Prognosis of advanced gastrointestinal stromal tumors (GIST) refractory to tyrosine kinase inhibitors (TKIs) is poor. This randomized, placebo-controlled, phase III trial evaluated the efficacy and ...safety of pimitespib, a novel heat shock protein 90 inhibitor, in advanced GIST refractory to standard TKIs.
Patients with histologically confirmed GIST refractory to imatinib, sunitinib, and regorafenib were randomized 2 : 1 to oral pimitespib 160 mg/day or placebo for 5 consecutive days per week in 21-day cycles. Following disease progression by blinded central radiological review (BCRR), cross-over to open-label pimitespib was permitted. The primary endpoint was progression-free survival (PFS) by BCRR in the full analysis set. Secondary endpoints included overall survival (OS) adjusted using the rank-preserving structural failure time (RPSFT) method to reduce the expected confounding impact of cross-over.
From 31 October 2018 to 30 April 2020, 86 patients were randomized to pimitespib (n = 58) or placebo (n = 28). Median PFS was 2.8 months 95% confidence interval (CI) 1.6-2.9 months with pimitespib versus 1.4 months (0.9-1.8 months) with placebo hazard ratio (HR) 0.51 (95% CI 0.30-0.87); one-sided P = 0.006. Pimitespib showed an improvement in cross-over-adjusted OS compared with placebo HR 0.42 (0.21-0.85), one-sided P = 0.007. Seventeen (60.7%) patients receiving placebo crossed-over to pimitespib; median PFS after cross-over was 2.7 months (95% CI 0.7-4.1 months). The most common (≥30%) treatment-related adverse events (AEs) with pimitespib were diarrhea (74.1%) and decreased appetite (31.0%); the most common (≥10%) grade ≥3 treatment-related AE was diarrhea (13.8%). Treatment-related AEs leading to pimitespib discontinuation occurred in three (5.2%) patients.
Pimitespib significantly improved PFS and cross-over-adjusted OS compared with placebo and had an acceptable safety profile in patients with advanced GIST refractory to standard TKIs.
•Pimitespib improved PFS compared with placebo in patients with previously treated advanced GIST.•OS was improved with pimitespib compared with placebo using the RPSFT model.•Exploratory pharmacogenomic analysis showed a benefit of pimitespib irrespective of KIT mutation status.•The safety profile of pimitespib was acceptable, and quality of life was not deteriorated by pimitespib compared with placebo.
Side-branch intraductal papillary mucinous neoplasms (SB-IPMNs), and associated synchronous and metachronous pancreatic cancers are increasingly detected as imaging modalities become more sensitive. ...We investigated the natural history of SB-IPMN, and the incidence and characteristics of pancreatic cancers among patients undergoing long-term follow-up.
We reviewed the clinical, imaging, and pathological features in 103 patients, diagnosed at the Aichi Cancer Center between September 1988 and September 2006 as having SB-IPMN, and conservatively followed up for ≥ 2 years (median 59 months) based on an endoscopic ultrasonography (EUS) database.
74 (71.8 %) patients had nonprogressive lesions. Overall, six patients (5.8 %) developed pancreatic cancers during follow-up, with intraductal papillary mucinous (IPM) carcinoma in four, and ductal carcinoma of pancreas that was not IPMN in two patients. Of the six pancreatic cancers, five were diagnosed at a resectable stage. The 5-year and 10-year actuarial rates of development of pancreatic cancer were 2.4 % and 20.0 %, respectively. Although, at the last follow-up, cyst size, main pancreatic duct (MPD) diameter, mural nodule size, and frequency of metachronous and/or synchronous cancers of other organs were significantly higher in patients who developed IPM carcinoma, resected SB-IPMNs without mural nodules and dilated MPDs had no IPM carcinomas.
The frequency of pancreatic cancers is high on long-term follow-up of SB-IPMN. Although conservative management is appropriate for selected patients, regular and long-term imaging, especially by EUS is essential, even if SB-IPMN remains unchanged for 2 years. Presence of mural nodule and dilated MPD seem to be more appropriate indicators for resection than cyst size alone for SB-IPMNs.
Five patients with obstructive jaundice caused by malignant periampullary biliary stenosis underwent EUS-guided choledochoduodenostomy (EUS-CDS) from the first portion of the duodenum using a convex ...echoendoscope and a needle knife. All the steps of the procedure including passage dilatation and the plastic stent placement were performed through the accessory channel of the echoendoscope over the guide wire. Stent insertion was technically successful in all five patients. The procedure was also clinically effective in relieving jaundice in all cases. One patient developed pneumoperitoneum, which resolved with conservative management. Stent exchange was successful in seven of eight attempts in patients with stent occlusion. One failure was due to tumor invasion to the choledochoduodenal fistula. Stent patency was maintained in the remaining patients throughout their survival period. The average stent patency was 211.8 days. EUS-CDS from the first portion of the duodenum appears to be feasible and safe in cases of obstructive jaundice caused by distal bile duct obstruction.
Neutropenia during chemotherapy has been reported to be a predictor of better survival in patients with several types of cancers, although there are no reports in pretreated patients.
We ...retrospectively analyzed 242 patients with advanced gastric cancer (AGC) who received weekly paclitaxel (Taxol) as second-line chemotherapy. Background characteristics and neutropenia as time-varying covariates (TVCs) were analyzed as prognostic factors.
Of the 242 patients, mild neutropenia (grades 1–2) occurred in 101 patients (41.7%) and severe neutropenia (grades 3–4) occurred in 63 patients (26.0%). The other 78 patients (32.2%) did not experience neutropenia. According to a multivariate Cox model with neutropenia as a TVC, hazard ratios of death were 0.61 95% confidence interval (CI) 0.43–0.85; P = 0.004 for patients with mild neutropenia and 0.61 (95% CI 0.41–0.88; P = 0.009) for those with severe neutropenia. Among the patients in landmark analysis (landmark of 2.5 months; median time to treatment failure of paclitaxel), mild and severe neutropenia remained significant prognostic factors.
Our results indicate that neutropenia during chemotherapy is associated with improved survival in patients with AGC who received weekly paclitaxel as second-line chemotherapy. Prospective trials are required to assess whether dosing adjustments based on neutropenia may improve chemotherapy efficacy.
Summary
Background
Some, but not all studies have provided evidence that the CagA status of Helicobacter pylori strains is a predictive factor for the outcome of eradication therapy.
Aim
To clarify ...the association between CagA status and eradication outcome.
Methods
We included studies reporting the numbers of successful and failed cases in H. pylori‐eradication therapy according to the CagA status. Fourteen studies (1529 patients) were included of 325 articles identified in the search. The pooled risk ratio for H. pylori‐eradication failure in CagA‐negative relative to CagA‐positive strains and the pooled risk difference in eradication success between the two groups were used as summary statistics. Meta‐regression was used for examining the source of heterogeneity.
Results
The summary risk ratio for eradication failure in CagA‐negative relative to CagA‐positive was 2.0 (95% CI: 1.6–2.4, P < 0.001), corresponding with the summary risk difference for eradication success between the groups of 11% (95% CI: 3–19%, P = 0.011). Meta‐regression analysis demonstrated that usage of polymerase chain reaction examination for CagA status and a high proportion of non‐ulcer dyspepsia patients were factors for heterogeneity among studies.
Conclusions
Our meta‐analysis confirmed the importance of the presence of CagA as a predictor for successful eradication of H. pylori.
S-1, a novel oral fluoropyrimidine, is well tolerated in patients with metastatic colorectal cancer (mCRC). The response rate of S-1 for colorectal cancer is high, ranging from 35% to 40%. This study ...aimed to evaluate the safety and efficacy of S-1 combined with oral leucovorin (LV) to enhance antitumor activity in chemotherapy-naive patients with mCRC.
S-1 was given orally twice daily for two consecutive weeks at a daily dose of 80–120 mg, followed by a 2-week rest period, within a 4-week cycle. LV was given orally twice a day at a daily dose of 50 mg, simultaneously with S-1.
Of the 56 patients with previously untreated mCRC, 32 (57%) had partial responses. The median follow-up period was 27.2 months. The median time to progression was 6.7 months (95% confidence interval 5.4–7.9). The median survival time was 24.3 months. There was no treatment-related death or grade 4 toxicity. The most common grade 3 toxic effects were diarrhea (32%), anorexia (21%), stomatitis (20%), and neutropenia (14%).
S-1 combined with LV therapy demonstrated promising efficacy and acceptable safety in chemotherapy-naive patients with mCRC without the concurrent use of irinotecan, oxaliplatin, or molecular-targeted drugs.
Endoscopic ultrasound-guided fine-needle tattooing (EUS-FNT) is an ideal technique for preoperative marking of lesions detected on preoperative examination. Although India ink has been used for ...endoscopic tattooing, there have been numerous reports of complications associated with its use. This is the first report of EUS-FNT using indocyanine green (ICG) and describes its use for preoperative marking of a tumor in a 78-year-old man with multiple pancreatic tumors. There were no complications associated with the EUS-FNT procedure and it is suggested that ICG is a more suitable dye for tattooing of pancreatic lesions than India ink, being far less frequently associated with side effects.
CYP2C19 polymorphisms and smoking influence the efficacy of H. pylori eradication therapy, but interaction between the two have hitherto not been examined. A total of 142 H. pylori-positive patients ...who received triple drug therapy with lansoprazole, amoxicillin and clarithromycin were categorized into three groups with regard to diplotypes of CYP2C19: homozygous extensive metabolizer (homEM), heterozygous EM (hetEM), and poor metabolizer (PM). The overall success rate was 61·3%. Smoking was an independent risk factor of eradication failure (OR 2·81, 95% CI 1·14–6·91), whereas CYP2C19 polymorphisms were less influential. Among non-smokers, the homEM and hetEM groups showed worse eradication rates (58·5 and 67·3%) relative to PM (76·2%) as expected; however, an opposite trend was observed among smokers (homEM 50·0%, hetEM 46·7%, PM 20·0%), indicating possible interactions with CYP2C19 polymorphisms. Smoking has a greater influence on H. pylori eradication than the CYP2C19 genotype. Interaction between smoking and CYP2C19 should be examined in the future.
PDF
