Summary Background Phosphatidylinositol 3-kinase (PI3K) pathway activation is a hallmark of endocrine therapy-resistant, hormone receptor-positive breast cancer. This phase 3 study assessed the ...efficacy of the pan-PI3K inhibitor buparlisib plus fulvestrant in patients with advanced breast cancer, including an evaluation of the PI3K pathway activation status as a biomarker for clinical benefit. Methods The BELLE-2 trial was a randomised, double-blind, placebo-controlled, multicentre study. Postmenopausal women aged 18 years or older with histologically confirmed, hormone receptor-positive and human epidermal growth factor (HER2)-negative inoperable locally advanced or metastatic breast cancer whose disease had progressed on or after aromatase inhibitor treatment and had received up to one previous line of chemotherapy for advanced disease were included. Eligible patients were randomly assigned (1:1) using interactive voice response technology (block size of 6) on day 15 of cycle 1 to receive oral buparlisib (100 mg/day) or matching placebo, starting on day 15 of cycle 1, plus intramuscular fulvestrant (500 mg) on days 1 and 15 of cycle 1, and on day 1 of subsequent 28-day cycles. Patients were assigned randomisation numbers with a validated interactive response technology; these numbers were linked to different treatment groups which in turn were linked to treatment numbers. PI3K status in tumour tissue was determined via central laboratory during a 14-day run-in phase. Randomisation was stratified by PI3K pathway activation status (activated vs non-activated vs and unknown) and visceral disease status (present vs absent). Patients, investigators, local radiologists, study team, and anyone involved in the study were masked to the identity of the treatment until unblinding. The primary endpoints were progression-free survival by local investigator assessment per Response Evaluation Criteria In Solid Tumors (version 1.1) in the total population, in patients with known (activated or non-activated) PI3K pathway status, and in PI3K pathway-activated patients. Efficacy analyses were done in the intention-to-treat population. Safety was analysed in all patients who received at least one dose of study drug and had at least one post-baseline safety assessment according to the treatment they received. This trial is registered with ClinicalTrials.gov , number NCT01610284 , and is currently ongoing but not recruiting participants. Findings Between Sept 7, 2012, and Sept 10, 2014, 1147 patients from 267 centres in 29 countries were randomly assigned to receive buparlisib (n=576) or placebo plus fulvestrant (n=571). In the total patient population (n=1147), median progression-free survival was 6·9 months (95% CI 6·8–7·8) in the buparlisib group versus 5·0 months (4·0–5·2) in the placebo group (hazard ratio HR 0·78 95% CI 0·67–0·89; one-sided p=0·00021). In patients with known PI3K status (n=851), median progression-free survival was 6·8 months (95% CI 5·0–7·0) in the buparlisib group vs 4·5 months (3·3–5·0) in the placebo group (HR 0·80 95% CI 0·68–0·94; one-sided p=0·0033). In PI3K pathway-activated patients (n=372), median progression-free survival was 6·8 months (95% CI 4·9–7·1) in the buparlisib group versus 4·0 months (3·1–5·2) in the placebo group (HR 0·76 0·60–0·97, one-sided p=0·014). The most common grade 3–4 adverse events in the buparlisib group versus the placebo group were increased alanine aminotransferase (146 25% of 573 patients vs six 1% of 570), increased aspartate aminotransferase (103 18% vs 16 3%), hyperglycaemia (88 15% vs one <1%), and rash (45 8% vs none). Serious adverse events were reported in 134 (23%) of 573 patients in the buparlisib group compared with 90 16% of 570 patients in the placebo group; the most common serious adverse events (affecting ≥2% of patients) were increased alanine aminotransferase (17 3% of 573 vs one <1% of 570) and increased aspartate aminotransferase (14 2% vs one <1%). No treatment-related deaths occurred. Interpretation The results from this study show that PI3K inhibition combined with endocrine therapy is effective in postmenopausal women with endocrine-resistant, hormone receptor-positive and HER2-negative advanced breast cancer. Use of more selective PI3K inhibitors, such as α-specific PI3K inhibitor, is warranted to further improve safety and benefit in this setting. No further studies are being pursued because of the toxicity associated with this combination. Funding Novartis Pharmaceuticals Corporation.
Radiation therapy (RT) is an effective method of palliating painful bone metastases and can improve function and reduce analgesic requirements. In advanced cancer patients, quality of life (QOL) is ...the primary outcome of interest over traditional endpoints such as survival. The purpose of our study was to compare bone metastasis-specific QOL scores among patients who responded differently to palliative RT.
Patients receiving RT for bone metastases across 6 countries were prospectively enrolled from March 2010-January 2011 in a trial validating the QLQ-BM22 and completed the QLQ-BM22 and the core measure (QLQ-C30) at baseline and after 1 month. Pain scores and analgesic intake were recorded, and response to RT was determined according to the latest published guidelines. The Kruskal-Wallis nonparametric and Wilcoxon rank sum tests compared changes in QOL among response groups. A Bonferroni-adjusted P<.003 indicated statistical significance.
Of 79 patients who received palliative RT, 59 were assessable. Partial response, pain progression, and indeterminate response were observed in 22, 8, and 29 patients, respectively; there were no patients with a complete response. Patients across all groups had similar baseline QOL scores apart from physical functioning (patients who progressed had better initial functioning). One month after RT, patients who responded had significant improvements in 3 of 4 QLQ-BM22 domains (painful site, P<.0001; painful characteristic, P<.0001; and functional interference, P<.0001) and 3 QLQ-C30 domains (physical functioning, P=.0006; role functioning, P=.0026; and pain, P<.0001). Patients with progression in pain had significantly worse functional interference (P=.0007) and pain (P=.0019).
Patients who report pain relief after palliative RT also have better QOL with respect to bone metastasis-specific issues. The QLQ-BM22 and QLQ-C30 are able to discriminate among patients with varying responses and are recommended for use in future bone metastasis clinical trials.
Summary Background In the primary analysis of the NeoSphere trial, patients given neoadjuvant pertuzumab, trastuzumab, and docetaxel showed a significantly improved pathological complete response ...compared with those given trastuzumab and docetaxel after surgery. Here, we report 5-year progression-free survival, disease-free survival, and safety. Methods In this multicentre, open-label, phase 2 randomised trial in hospitals and medical clinics, treatment-naive adults with locally advanced, inflammatory, or early-stage HER2-positive breast cancer were randomly assigned (1:1:1:1) to receive four neoadjuvant cycles of trastuzumab (8 mg/kg loading dose, followed by 6 mg/kg every 3 weeks) plus docetaxel (75 mg/m2 every 3 weeks, increasing to 100 mg/m2 from cycle 2 if tolerated; group A), pertuzumab (840 mg loading dose, followed by 420 mg every 3 weeks) and trastuzumab plus docetaxel (group B), pertuzumab and trastuzumab (group C), or pertuzumab and docetaxel (group D). After surgery, patients received three cycles of FEC (fluorouracil 600 mg/m2 , epirubicin 90 mg/m2 , and cyclophosphamide 600 mg/m2 ) every 3 weeks (patients in group C received four cycles of docetaxel prior to FEC), and trastuzumab 6 mg/kg every 3 weeks to complete 1 year's treatment (17 cycles in total). Randomisation was done by a central centre using dynamic allocation, stratified by operable, locally advanced, and inflammatory breast cancer, and by oestrogen and/or progesterone receptor positivity. Safety analyses were done according to treatment received. The primary endpoint (pathological complete response) was previously reported; secondary endpoints reported here are 5-year progression-free survival (analysed in the intention-to-treat population) and disease-free survival (analysed in patients who had surgery). Secondary and exploratory analyses were not powered for formal statistical hypothesis testing, and therefore results are for descriptive purposes only. The study ended on Sept 22, 2014 (last patient, last visit). This study is registered with ClinicalTrials.gov , number NCT00545688. Findings Between Dec 17, 2007, and Dec 22, 2009, 417 eligible patients were randomly assigned to group A (107 patients), group B (107 patients), group C (107 patients), or group D (96 patients). One patient in group A withdrew before treatment. One patient assigned to group D received group A treatment, one patient assigned to group D received group B treatment, and one patient assigned to group B received group C treatment. At clinical cutoff, 87 patients had progressed or died. 5-year progression-free survival rates were 81% (95% CI 71–87) for group A, 86% (77–91) for group B, 73% (64–81) for group C, and 73% (63–81) for group D (hazard ratios 0·69 95% CI 0·34–1·40 group B vs group A, 1·25 0·68–2·30 group C vs group A, and 2·05 1·07–3·93 group D vs group B). Disease-free survival results were consistent with progression-free survival results and were 81% (95% CI 72–88) for group A, 84% (72–91) for group B, 80% (70–86) for group C, and 75% (64–83) for group D. Patients who achieved total pathological complete response (all groups combined) had longer progression-free survival compared with patients who did not (85% 76–91 in patients who achieved total pathological response vs 76% 71–81 in patients who did not achieve total pathological response; hazard ratio 0·54 95% CI 0·29–1·00). There were no new or long-term safety concerns and tolerability was similar across groups (neoadjuvant and adjuvant treatment periods combined). The most common grade 3 or worse adverse events were neutropenia (group A: 71 66% of 107 patients; group B: 59 55% of 107; group C: 40 37% of 108; group D: 60 64% of 94), febrile neutropenia (group A: 10 9%; group B: 12 11%; group C: 5 5%; group D: 15 16%), and leucopenia (group A: 13 12%; group B: 6 6%; group C: 4 4%; group D: 8 9%). The number of patients with one or more serious adverse event was similar across groups (19–22 serious adverse events per group in 18–22% of patients). Interpretation Progression-free survival and disease-free survival at 5-year follow-up show large and overlapping CIs, but support the primary endpoint (pathological complete response) and suggest that neoadjuvant pertuzumab is beneficial when combined with trastuzumab and docetaxel. Additionally, they suggest that total pathological complete response could be an early indicator of long-term outcome in early-stage HER2-positive breast cancer. Funding F Hoffmann-La Roche.
Summary Background Studies with pertuzumab, a novel anti-HER2 antibody, show improved efficacy when combined with the established HER2-directed antibody trastuzumab in breast cancer therapy. We ...investigated the combination of pertuzumab or trastuzumab, or both, with docetaxel and the combination of pertuzumab and trastuzumab without chemotherapy in the neoadjuvant setting. Methods In this multicentre, open-label, phase 2 study, treatment-naive women with HER2-positive breast cancer were randomly assigned (1:1:1:1) centrally and stratified by operable, locally advanced, and inflammatory breast cancer, and by hormone receptor expression to receive four neoadjuvant cycles of: trastuzumab (8 mg/kg loading dose, followed by 6 mg/kg every 3 weeks) plus docetaxel (75 mg/m2 , escalating, if tolerated, to 100 mg/m2 every 3 weeks; group A) or pertuzumab (loading dose 840 mg, followed by 420 mg every 3 weeks) and trastuzumab plus docetaxel (group B) or pertuzumab and trastuzumab (group C) or pertuzumab plus docetaxel (group D). The primary endpoint, examined in the intention-to-treat population, was pathological complete response in the breast. Neither patients nor investigators were masked to treatment. This study is registered with ClinicalTrials.gov , number NCT00545688. Findings Of 417 eligible patients, 107 were randomly assigned to group A, 107 to group B, 107 to group C, and 96 to group D. Patients given pertuzumab and trastuzumab plus docetaxel (group B) had a significantly improved pathological complete response rate (49 of 107 patients; 45·8% 95% CI 36·1–55·7) compared with those given trastuzumab plus docetaxel (group A; 31 of 107; 29·0% 20·6–38·5; p=0·0141). 23 of 96 (24·0% 15·8–33·7) women given pertuzumab plus docetaxel (group D) had a pathological complete response, as did 18 of 107 (16·8% 10·3–25·3) given pertuzumab and trastuzumab (group C). The most common adverse events of grade 3 or higher were neutropenia (61 of 107 women in group A, 48 of 107 in group B, one of 108 in group C, and 52 of 94 in group D), febrile neutropenia (eight, nine, none, and seven, respectively), and leucopenia (13, five, none, and seven, respectively). The number of serious adverse events was similar in groups A, B, and D (15–20 serious adverse events per group in 10–17% of patients) but lower in group C (four serious adverse events in 4% of patients). Interpretation Patients given pertuzumab and trastuzumab plus docetaxel (group B) had a significantly improved pathological complete response rate compared with those given trastuzumab plus docetaxel, without substantial differences in tolerability. Pertuzumab and trastuzumab without chemotherapy eradicated tumours in a proportion of women and showed a favourable safety profile. These findings justify further exploration in adjuvant trials and support the neoadjuvant approach for accelerating drug assessment in early breast cancer. Funding F Hoffmann-La Roche.
Breast cancer subtypes can be stratified by immunohistochemical (IHC) expression of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor 2 (HER2). The signaling ...pathways mediated by these receptors are the dominant drivers of cell proliferation and survival in the majority of human breast cancers. One of the most frequently overactivated pathways in breast cancer is the AKT signaling cascade. Protein phosphatase 2A (PP2A) acts as a switch to turn off signal transduction in the AKT pathway; however, it is frequently inactivated in many cancers by phosphorylation of Tyr-307 to form phosphoprotein phosphatase 2A (p-PP2A). This study aimed to investigate the clinical significance of p-PP2A and phospho-AKT (p-AKT) expression in patients with 672 breast cancer during a 15-year follow-up. The breast tissue microarray (TMA) was evaluated for p-PP2A and p-AKT expression using IHC staining and scores. Analysis of IHC staining results revealed that p-PP2A expression was positively correlated with HER2, Ki67, and p-AKT overexpression (P < .001, P = .003, and P = .001, respectively). At the time of diagnosis, breast cancer patients with higher p-PP2A expression had significantly shorter 15-year overall survival (OS) than patients with lower p-PP2A expression did (P = .017). Multivariate Cox regression analysis revealed that high p-PP2A expression was an independent prognostic factor for shorter OS (hazard ratio 1.741, P = .012). Our data revealed that high p-PP2A expression is positively associated with HER-2, Ki67, and p-AKT expression. High p-PP2A expression correlates with poor clinical outcomes in breast cancer, especially in patients with triple-negative breast cancer (TNBC).
Abstract Objective This study aimed to identify pre-endoscopic clinical parameters independently associated with 6-week mortality and to develop a prognostic model in cirrhotic patients with acute ...upper gastrointestinal (UGI) bleeding. Methods A total of 542 consecutive admissions of 389 cirrhotic patients with acute UGI bleeding were retrospectively investigated. Pertinent clinical data obtained at the emergency department were analyzed. Multivariate logistic regression analysis was performed to determine risk factors for 6-week mortality and to develop a predictive model. Results Forty-four patients (8.12%) died within 6 weeks. The 6-week mortality was independently associated with male sex, hepatocellular carcinoma, non–hepatocellular carcinoma malignancy, hypoxemia with peripheral oxygen saturation less than 95%, serum bilirubin, and prothrombin time. A predictive model consisting of these 6 simple parameters was built. The c statistic of our model was 0.84, significantly superior to that (0.71) of the model for end-stage liver disease score ( P = .002). Conclusions Simple pre-endoscopic clinical parameters are valuable for early risk stratification in cirrhotic patients with acute UGI bleeding. Our prognostic model warrants prospective validation by further studies.
In the era of the coronavirus disease 2019 (COVID-19) pandemic, surgeons and medical staff are often at a high risk of infection in the operating room, especially when the patient is spontaneously ...breathing. In this study, we examined the minimum requirements for personal protective equipment with double surgical masks to potentially reduce unnecessary waste of supplies.
Two mannequins were each connected to a test lung machine simulating a surgeon and patient with spontaneous breathing. An aerosol generator containing severe acute respiratory syndrome coronavirus 2 virion particle substitutes was connected to the patient mannequin. The sampling points for the target molecules were set at different distances from the patient mannequin and sent for multiplex quantitative polymerase chain reaction analysis. Three clinical scenarios were designed, which differed in terms of the operating room pressure and whether a fabric curtain barrier was installed between the mannequins.
Analysis of the multiplex quantitative polymerase chain reaction results showed that the cycle threshold (Ct) value of the target molecule increased as the distance from the aerosol source increased. In the negative-pressure operating room, the Ct values were significantly increased at all sample points compared with the normal pressure room setting. The Ct value sampled at the surgeon mannequin wearing double face masks was significantly increased when a cloth curtain barrier was set up between the two mannequins.
Double surgical masks provide elementary surgeon protection against COVID-19 in a negative pressure operating room, with a physical barrier in place between the surgeon and patient who is spontaneously breathing during local anesthesia or sedated surgery.
The CHA₂DS₂-VASC scoring scheme may not be better than the CHADS₂ scoring scheme in predicting thromboembolic risk for patients with atrial fibrillation (AF) in Asians. Metabolic syndrome is ...associated with an increased risk of thrombosis.
To evaluate whether metabolic syndrome offers incremental information over the CHADS₂ scheme in predicting thromboembolic risk for patients with AF in the Taiwanese population.
The study population consisted of 721 consecutive patients with AF who had been followed up for a median of 10.8 years. Thromboembolic end points were defined as ischemic stroke/transient ischemic accident and peripheral embolisms. Clinical factors associated with thromboembolic end points were identified by Cox regression analysis. Different scoring systems were compared by receiver operating characteristic (ROC) analysis.
We found that components in the CHADS₂ scheme were associated with an increased risk of thromboembolism. The CHA2DS₂-VASC scheme did not provide information additional to that provided by the CHADS₂ scheme on thromboembolism risk (ROC area: 0.670 vs 0.665; P > .05). Metabolic syndrome components were also associated with increased risk of thromboembolism. The incident thromboembolic rate increased incrementally when metabolic syndrome score increased. Additional metabolic syndrome components provide additional information to the CHADS₂ scheme on thromboembolism risk (ROC area: 0.670 vs 0.729; P = .034). We therefore proposed a new scoring scheme called CHADS₂-MS scoring scheme. In patients with low to intermediate CHADS₂ scores (0-1), the use of the CHADS₂-MS score may additionally identify patients with high-risk AF for future thromboembolism.
We, for the first time, demonstrated that metabolic syndrome components were associated with thromboembolic risk in Taiwanese patients with AF. In addition to the conventional CHADS₂ scheme, the calculation of the CHADS₂-MS score provides additional information on stroke risk assessment.
A variety of bowel interpositions have been well-developed for esophageal replacement surgery. However the choices are often limited in the case of alimentary corrosive injury due to frequent ...associated injuries. Herein we present a case of caustic injury with compromised mesocolon. Successful reconstruction of the alimentary integrity was accomplished using an ileocolic graft pedicled on an ileocolic artery.
Background We investigated the impact of serum cholesterol levels on 30-day mortality after ischemic stroke in dialysis patients. Methods From the Taiwan Stroke Registry data, we identified 46,770 ...ischemic stroke cases, including 1101 dialysis patients and 45,669 nondialysis patients from 2006 to 2013. Results Overall, the 30-day mortality was 1.46-fold greater in the dialysis group than in the nondialysis group (1.75 versus 1.20 per 1000 person-days). The mortality rates were 1.64, .62, 2.82, and 2.23 per 1000 person-days in dialysis patients with serum total cholesterol levels of <120 mg/dL, 120-159 mg/dL, 160-199 mg/dL, and ≥200 mg/dL, respectively. Compared to dialysis patients with serum total cholesterol levels of 120-159 mg/dL, the corresponding adjusted hazard ratios of mortality were 4.20 (95% confidence interval CI = 1.01-17.4), 8.06 (95% CI = 2.02-32.2), and 6.89 (95% CI = 1.59-29.8) for those with cholesterol levels of <120 mg/dL, 160-199 mg/dL, and ≥200 mg/dL, respectively. Conclusions Dialysis patients with serum total cholesterol levels of ≥160 mg/dL or <120 mg/dL on admission are at an elevated hazard of 30-day mortality after ischemic stroke.
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