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This study analyzed outcomes of systemic chemotherapy for advanced neuroendocrine carcinoma (NEC) of the digestive system. Clinical data from 258 patients with unresectable or recurrent NEC of the gastrointestinal tract (GI) or hepato‐biliary‐pancreatic system (HBP), who received chemotherapy, were collected from 23 Japanese institutions and analyzed retrospectively. Patients had primary sites in the esophagus (n = 85), stomach (n = 70), small bowel (n = 6), colorectum (n = 31), hepato‐biliary system (n = 31) and pancreas (n = 31). Median overall survival (OS) was 13.4 months the esophagus, 13.3 months for the stomach, 29.7 months for the small bowel, 7.6 months for the colorectum, 7.9 months for the hepato‐biliary system and 8.5 months for the pancreas. Irinotecan plus cisplatin (IP) and etoposide plus cisplatin (EP) were most commonly selected for GI‐NEC and HBP‐NEC. For patients treated with IP/EP (n = 160/46), the response rate was 50/28% and median OS was 13.0/7.3 months. Multivariate analysis among patients treated with IP or EP showed that the primary site (GI vs HBP; hazard ratio [HR] 0.58, 95% confidence interval [CI] 0.35–0.97) and baseline serum lactate dehydrogenase levels (not elevated vs elevated; HR 0.65, 95% CI 0.46–0.94) were independent prognostic factors for OS, while the efficacy of IP was slightly better than for EP (HR 0.80, 95% CI 0.48–1.33; P = 0.389). IP and EP are the most common treatment regimens for NEC of the digestive system. HBP primary sites and elevated lactate dehydrogenase levels are unfavorable prognostic factors for survival. A randomized controlled trial is required to establish the appropriate chemotherapy regimen for advanced NEC of the digestive system. This study was registered at UMIN as trial number 000005176. Clinical data from patients with unresectable or recurrent NEC of the gastrointestinal tract (GI) or hepato‐biliary‐pancreatic system (HBP), who received chemotherapy, were collected from 23 Japanese institutions and analyzed retrospectively. This study included 258 patients. Multivariate analysis among the patients treated with IP or EP showed that the primary site (GI vs. HBP; HR 0.58, 95% CI 0.35–0.97) and baseline serum lactate dehydrogenase (LDH) levels (not elevated vs elevated; HR 0.65, 95% CI 0.46–0.94) were independent prognostic factors for OS, while the efficacy of IP was slightly better than EP (HR 0.80, 95% CI 0.48–1.33; P = 0.389).

Although gastric endoscopic submucosal dissection (ESD) is widely used, the degree of difficulty varies greatly depending on the lesion. Since the multi-loop traction device (MLTD) has been suggested to shorten the procedure time in colorectal ESD, we examined the efficacy and safety of using the MLTD in gastric ESD. Thirty patients with gastric neoplasms were prospectively enrolled from February 2022 to December 2022, and the outcomes of ESD with the MLTD were evaluated. The primary outcomes were procedure time and dissection speed. The secondary outcomes were en bloc and R0 resection rates, MLTD attachment time, and complications of ESD with the MLTD. After excluding 1 patient, 29 patients (29 lesions) were treated by ESD with the MLTD. The median procedure time was 26 min (range, 9–210 min), and the median submucosal dissection speed was 39.9 mm 2 /min (12.4–102.7 mm 2 /min). The rate of en bloc resection was 100%, the median MLTD attachment time was 3 min (1–7 min), and none of the patients showed intraoperative or postoperative perforations. Thus, gastric ESD with the MLTD showed a favorable procedure time and dissection speed and an acceptable complication rate. Hence, the MLTD may be effective for gastric ESD.

The KEYNOTE‐659 study evaluated the efficacy and safety of first‐line pembrolizumab plus S‐1 and oxaliplatin (SOX) (cohort 1) or S‐1 and cisplatin (SP) (cohort 2) for advanced gastric/gastroesophageal junction (G/GEJ) cancer in Japan. Herein, we update the results of cohort 1 and describe the results of cohort 2. This open‐label phase IIb study enrolled patients with advanced programmed death‐ligand 1 (PD‐L1)‐positive (combined positive score ≥ 1) human epidermal growth factor receptor 2 (HER2)‐negative G/GEJ adenocarcinoma. The primary end‐point was the objective response rate (ORR). Other end‐points were duration of response (DOR), disease control rate (DCR), progression‐free survival (PFS), overall survival (OS), and safety. One hundred patients were enrolled. In cohorts 1 and 2, median follow‐up time was 16.9 and 17.1 months; ORR (central review), 72.2% and 80.4%; DOR, 10.6 and 9.5 months; DCR (central review), 96.3% and 97.8%; median PFS (central review), 9.4 and 8.3 months; and median OS, 16.9 and 17.1 months, respectively. Treatment‐related adverse events (TRAEs) occurred in all patients, including peripheral sensory neuropathy (94.4%, cohort 1), decreased neutrophil count (82.6%, cohort 2), nausea (59.3% and 60.9% in cohorts 1 and 2), and decreased appetite (61.1% and 60.9% in cohorts 1 and 2). Grade 3 or higher TRAEs were reported by 59.3% (cohort 1) and 78.3% (cohort 2), including decreased platelet count (14.8%, cohort 1) and decreased neutrophil count (52.2%, cohort 2). Pembrolizumab in combination with SOX or SP showed favorable efficacy and safety in patients with PD‐L1‐positive, HER2‐negative G/GEJ adenocarcinoma. The KEYNOTE‐659 study was a multicenter, open‐label phase IIb study that evaluated the efficacy and safety of first‐line pembrolizumab with S‐1 + oxaliplatin (cohort 1) or S‐1 + cisplatin (cohort 2) for advanced gastric/gastroesophageal junction cancer in Japan. In cohorts 1 and 2, the median follow‐up times were 16.9 and 17.1 months, respectively; the objective response rates (primary endpoint) were 72.2% and 80.4%, respectively; and treatment‐related adverse events occurred in all patients, including peripheral sensory neuropathy (94.4%, cohort 1), decreased neutrophil count (82.6%, cohort 2), nausea (59.3% and 60.9% in cohorts 1 and 2) and decreased appetite (61.1% and 60.9% in cohorts 1 and 2). First‐line pembrolizumab with S‐1 + oxaliplatin or S‐1 + cisplatin showed favorable efficacy and manageable safety in PD‐L1‐positive, HER2‐negative advanced gastric or gastroesophageal junction adenocarcinoma in Japanese patients.

Objective The indications for endoscopic submucosal dissection (ESD) in patients with early gastric cancer (EGC) have been expanded. However, the long-term outcomes of ESD remain unclear. We retrospectively investigated the long-term outcomes of ESD in patients with EGC. Methods We retrospectively studied patients with EGC who underwent ESD at 11 institutions between January 2003 and December 2010. A total of 6456 patients (7979 lesions) who met the absolute indications for ESD and 4202 patients (5781 lesions) who met the expanded indications for ESD were studied. Clinicopathological features, clinical course, and outcomes were studied in 67 patients in whom local recurrence or metastatic recurrence was diagnosed as of March 31, 2014. The median follow-up period was 56 months. Results Local recurrence was diagnosed in 14 patients (0.22%) who met the absolute indications and 53 patients (1.26%) who met the expanded indications. The rate of local recurrence was significantly higher in patients with expanded-indication lesions ( p  < 0.05). As additional treatment for recurrence, most patients received endoscopic treatment. Metastatic recurrence did not develop in any patient with absolute-indication lesions, but was diagnosed in 6 patients (0.14%) with expanded-indication lesions ( p  < 0.05). The histological type was undifferentiated mixed type in half the patients. Three patients died of primary gastric cancer. Conclusions ESD for expanded-indication lesions of EGC is considered an effective therapy associated with an extremely low rate of metastatic recurrence on long-term follow-up. However, fully informed consent concerning the risk of metastatic recurrence should be obtained before ESD, and close postoperative follow-up is essential.

Background Few studies have compared the outcomes of endoscopic mucosal resection (EMR) and endoscopic submucosal dissection (ESD) in patients with early gastric cancer. Methods We studied 780 lesions for which endoscopic treatment was indicated according to the Japanese Gastric Cancer Association (JGCA) criteria or the extended National Cancer Center (NCC) criteria from April 1995 to December 2007. A total of 359 lesions were treated by endoscopic aspiration mucosectomy (EAM) between April 1995 and March 2003 (EAM group), and 421 lesions were treated by ESD between April 2003 and December 2007 (ESD group). Long-term outcomes (local recurrence rate, overall survival) were compared between the groups. Results The median follow-up was 73 months in the EAM group and 65 months in the ESD group. Overall, the local recurrence rate was significantly lower in the ESD group (0.2 %, 1/421) than in the EAM group (4.2 %, 15/359) ( p  < 0.05). For lesions meeting the JGCA criteria, the local recurrence rate was 2.9 % in the EAM group and 0 % in the ESD group ( p  < 0.05). For lesions meeting the NCC criteria, the local recurrence rate was 12.5 % in the EAM group and 0.6 % in the ESD group ( p  < 0.05). There was no significant difference between the groups in overall survival. Conclusions On long-term follow-up, ESD was associated with a lower rate of local recurrence than EAM for lesions that met the JGCA or the NCC criteria. From the point of view of radical curability, ESD can be recommended for the management of lesions that meet either set of criteria.

Objectives There is concern that underwater endoscopic mucosal resection (UWEMR) uses buoyancy to elevate the lesion for snare resection, resulting in a shallower resection depth than that in endoscopic mucosal resection (EMR). We aimed to compare conventional EMR and UWEMR in terms of resection depth. Methods We retrospectively reviewed cases in which EMR or UWEMR was performed for superficial non‐ampullary duodenal epithelial tumors of ≤20 mm between April 2018 and February 2024. The endpoints were histological complete resection rate, en bloc resection rate, presence of muscularis mucosa and submucosa in the resection specimen, and submucosal index calculated from the resection specimen. Results EMR was performed on 19 lesions and UWEMR was performed on 52 lesions. Histological complete and en bloc resection rates were not significantly different between EMR and UWEMR (57.9% and 63.5%, respectively, p = 0.78; 78.9% and 90.4%, respectively, p = 0.24). No significant differences were observed between EMR and UWEMR in the muscularis mucosa of the resected specimens (78.9% and 92.3%, respectively, p = 0.20). The presence of submucosa in resected specimens was encountered less often in EMR cases than in UWEMR cases (57.9% versus [vs.] 84.6%, p = 0.03). There were significant differences in the submucosal index in the resected specimens between EMR and UWEMR cases (median 0.15 [interquartile range 0–0.39] vs. 0.33 [0.17–0.57], p = 0.04). Conclusion UWEMR potentially includes the submucosa within the specimen.

Objectives The efficacy and safety of a sedation regimen combining dexmedetomidine and midazolam during endoscopic submucosal dissection for upper gastrointestinal tumors remains unclear. In this study, we aimed to evaluate the efficacy and safety of this sedation regimen, where non‐anesthesiologists performed sedation. Methods Sixty‐eight patients who underwent endoscopic submucosal dissection for upper gastrointestinal tumors, sedated by non‐anesthesiologists, were retrospectively evaluated. The sedation was performed by non‐anesthesiologists as part of on‐the‐job training (OJT) under anesthesiologists' supervision. Each non‐anesthesiologist received OJT at least thrice. Proficiency levels were assessed during the third OJT session. The target sedation depth was a Richmond Agitation‐Sedation Scale of −2 to −4, with 2 L/min of oxygen delivered via a nasal cannula at sedation initiation. The treatment completion rates, which measured efficacy and safety, were assessed by the frequencies of respiratory depression, hypotension, and bradycardia. Results The study included 14, 52, and two patients with superficial esophageal cancer, early gastric cancer, and gastric adenoma, respectively. The median treatment time was 68 and 84 min for superficial esophageal cancer, early gastric cancer, and adenoma, respectively. Endoscopic submucosal dissection was completed in all patients. No severe sedation‐related adverse events were reported; however, peripheral arterial oxygen saturation <90%, hypotension, and bradycardia occurred in 1 (1.5%), 30 (44.1%), and 30 patients (44.1%), respectively. All 22 non‐anesthesiologists who underwent the proficiency evaluation passed the test. Conclusions A sedation regimen combining dexmedetomidine and midazolam can be feasibly administered by non‐anesthesiologists. Further studies are needed to verify the effectiveness of OJT.

BackgroundThe prognosis of patients with gastric cancer with bulky node metastasis, linitis plastica (type 4), or large ulcero-invasive-type tumors (type 3) remains poor. We conducted a phase II study to evaluate the safety and efficacy of neoadjuvant chemotherapy with docetaxel, cisplatin, and S-1 (DCS) for establishing a new treatment modality that improves prognosis.MethodsPatients received up to four 28-day cycles of DCS therapy (docetaxel at 40 mg/m2, cisplatin at 60 mg/m2 on day 1, and S-1 at 40 mg/m2 twice daily for 2 weeks) followed by gastrectomy with D2 nodal dissection. S-1 chemotherapy was administered for 1 year after surgical resection. The primary endpoint was the percentage of complete resections of the primary tumor with clear margins (R0 resection). The planned sample size was 40; this was calculated based on an expected R0 rate of 85% and a threshold R0 rate of 65%, with a one-sided alpha of 5% and a power of 90%.ResultsBetween 2010 and 2017, 40 patients were enrolled. The R0 resection rate was 90%. The most common grade 3 or 4 adverse events during DCS therapy were leukocytopenia (27.5%), neutropenia (55.0%), and hyponatremia (22.5%). The most common grade 3 or 4 surgical morbidity was pancreatic fistula (12.5%); mortality was 0%. The pathological response rate was 57.5% with a grade 3 histological response rate of 8%.ConclusionsNeoadjuvant chemotherapy with DCS was feasible and showed a sufficient R0 resection rate. A future study with a sufficient follow-up period should confirm survival outcomes.

Background Little information is available on the long-term outcomes of endoscopic submucosal dissection (ESD) for early gastric cancer (EGC) in patients of advanced age (≥80 years). Methods A multicenter study was conducted at 10 Japanese institutions concerning their results for ESD. Data on 440 patients of advanced age (≥80 years) with EGC (470 lesions) were collected and reviewed. Early and long-term outcomes of ESD were assessed. We compared the overall survival rates between 3 patient groups, those with curative ESD, additional surgery after noncurative ESD, and nonsurgical follow-up after noncurative ESD. Results Bleeding and perforation rates were 3.2 and 2.8%, respectively. Curative ESD was achieved in 366 of the 470 lesions (77.9%). Of the 104 patients with noncurative ESD, 12 patients (11.5%) underwent additional surgery and 91 patients (87.5%) were followed without surgery. The 5-year survival rate in the patients with nonsurgical follow-up after noncurative ESD (66.7%) was significantly lower than that in the patients with curative ESD (80.3%, p  = 0.0001). There was no significant difference in the 5-year survival rates between the patients with curative ESD and those with surgery after noncurative ESD (100%, p  = 0.21), nor was there a difference in these rates between the patients with surgery after noncurative ESD and those with nonsurgical follow-up after noncurative ESD ( p  = 0.061). None of the patients developed cancer recurrence after curative ESD, and none developed cancer recurrence following the additional surgery after noncurative ESD. In the patients with curative ESD and in those with surgery after noncurative ESD, the cumulative observed survival was better than the expected survival for the general population of similar age and gender. Conclusions ESD is safe for the treatment of EGC in patients 80 years of age or older. Both curative ESD and additional surgery after noncurative ESD may contribute to the extension of life expectancy.

Background This randomized study was designed to evaluate the clinical effect of an elemental diet during chemotherapy in patients with esophageal cancer. Methods The inclusion criteria were as follows: (1) esophageal squamous cell carcinoma, (2) stage IB-IV, (3) schedule to receive docetaxel, cisplatin, and 5-fluorouracil (DCF chemotherapy), (4) 20–80 years old, (5) performance status of 0–2, (6) oral intake ability, and (7) written informed consent. Patients were divided into two groups: the elemental supplementary group and the non-supplementary group. Patients received ELENTAL ® (160 g/day) orally 9 weeks after the start of chemotherapy. Primary endpoint was the incidence of grade 2 or higher gastrointestinal toxicity according to the Common Terminology Criteria for Adverse Events, version 4.0. Secondary endpoints were the incidence of all adverse events and the evaluation of nutritional status. Results Thirty-six patients in the elemental supplementary group and 35 patients in the non-supplementary group were included in the analysis. The incidence of grade 2 or higher gastrointestinal toxicity and all grade 3 or 4 adverse events did not differ significantly between the groups. In the elemental supplementary group, the body weight ( p  = 0.057), muscle mass ( p  = 0.056), and blood levels of transferrin ( p  = 0.009), total amino acids ( p  = 0.019), and essential amino acids ( p  = 0.006) tended to be maintained after chemotherapy. Conclusion Nutritional support provided by an amino acid-rich elemental diet was ineffective for reducing the incidence of adverse events caused by DCF chemotherapy in patients with esophageal cancer.