Pimitespib in patients with advanced gastrointestinal stromal tumor (CHAPTER-GIST-301): a randomized, double-blind, placebo-controlled phase III trial.

BACKGROUND: 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 AND METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Development of pancreatic cancers during long-term follow-up of side-branch intraductal papillary mucinous neoplasms.

BACKGROUND AND STUDY AIMS: 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. PATIENTS AND METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Neutropenia as a prognostic factor in advanced gastric cancer patients undergoing second-line chemotherapy with weekly paclitaxel.

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Phase II study of S-1 plus leucovorin in patients with metastatic colorectal cancer.

BACKGROUND: 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. PATIENTS AND METHODS: 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. RESULTS: 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%). CONCLUSION: 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.

EUS-guided choledochoduodenostomy for palliative biliary drainage in patients with malignant biliary obstruction: results of long-term follow-up.

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.

Influence of smoking and CYP2C19 genotypes on H. pylori eradication success.

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.

Systematic review and meta-analysis: importance of CagA status for successful eradication of Helicobacter pylori infection.

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.

Indocyanine green is an ideal dye for endoscopic ultrasound-guided fine-needle tattooing of pancreatic tumors.

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.

Three-dimensional image display without special eyeglasses: observation of magnetic resonance angiography using the stereoscopic liquid crystal display.

The authors have developed a new stereoscopic liquid crystal display that provides real-time 3-dimensional image viewing without special eyeglasses. The device consists of 3 major parts: (1) an image display composed of a 10.4-inch color liquid crystal plate with a resolution of 640 x 480, (2) an automatic head tracking system, and (3) a special backlight unit for the right and left eyes. Eight radiologists interpreted 60 cases of magnetic resonance angiography (29 cases of cerebrovascular disease and 31 normal cases) to compare film display and the liquid crystal display (ie, pseudo 3-dimensional display and true 3-dimensional display). Using a continuously distributed scale ranging from 0% to 100%, the observers ranked their confidence levels in determining the presence or absence of steno-occlusive disease, aneurysm, and arteriovenous malformation (AVM) and their locations. For statistical evaluation, receiver operating characteristic (ROC) analysis and Brier score were used. For detecting AVM, film reading showed a significantly higher value in the area under the binormal ROC curve (Az) than did pseudo-3-dimensional display (P < .05). Excluding this, however, no significant difference existed in Az values among the 3 viewing methods. Also, there was no significant difference in Brier score between not only the stereoscopic view and nonstereoscopic view groups, but also the senior and junior groups. Subjective estimation of true 3-dimensional display showed that vessels were more distinguishable with less eye fatigue compared with stereoscopic film reading. The stereoscopic liquid crystal display provided almost equal efficacy to film reading; however, the short optimum distance for observation and the low resolution should be improved.

Further reduction of radiation dose in helical CT for lung cancer screening using small tube current and a newly designed filter.

A new aluminum filter, 5.8 mm thick at the center, was designed. The effective energy, exposure dose, absorbed dose, and noise were measured by using low-dose technique, very low-dose technique with a conventional filter, and very low-dose technique with a new filter on a chest phantom. Accuracy of very low-dose computed tomography (CT) with a new filter was compared against standard helical CT in 40 patients and against chest radiography in 35 patients. Effective energies were 42.6 keV and 51.6 keV at a conventional filter and the new filter, respectively. Compared against 20mA with a conventional filter, exposure dose was reduced by 17%, and absorbed dose was equivalent, at 30 mA with the new filter. Noise was improved by 9%. Compared with standard helical CT, the sensitivity, specificity, and accuracy of very-low-dose helical CT were 100%, 88%, and 95%, respectively. Very-low-dose helical CT was found to be significantly superior to chest radiography in the detection of lung cancers. Using a smaller tube current and an appropriate filter allows a further reduction in radiation dose in helical CT for lung cancer screening.

Role of ultrasonography in the detection of intraductal spread of breast cancer: correlation with pathologic findings, mammography and MR imaging.

The purpose of this study was to assess the role of US in the detection of intraductal spread of breast cancer in comparison with mammography (MMG) and MRI. In 46 patients with breast cancer, US features of the intraductal component were classified as ductal type or distorted type. Histopathologically, 29 of 46 (63%) cases had intraductal components, and the sensitivity, specificity, and accuracy rates in detection of intraductal spread were 89, 76, and 85%, respectively. Each US pattern demonstrated good correspondence to the histologic components, and the distorted type correlated well with comedo-type carcinoma. Mammography was performed in all cases, and the sensitivity, specificity, and accuracy rates in detection of intraductal spread were 55, 100, and 72%, respectively. In comedo type, MMG could diagnose the extent of intraductal spread more accurately compared with US examination. Magnetic resonance imaging comparison was available in 25 cases. Magnetic resonance imaging depicted intraductal extension as an enhanced area during the early phase of a contrast enhancement study with a sensitivity of 93%. Ultrasound and MRI were closely related in terms of morphologic characteristics: the ductal type of US image correlated well with linear enhancement on MRI, whereas the distorted type correlated with regional or segmental enhancement. Current US examination is useful in depicting the intraductal spread of breast cancer; however, US has a tendency to underestimate intraductal component of comedo type compared with MMG and MRI.

Breast ultrasonography: diagnostic efficacy of a computer-aided diagnostic system using fuzzy inference.

We have developed a computer-aided diagnostic (CAD) system using fuzzy inference for breast sonography and have evaluated the performance of the system. Our CAD system is not an automated image processing method, but requires the observer's subjective "scoring." Seven radiologists interpreted 54 breast mass lesions (24 malignant, 30 benign). Six criteria (shape, border, halo, internal echoes, posterior echoes, and edge shadows) were scored using a five-point rating scale. The output was described as a real number from 0.0 to 1.0. For cancer diagnosis, the sensitivity of the radiologists, a six-criteria CAD version, and a four-criteria version (excluding posterior echoes and edge shadows) were 63.1%, 82.1%, and 78.0%, respectively. Specificity was 71.0%, 42.9%, and 51.0%, respectively, while accuracy was 67.5%, 60.3%, and 63.0%, respectively. No significant differences in the areas under ROC curve (Az) were found between the observers and CAD system. Several cases assessed as false-negative by observers were correctly diagnosed by the CAD system, and diagnostic efficacy could be improved, especially among novice sonographers. Although the system's high false-positive rate needs to be reduced, it will assist radiologists in generating a level of suspicion for malignancy.

Interobserver agreement in sonographic diagnosis of breast tumors.

OBJECTIVE: To evaluate interobserver agreement in the interpretation of breast ultrasonography. METHODS: 55 breast masses (30 benign, 24 malignant) were interpreted by seven radiologists using a CRT viewing station. US criteria for differentiating between benign and malignant lesions included shape, border, boundary echoes, internal echoes, posterior echoes, and bilateral shadows. Each criterion and the observers' final impression was scored using the 5-point rating scales. For analyzing interobserver agreement, the kappa (kappa) values were employed. RESULTS: The kappa values of shape and posterior echoes were significantly higher than those of the other four criteria (P<0.05). Agreement was intermediate in border and internal echoes, and was low in boundary echoes and bilateral shadows. Agreement in the senior group (four observers) was relatively higher than that in the junior group (three observers) for all criteria but for internal echoes. Easily-diagnosed cases showed significantly higher kappa values compared with more ambiguous cases (P<0.05). CONCLUSION: Interobserver agreement in shape and posterior echoes was significantly higher than those of the other four criteria. Agreement was significantly dependent on case difficulty.

Preoperative staging of thyroid papillary carcinoma with ultrasonography.

OBJECTIVE: To evaluate the usefulness of ultrasonography including Doppler flow imaging for the preoperative staging of thyroid papillary carcinoma. MATERIALS AND METHODS: In 77 patients with thyroid papillary carcinoma who underwent total thyroidectomy, the accuracy of ultrasonography in preoperative clinical staging was assessed with use of pathologic examination on the basis of TNM classification by the International Union Against Cancer (UICC). RESULTS: In 63 (81.8%) cases, T categories were estimated accurately. The sensitivity in depicting tumor extension into the prethyroidal muscle and/or the sternocleidomastoid muscle was 77.8%, whereas the sensitivity for invasion into the trachea and the esophagus was 42.9 and 28.6%, respectively. In 37 (48.1%) cases, N categories were underestimated, and the sensitivity in the detection of regional lymph node metastasis was 36.7%. Doppler flow imaging was performed in 36 patients, and no correlation was found between flow patterns and the presence of local invasion or regional lymph node metastasis. CONCLUSION: Ultrasonography was useful for preoperative investigation of thyroid papillary carcinoma, but several limitations existed, especially in evaluating extracapsular invasion to deep locations and regional lymph node metastasis.