.2–7.2 months, 87.8% at 6 months). Responses were observed across seven tumour types. Median OS was 9.7 months (95% CI, 7.5–12.2 months). Additional patients without measurable diseases had a median PFS of 4.5 months. Adverse events (AEs) were consistent with previous reports, with 45.6% of patients experiencing grade ≥3 AEs. Interpretation: This study reported promising efficacy against BRAF V600-mutant tumours. Dabrafenib and trametinib would offer a new therapeutic option for rare cancers, such as high-grade gliomas, biliary tract cancer, and thyroid cancer. Funding: This study was funded by the Japan Agency for Medical Research and Development (22ck0106622h0003) and a Health and Labour Sciences Research Grant (19EA1008).

Abstract Background The multikinase inhibitors (MKIs) sorafenib, lenvatinib, and vandetanib are approved for advanced thyroid cancer (TC) in Japan. How sequential treatment with MKIs is conducted in Japanese clinical practice is unknown. Methods This retrospective observational cohort study used a Japanese administrative claims database (April 2008–September 2021). Patients with a confirmed TC subtype diagnosis of papillary (PTC), follicular (FTC), medullary (MTC), or anaplastic (ATC), who received MKI treatment after TC diagnosis within the index period (June 2014–August 2021), were included. Overall MKI treatment duration was estimated by Kaplan–Meier analysis. Results The analysis population included 795 patients (PTC, N = 447; FTC, N = 86; MTC, N = 32; ATC, N = 230). Median age was ≥ 64 years; most patients (> 60%) were female except for the MTC subgroup (43.8%). First-line (1L) MKI treatment was mainly lenvatinib for PTC (81.7%), FTC (83.7%), and ATC (97.8%), and vandetanib for MTC (62.5%). Among patients discontinuing 1L MKI treatment and evaluable for subsequent therapy [PTC: 57.9% (259/447); FTC: 48.8% (42/86); MTC: 62.5% (20/32); ATC: 70.4% (162/230)], 26.3% (68/259), 21.4% (9/42), 50.0% (10/20), and 4.9% (8/162) of PTC, FTC, MTC, and ATC patients, respectively, received second-line (2L) treatment. Median (95% CI) overall MKI treatment duration was 21.2 (17.9–27.5), 43.9 (30.9–not assessable), 39.0 (17.7–not assessable), and 4.0 (3.0–4.8) months for PTC, FTC, MTC, and ATC, respectively. Conclusion Advanced TC treatment options are limited. In this study, most patients received only 1L MKI treatment; of those who discontinued 1L, ≤ 50% progressed to 2L.

Abstract Background A giant inguinoscrotal hernia is a rare inguinal hernia that extends below the midpoint of the inner thigh while standing. Although reports of laparoscopic surgery for giant inguinoscrotal hernias have increased, the risk of delayed hematocele has not yet been clarified. Case presentation A 68-year-old man was evaluated for a left giant inguinoscrotal hernia, and laparoscopic transabdominal preperitoneal repair (TAPP) was performed. In the procedure, the distal hernia sac was not resected. The postoperative course was uneventful for 3 months postsurgery, after which he complained of giant scrotal swelling, which gradually grew to 13 cm. It did not improve with several punctures and caused dysuria because of increased pressure on the urethra. Thus, reoperation was performed 9 months after surgery. The hematocele consisted of a thickened hernia sac, which was tightly adhered to the spermatic cord and testicle. The hernia sac including the hematocele was removed from the scrotum through an anterior approach, preserving the spermatic cord and testicle. On the third postoperative day, an orchiectomy was performed due to poor testicular perfusion caused by spermatic cord injury. There was no hematocele or hernia at the 3-year follow-up. The remnant sac after laparoscopic TAPP for a giant inguinoscrotal hernia possibly caused refractory hematocele. Additionally, the removal of the hernia sac, including hematocele, from the spermatic cord and testicle has a risk of inducing injury, leading to orchiectomy. Conclusion Surgeons should be aware of the possibility of delayed refractory hematoceles after laparoscopic TAPP for giant inguinoscrotal hernias when the hernia sac is not resected.

Abstract Background A leiomyosarcoma of the gastrointestinal tract is extremely rare. We report a case of jejunal leiomyosarcoma with intestinal intussusception at the angle of Treitz that was successfully treated with laparoscopic resection followed by intracorporeal reconstruction using a delta-shaped anastomosis. Case presentation A 54-year-old man was referred to our hospital due to fatigue and loss of appetite. Blood tests showed anemia. Enteroscopy and subsequent enterography using meglumine sodium amidotrizoate showed easily hemorrhagic tumor (10 cm in diameter) in the jejunum just beyond the angle of Treitz. Contrast-enhanced computed tomography revealed jejunojejunal intussusception. Histopathological examination of a biopsy specimen revealed a leiomyosarcoma. Laparoscopic resection of the tumor without reduction of the intussusception was performed. The resected line of the proximal intestine was very close to the ligament of Treitz in the present case. Intracorporeal jejunojejunostomy was completed using a delta-shaped anastomosis, wherein anastomosis was performed between the posterior walls of the proximal and distal jejunums after minimal mobilization around the ligament of Treitz. The patient’s postoperative course was uneventful, and he was discharged at 10 days postoperatively. No recurrence has been observed within 2 years after surgery. Conclusions We present a case in which a totally laparoscopic surgery for leiomyosarcoma located at the angle of Treitz with jejunojejunal intussusception was performed successfully.

Abstract Background Aberrant fibroblast growth factor receptor (FGFR) signaling can substantially influence oncogenicity. Despite that FGFR gene abnormality is often detected by cancer genome profiling tests, there is no tumor-agnostic approval yet for these aberrations. E7090 (tasurgratinib) is an orally available selective tyrosine kinase inhibitor of FGFR1-3. Specific FGFR alterations were previously reported to be highly sensitive to E7090 based on a high-throughput functional evaluation method, called mixed-all-nominated-mutants-in-one (MANO) method, narrowing down the most promising targets. This trial was focused on the alterations identified by the MANO method and was performed under the nationwide large registry network for rare cancers in Japan (MASTER KEY Project). Methods/Design This single-arm Phase 2 trial was designed to evaluate the safety and efficacy of E7090 in patients with advanced or recurrent solid tumors harboring FGFR alterations. Three cohorts were set based on the type of FGFR alterations and the results of MANO method. A maximum of 45 patients will be enrolled from 5 institutions over 2.5 years. E7090 will be administered once daily as an oral single agent in 28-day cycles. The primary endpoint is the objective overall response rate; whereas, the secondary endpoints include progression-free survival, overall survival, disease control rate, safety, duration of response, and time to response. Ethics approval was granted by the National Cancer Center Hospital Certified Review Board. Patient enrollment began in June 2021. Discussion A unique investigator-initiated multicenter Phase 2 trial was designed based on the results of preclinical investigation aiming to acquire the approval of E7090 for solid tumors harboring FGFR gene alterations. The findings may serve as a novel model for the development of tumor-agnostic molecular targeted therapies against rare genetic abnormalities. Trial registration Japan Registry of Clinical Trial: jRCT2031210043 (registered April 20, 2021) ClinicalTrials.gov: NCT04962867 (registered July 15, 2021).

An 18-year-old Japanese man was diagnosed with an undifferentiated sarcoma of the spermatic cord, with multiple distant metastases to the lungs and bones. The patient received doxorubicin-based standard chemotherapy. Although the chemotherapy was effective, it induced severe adverse events, which led to treatment discontinuation. A comprehensive genomic profiling test using resected tumor tissue revealed the BRAF V600E mutation. Based on the result, the patient received combination therapy with dabrafenib and trametinib. The combination therapy achieved a good response with few adverse events. However, 6.5 months later, pleural metastases and meningeal dissemination had emerged. A liquid comprehensive genomic profiling test was performed after the progression to identify the resistance mechanism, which resulted in the detection of no actionable gene alterations other than BRAF V600E. This report shows that the BRAF V600E mutation may be a promising therapeutic target and that resistance to the targeted therapy could also occur in soft tissue sarcoma. The significance of BRAF mutations across different types of cancer should be validated, and it is necessary to apply targeted therapies and develop methods to overcome resistance based on the optimal use of comprehensive genomic profiling tests.

Abstract Background A variety of factors for short‐ and long‐term outcomes have been reported after radical resection for gastric cancer (GC). Obesity and emaciation had been reported to be a cause of poor short‐ and long‐term outcomes with gastrointestinal cancer. However, the indicators are still controversial. The purpose of this study was to evaluate the relationship between perirenal thickness (PT) and short‐ and long‐term outcomes after radical surgery for GC. Methods We analyzed the data of 364 patients with GC who underwent radical surgery. We evaluated the distance from the anterior margin of the quadratus lumborum muscle to the dorsal margin of the left renal pole using computed tomography (CT) as an indicator of PT. The association between PT and clinicopathological factors and short‐ and long‐term outcomes was evaluated. Results The PT data were divided into low, normal, and high groups by gender using the tertile value. We found that the PT low group was 121 patients, normal group was 121 patients, and high group was 122 patients. Multivariate analyses showed that the high PT group was an independent risk factor for a short‐outcome after curative surgery in GC patients (odds ratio 2.163; 95% confidence interval [CI] 1.156–4.046; P = .016). And the low PT group was an independent risk factor for overall survival (hazard ratio 2.488; 95% CI 1.400–4.421; P = .0019) and relapse‐free survival (hazard ratio 2.342; 95% CI 1.349–4.064; P = .0025) after curative surgery in GC patients. Conclusion Perirenal thickness is a simple and useful factor for predicting short‐ and long‐term outcomes after radical surgery for GC.

Abstract Background Gastric cancer is relatively prone to metastasis, although distant metastasis is rare during the early stage of disease. Here we report a rare case of schwannoma-associated Virchow metastasis of a patient with early-stage gastric cancer. Case presentation A 73-year-old man, diagnosed with early-stage gastric cancer, underwent preoperative scrutiny, and was only suspected to have Virchow metastasis. Owing to atypical metastatic findings, a lymph node biopsy was performed to confirm the diagnosis and to determine the treatment strategy. The pathology results of the biopsy showed a diagnosis of schwannoma, the patient was judged to be surgically resectable, and a laparoscopic gastrectomy was performed to achieve a radical resection. The patient is currently under outpatient observation with no apparent recurrence. Conclusion Systemic chemotherapy is generally administered according to the physician’s clinical judgment, although the results of a lymph node biopsy contribute to a more curative treatment. When nonspecific metastases are found, it is important to make a reliable diagnosis and to select a treatment that achieves a cure.

Abstract Background It is estimated that approximately 50% of patients with hepatitis C virus (HCV) infection in Japan are currently over 75 years old. However, patients aged ≥ 75 years are typically underrepresented in clinical trials of direct-acting antivirals. This study aimed to evaluate the efficacy and safety of glecaprevir and pibrentasvir (G/P) treatment in Japanese patients with HCV infection aged ≥ 75 years. Methods This multicenter, retrospective study included 271 Japanese patients with HCV infection from 12 centers in Miyazaki Prefecture, Japan. Demographic, clinical, virological, and adverse events (AEs) data obtained during and after G/P treatment were collected from medical records. The patients were divided into two groups: younger (n = 199, aged

Abstract To identify the factors associated with the surgical outcomes of Baerveldt glaucoma implant (BGI) for open-angle glaucoma (OAG), the medical records of 51 consecutive OAG patients (age, 43–91 years) who underwent BGI were retrospectively reviewed (median follow-up, 21.7 months). Surgical success was defined as the following postoperative intraocular pressures (IOPs, mmHg): (A) 6 ≤ IOP ≤ 21; (B) 6 ≤ IOP ≤ 18; and (C) 6 ≤ IOP ≤ 15 without loss of light perception or additional glaucoma surgery. Univariate analysis showed that age (all criteria), glaucoma type (criterion C), and preoperative IOP (criteria A and B) were the candidate factors (P

Abstract Background Institutional variation in outcomes is a key factor to ascertain the generalizability of results and reliability of the clinical trial. This study evaluated institutional variation in survival and postoperative complications using data from JCOG0404 comparing laparoscopic colectomy (LAP) with open colectomy (OP). Methods Institutions with fewer than 10 registered patients were excluded from this analysis. Institutional variation was evaluated in terms of early postoperative complications, overall survival, and relapse‐free survival and estimated using a mixed‐effect model with institution as a random effect after adjusting for background factors. Results This analysis included 1028 patients in the safety analysis and 1040 patients in the efficacy analysis from 26 institutions. In the safety analysis, there was no variation in grades 3–4 early postoperative complications (in OP, median 6.3% [range 6.3%–6.3%]; in LAP, median 2.6% [range 2.6%–2.6%]), but some variation in grades 1–4 early postoperative complications was observed (in OP, median 20.8% [range 13.2%–31.8%]; in LAP, median 11.9% [range 7.2%–28.7%]), and that in grades 2–4 was observed only in LAP (median 8.8% [range 4.7%–24.0%]; in OP, median 12.7% [range 12.7%–12.7%]). Two specific institutions showed especially high incidences of postoperative complications in LAP. In the efficacy analysis, there was no institutional variation in OP, although a certain variation was observed in LAP. Conclusions Some institutional variations in safety and efficacy were observed, although only in LAP. We conclude that a qualification system, including training and education, is needed when new surgical techniques such as laparoscopic surgery are introduced in clinical practice.

Background: Intermediate-stage hepatocellular carcinoma (HCC), as defined by Barcelona Clinic Liver Cancer (BCLC) stage B, is heterogeneous in terms of liver function and tumor burden. REACH and REACH-2 investigated ramucirumab in patients with HCC after prior sorafenib, with REACH-2 enrolling only patients with baseline α-fetoprotein (AFP) ≥400 ng/mL. An exploratory analysis of outcomes by BCLC stage was performed. Methods: A pooled meta-analysis of independent patient data (stratified by study) from REACH (AFP ≥ 400 ng/mL) and REACH-2 was performed. All patients had Child-Pugh A, Eastern Cooperative Oncology Group performance status 0–1, prior sorafenib treatment, and either HCC BCLC stage B (refractory/not amenable to locoregional therapy) or BCLC stage C. Patients were randomized to ramucirumab 8 mg/kg or placebo every 2 weeks. Median overall survival (OS) and progression-free survival were estimated by the Kaplan-Meier method. Treatment effects in BCLC stage B and C were evaluated by Cox proportional-hazards model; prognosis of BCLC staging for OS was evaluated by multivariate Cox proportional-hazards model. Tumor responses were evaluated according to Response Evaluation in Solid Tumors v1.1. Liver function was assessed with albumin-bilirubin score. Results: Baseline characteristics were generally balanced between treatment arms in each BCLC stage. BCLC staging trended as an independent prognostic factor for OS (B vs. C; hazard ratio [HR] 0.756 [95% CI 0.546–1.046]). Consistent treatment benefit was observed for ramucirumab versus placebo across BCLC stages. Median OS for ramucirumab versus placebo was 13.7 versus 8.2 months; HR (95%): 0.43 (0.23–0.83) and 7.7 versus 4.8 months; HR (95%): 0.72 (0.59–0.89) for BCLC stage B and C, respectively. Adverse events (AEs) were consistent with observations from both studies; hypertension was the most frequent grade ≥3 AE. Liver function was preserved throughout the study and similar between treatment arms in both BCLC stages. Conclusions: Ramucirumab provided a better survival benefit irrespective of BCLC stage and was well tolerated without compromising liver function during treatment.

Abstract The vascular endothelial growth factor (VEGF)/VEGF receptor (VEGFR) axis is an essential regulator of angiogenesis and important therapeutic target in cancer. Ramucirumab is an anti-VEGFR2 monoclonal antibody used for the treatment of several cancers. Increased circulating VEGF-A levels after ramucirumab administration are associated with a worse prognosis, suggesting that excess VEGF-A induced by ramucirumab negatively affects treatment efficacy and that neutralizing VEGF-A may improve treatment outcomes. Here, we evaluated the effect of combination treatment with an anti-VEGFR2 antibody and anti-VEGF-A antibody on gastric tumor progression and normal tissues using a preclinical BALB/c-nu/nu mouse xenograft model. After anti-VEGFR2 antibody treatment in mice, a significant increase in plasma VEGF-A levels was observed, mirroring the clinical response. The elevated VEGF-A was host-derived. Anti-VEGF-A antibody co-administration enhanced the anti-tumor effect of the anti-VEGFR2-antibody without exacerbating the toxicity. Mechanistically, the combination treatment induced intra-tumor molecular changes closely related to angiogenesis inhibition and abolished the gene expression changes specifically induced by anti-VEGFR2 antibody treatment alone. We particularly identified the dual treatment-selective downregulation of ZEB1 expression, which was critical for gastric cancer cell proliferation. These data indicate that the dual blockade of VEGF-A and VEGFR2 is a rational strategy to ensure the anti-tumor effect of angiogenesis-targeting therapy.

Abstract There are many differences between Asian regions in terms of the regulatory requirements and operational procedures in conducting international academic clinical trials for the approval of new drugs. The National Cancer Center Hospital in Japan has launched an international investigator‐initiated registration‐directed trial (IIRDT) in Japan, Korea, Taiwan, and Singapore, aiming at obtaining pharmaceutical approval in participating regions. Differences in regulatory and operational procedures were identified while coordinating the trial. In Japan, regulatory authority reviews should be performed after approval by institutional review boards for IIRDT, whereas in other regions these can be done in parallel. There were disparities in Good Manufacturing Practice‐related documents between regions. Several differences were found regarding investigational product (IP) management, specifically concerning labeling, import/export procedures, and customs clearance costs. On the other hand, safety reporting procedures were relatively well‐harmonized in accordance with International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use, Clinical Safety Data Management: Definitions and Standards for Expedited Reporting (ICH‐E2A). Regions also differed in per‐patient costs, due to varying regulations for academic registration‐directed trials. In conclusion, the observed differences among Asian regions should be harmonized to facilitate international academic trials in Asia and thus resolve unmet patient needs worldwide. Study Highlights WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC? International clinical trials have become common because they make it possible to accrue patients faster and obtain new drug approval in wider areas. However, pharmaceutical regulatory differences hinder the efficient conduct of international clinical trials, especially in academia. WHAT QUESTION DID THIS STUDY ADDRESS? We conducted an academic international clinical trial on new drug applications in four Asian countries and clarified pharmaceutical regulatory differences and operational difficulties. WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE? The study identified differences between countries in terms of regulatory affairs, institutional review board (IRB) review processes, investigational new drug (IND) dossiers, investigational product (IP) management procedures, and clinical trial costs, while safety reporting procedures were relatively harmonized. Japan utilizes investigator‐initiated registration‐directed trials, an advanced regulatory system for new drug application by academia, but the other countries do not. HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE? Harmonization of pharmaceutical regulations and trial initiation procedures, and regulatory reform of clinical trial costs are important to accelerate academic international clinical trials for new drug applications.

PurposePatients with advanced/relapsed rare cancers have few treatment options. Analysis of circulating tumor DNA in plasma may identify actionable genomic biomarkers using a non-invasive approach.Patients and MethodsRare cancer patients underwent prospective plasma-based NGS testing. Tissue NGS to test concordance was also conducted. Plasma DNA alterations were assessed for incidence, functional impact, therapeutic implications, correlation to survival, and comparison with tissue NGS.ResultsNinety-eight patients were analyzed. Diseases included soft-tissue sarcoma, ovarian carcinoma, and others. Mean turn-around-time for results was 9.5 days. Seventy-six patients had detectable gene alterations in plasma, with a median of 2.8 alterations/patient. Sixty patients had a likely pathogenic alteration. Five received matched-therapy based on plasma NGS results. Two developed known resistance mutations while on targeted therapy. Patients with an alteration having VAF ≥5% had a significantly shorter survival compared to those of lower VAF. Tissue NGS results from eleven of 22 patients showed complete or partial concordance with plasma NGS.ConclusionPlasma NGS testing is less invasive and capable of identifying alterations in advanced rare cancers in a clinically meaningful timeframe. It should be further studied as a prospective enrollment assay in interventional studies for patients with rare advanced stage cancers.Clinical Registration[https://www.umin.ac.jp/ctr/index-j.htm], identifier UMIN000034394.

Hyperglycosylated human chorionic gonadotropin (H-hCG) is secreted from choriocarcinoma and contains a core2 O-glycan formed by core2 β1,6-N-acetylglucosaminyl transferase (C2GnT). Choriocarcinoma is considered immunogenic as it is gestational and contains paternal chromosomal components. Here we examined the function of C2GnT in the evasion of choriocarcinoma cells from natural killer (NK) cell-mediating killing. We determined that C2GnT is highly expressed in malignant gestational trophoblastic neoplasms. C2GnT KO downregulates core2 O-glycan expression in choriocarcinoma cells, which are more efficiently killed by NK cells than control cells. C2GnT KO cell containing tumor necrosis factor-related apoptosis inducing ligand have lower viability than control cells. Additionally, poly-N-acetyllactosamine in core2 branched oligosaccharides on MHC class I-related chain A (MICA) and mucin1 (MUC1) is significantly reduced in C2GnT KO cells. Meanwhile, the cumulative survival rate of nude mice inoculated with C2GnT KO tumors was higher than that of the control group. These findings suggest that choriocarcinoma cells may escape NK cell-mediated killing via glycosylation of MICA and MUC1.

Objectives: Anastomotic leak is a common complication after esophagectomy for esophageal cancer. This study evaluated the impact of the Kocher maneuver on the incidence of anastomotic leak following esophagogastrostomy using a 3-cm-wide gastric conduit. Methods: This single-institution, retrospective, cohort study included 43 patients who underwent thoraco-laparoscopic esophagectomy. The Kocher maneuver was not performed in the first half of the study period between April 2014 and May 2015 (first half group, n=14), but was performed in the second half between May 2015 and January 2017 (second half group, n=29). Primary endpoint was the incidence of anastomotic leak. Metrological values of the gastric conduit were postoperatively assessed on computed tomography. Blood perfusion of the gastric conduit was prospectively examined using the indocyanine green fluorescence method. Results: The incidence of anastomotic leak was 14%; the incidence was significantly lower in the second half group than in the first half group (3.4% vs. 35.7%, p=0.01). The Kocher maneuver was the only significant independent risk factor associated with anastomotic leak (OR 0.064, 95% CI 0.007–0.625, p=0.018). The postoperative length of the entire gastric conduit was significantly shorter in the second half group than in the first half group. A more anal location of the 3-cm-wide gastric conduit was associated with better blood perfusion. Conclusions: The Kocher maneuver may enable shortening of the gastric conduit, leading to better blood perfusion of the tip of the gastric conduit, and a significant reduction in the occurrence of anastomotic leak.

Objectives: Current evidence regarding metabolic surgery suggests that different types of digestive tract reconstruction can result in differences in postoperative glucose tolerance. This study evaluated the impact of Billroth I (B-I), Billroth II (B-II), and Roux-en-Y (R-Y) procedures on peri-operative glucose tolerance in patients with gastric carcinoma who had diabetes mellitus. Methods: A single-institution, retrospective cohort study was conducted using data from patients who underwent totally laparoscopic distal gastrectomy. These patients were grouped according to the type of reconstruction (B-I, B-II, or R-Y). After the operation, we addressed the changes in glucose tolerance—including changes in HbA1c levels, remission of diabetes, and overall effects of the treatment. Results: We studied 57 patients (B-I, n=32; B-II, n=17; R-Y, n=8). B-II and R-Y reconstruction improved HbA1c levels more than B-I. Notably, R-Y improved tolerance the most (B-I vs. B-II, p

Late-onset erythropoietic protoporphyria (EPP) is rare, and it is usually associated with an acquired somatic mutation of the ferrochelatase gene secondary to hematological malignancy such as myelodysplastic syndrome or myeloproliferative disorder. In 0.5–1% of patients with EPP, deposition of protoporphyrin in the liver leads to progressive liver insufficiency. Herein, we report the case of a 67-year-old female who developed EPP with typical photosensitivity and hemolytic anemia. Six months later, she was admitted with acute liver damage with a rapidly progressing course, and developed liver insufficiency. She recovered from the liver insufficiency after undergoing plasmapheresis and red blood cell exchange transfusion. A bone marrow examination revealed normal features; however, a cytogenetic analysis identified an abnormal clone of cells with a translocation between chromosomes 13q12 and 18q21.1. This is the first report of a patient who recovered from liver insufficiency. The results of this report suggest that plasmapheresis and red blood cell exchange transfusion are effective for treating liver insufficiency in patients with late-onset EPP.