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SummaryBackgroundWe aimed to report on long-term outcomes of patients with small, node-negative, HER2-positive breast cancer treated with adjuvant paclitaxel and trastuzumab and to establish potential biomarkers to predict prognosis. MethodsIn this open-label, single-arm, phase 2 study, patients aged 18 years or older, with small (≤3 cm), node-negative, HER2-positive breast cancer, and an Eastern Cooperative Oncology Group performance status of 0–1, were recruited from 16 institutions in 13 cities in the USA. Eligible patients were given intravenous paclitaxel (80 mg/m 2) with intravenous trastuzumab (loading dose of 4 mg/kg, subsequent doses 2 mg/kg) weekly for 12 weeks, followed by trastuzumab (weekly at 2 mg/kg or once every 3 weeks at 6 mg/kg) for 40 weeks to complete a full year of trastuzumab. The primary endpoint was 3-year invasive disease-free survival. Here, we report 10-year survival outcomes, assessed in all participants who received protocol-defined treatment, with exploratory analyses using the HER2DX genomic tool. This study is registered on ClinicalTrials.gov, NCT00542451, and is closed to accrual. FindingsBetween Oct 29, 2007, and Sept 3, 2010, 410 patients were enrolled and 406 were given adjuvant paclitaxel and trastuzumab and included in the analysis. Mean age at enrolment was 55 years (SD 10·5), 405 (99·8%) of 406 patients were female and one (0·2%) was male, 350 (86·2%) were White, 28 (6·9%) were Black or African American, and 272 (67·0%) had hormone receptor-positive disease. After a median follow-up of 10·8 years (IQR 7·1–11·4), among 406 patients included in the analysis population, we observed 31 invasive disease-free survival events, of which six (19·4%) were locoregional ipsilateral recurrences, nine (29·0%) were new contralateral breast cancers, six (19·4%) were distant recurrences, and ten (32·3%) were all-cause deaths. 10-year invasive disease-free survival was 91·3% (95% CI 88·3–94·4), 10-year recurrence-free interval was 96·3% (95% CI 94·3–98·3), 10-year overall survival was 94·3% (95% CI 91·8–96·8), and 10-year breast cancer-specific survival was 98·8% (95% CI 97·6–100). HER2DX risk score as a continuous variable was significantly associated with invasive disease-free survival (hazard ratio [HR] per 10-unit increment 1·24 [95% CI 1·00–1·52]; p=0·047) and recurrence-free interval (1·45 [1·09–1·93]; p=0·011). InterpretationAdjuvant paclitaxel and trastuzumab is a reasonable treatment standard for patients with small, node-negative, HER2-positive breast cancer. The HER2DX genomic tool might help to refine the prognosis for this population. FundingGenentech.

Pesticide residue in food, especially in vegetables, is one of the important parameters to assess food safety. This study evaluates the pesticide use in vegetables from two provinces in Central Vietnamand and present data on pesticides detected in vegetables sampled from the sites. The potential health risk associated with the contamination of four commonly used pesticides in different vegetables is also discussed. Both household surveys and monitoring campaigns were conducted. The survey showed that improper pesticide application, storage, and waste disposal prevailed at the study sites. Only 20% of the respondent were aware of pesticide toxicity. As a result, pesticides were detected in 81% out of 290 vegetable samples collected at harvesting time. Up to 23% of samples had pesticide residues above the Maximum Residue Limit values. The highest total pesticide concentration quantified in vegetables in Thua Thien Hue was 11.9 mg/kg (green onions), and in Quang Binh was 38.6 mg/kg (mustard greens). Median residue levels of individual pesticides in vegetables ranged from 0.007 to 0.037 mg/kg. Among the ten target pesticides, cypermethrin, difenoconazole, and fenobucarb were detected at the highest frequencies (72%, 41%, and 37%, respectively). Pesticide residues varied between seasons at both study provinces. Pesticide contamination in the wet season was significantly higher than in the dry season. This study also discovered a potential health risk associated with fipronil residues in vegetables in Thua Thien Hue province. The paper provides recommendations for mitigation measures (both technological and social) in reducing potential health risks linked to pesticide use in vegetables in the region.

A multicenter single-group trial suggests that adjuvant therapy with paclitaxel plus trastuzumab lowers the risk of relapse in women with small HER2-positive breast cancers. Overexpression of the human epidermal growth factor receptor type 2 (HER2) occurs in approximately 15 to 20% of invasive breast cancers and was historically associated with poor clinical outcomes. 1 – 4 Trastuzumab, a humanized monoclonal antibody that binds HER2, improves the outcomes for patients with HER2-positive breast cancer. Four phase 3 randomized trials involving more than 8000 patients showed that when trastuzumab was administered in combination with or after chemotherapy, the risk of recurrence was decreased by approximately 50% and overall survival improved. 5 – 9 These trials focused largely on patients with stage II or stage III HER2-positive breast cancers. Although patients . . .

IntroductionRates of downstaging and tolerability to NAC in women age ≥ 70 years with operable breast cancer have not been well studied. We sought to compare downstaging rates and NAC completion between women age 50–69 years and age ≥ 70 years.MethodsConsecutively treated women age ≥ 50 years with cT1–3N0–1 breast cancer receiving NAC followed by surgery from November 2013 to April 2020 were studied. Rates of downstaging from breast-conserving surgery (BCS)-ineligible to BCS-eligible and avoidance of axillary dissection (ALND) in cN1 patients were compared between patients age 50–69 and ≥ 70 years. NAC regimens and rates of completion also were assessed.ResultsOverall, 651 women, age ≥ 50 years, with 668 cT1–3N0–1 breast cancers that were treated with NAC, were identified; 75 (11.1%) were age ≥ 70 years. Patients age ≥ 70 years were less likely to have lobular cancers (5% vs. 10%, p = 0.03), receive an anthracycline-based regimen (69% vs. 93%, p < 0.001), and complete their entire prescribed regimen (57% vs. 78%, p < 0.001). Of 312 BCS-ineligible patients eligible for downstaging, conversion rates to BCS-eligibility were similar between age groups (72% [≥ 70] vs. 74% [50–69], p > 0.9). Women age ≥ 70 years who converted to BCS-eligible post-NAC were more likely to undergo BCS than younger patients (93% vs. 74%, p = 0.04). Of 390 cN1 patients, 162 (42%) achieved a nodal pCR; ALND avoidance was similar between age groups (43% [≥ 70] vs. 42% [50–69], p > 0.9).ConclusionsWhile patients age ≥ 70 years received less anthracycline-based NAC and were less likely to complete their prescribed regimen, they experienced high rates of breast and axillary downstaging, similar to younger patients, suggesting that well-selected elderly patients can safely receive NAC with substantial clinical benefit.

Breast cancer (BC) with expression of the estrogen receptor (ER) and/or progesterone receptor (PR) protein and with overexpression/amplification of the human epidermal growth factor receptor 2 (HER2), termed hormone receptor-positive (HR+)/HER2+ BC, represents ∼10% of all BCs in the United States. HR+/HER2+ BC includes HER2+ BCs that are ER+, PR+, or both ER+ and PR+ (triple-positive BC). Although the current guideline-recommended treatment combination of anti-HER2 monoclonal antibodies plus chemotherapy is an effective first-line therapy for many patients with HER2+ advanced disease, intratumoral heterogeneity within the HR+/HER2+ subtype and differences between the HR+/HER2+ subtype and the HR−/HER2+ subtype suggest that other targeted combinations could be investigated in randomized clinical trials for patients with HR+/HER2+ BC. In addition, published data indicate that crosstalk between HRs and HER2 can lead to treatment resistance. Dual HR and HER2 pathway targeting has been shown to be a rational approach to effective and well-tolerated therapy for patients with tumors driven by HER2 and HR, as it may prevent development of resistance by blocking receptor pathway crosstalk. However, clinical trial data for such approaches are limited. Treatments to attenuate other signaling pathways involved in receptor crosstalk are also under investigation for inclusion in dual receptor targeting regimens. These include cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors, based on the rationale that association of CDK4/6 with cyclin D1 may play a role in resistance to HER2-directed therapies, and others such as phosphatidylinositol-3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) pathway inhibitors. Herein, we will review the scientific and clinical rationale for combined receptor blockade targeting HER2 and ER for patients with advanced-stage HR+/HER2+ disease.

A comparative study of optical spectra of Type Ia supernovae (SNe Ia) is extended, in light of new data. The discussion is framed in terms of the four groups defined in previous papers of this series: core normal (CN), broad line (BL), cool (CL), and shallow silicon (SS). Emerging features of the SN Ia spectroscopic diversity include evidence (1) that extreme CL SN 1991bg–likes are not a physically distinct subgroup and (2) for the existence of a substantial number of SN 1999aa–like SSs that are very similar to each other and distinguishable from CN even as late as 3 weeks after maximum light. SN 1999aa–likes may be relatively numerous yet not a physically distinct subgroup. The efficacy of quantitative spectroscopic subclassification of SNe Ia based on the equivalent widths of absorption features near 5750 Å and 6100 Å near maximum light is discussed. The absolute-magnitude dispersion of a small sample of CNs is no larger than the characteristic absolute-magnitude uncertainty.

This work proposed a novel procedure of Water Quality Index (WQI) development that could be used for practical applications on a local or regional scale, based on available monitoring data. Principal component analysis (PCA) was applied to the monthly data of 11 water quality parameters (pH, conductivity (EC), total suspended solid (TSS), dissolved oxygen (DO), five -day biological oxygen demand (BOD), chemical oxygen demand (COD), ammonia (N-NH 4 ), nitrate (N-NO 3 ), phosphate (P-PO 4 ), total coliform, and total dissolved iron monitored at 11 sites at Huong river in the years 2014–2016. From the PCA, the three extracted principal components explained 67% of the total variance of original variables. From the set of communality values, the weight (w i ) for each parameter was determined. Linear sub-index functions were established based on the permissible limits from the National Technical Regulations on Surface Water Quality set up by the Vietnam Environment Agency (VEA) to derive the sub-index (q i ) for each parameter. The multiplicative formula that is the product of the sub-indices (q i ) raised to the respective weights (w i ), was used for calculation of the final WQI values. The proposed index (WQI) was then applied to the river with quarterly data of the 11 parameters monitored at ten sites in the years 2017–2020. The WQI representatively reflected the actual status of the river overall water quality, of which 97.8% of the WQI values belonged to grades of EXCELLENT and GOOD, and 2.2% of grade MODERATE. Comparison between the river water quality evaluations resulting from the developed WQI with the WQI adopted by National Sanitation Foundation (NSF-WQI) and the index issued by Vietnam Environment Agency (VN-WQI) indicated that the proposed WQI was more suitable for river quality assessment.

Breast cancer and cardiovascular-specific mortality are higher among blacks compared with whites, but disparities in cancer therapy-related adverse cardiovascular outcomes have not been well studied. We assessed for the contribution of race and socioeconomic status on cardiotoxicity among women with HER2-positive breast cancer. This retrospective cohort analysis studied women diagnosed with stage I-III HER2-positive breast cancer from 2004-2013. All underwent left ventricular ejection fraction assessment at baseline and at least one follow-up after beginning trastuzumab. Multivariable logistic regression was used to assess the association between race and socioeconomic status (SES) on cardiotoxicity, defined by clinical heart failure (New York Heart Association class III or IV) or asymptomatic left ventricular ejection fraction decline (absolute decrease ≥ 10% to < 53%, or ≥ 16%). Blacks had the highest prevalence of hypertension, diabetes, and increased BMI. Neighborhood-level SES measures including household income and educational attainment were lower for blacks compared with whites and others. The unadjusted cardiotoxicity risk was significantly higher in black compared with white women (OR, 2.10; 95% CI, 1.42 to 3.10). In a multivariable analysis, this disparity persisted after controlling for relevant cardiovascular risk factors (adjusted OR, 1.88; 95% CI, 1.25 to 2.84). Additional models adjusting for SES factors of income, educational attainment, and insurance status did not significantly alter the association between race and cardiotoxicity. In conclusion, black women are at increased risk of cardiotoxicity during HER2-targeted breast cancer therapy. Future etiologic analyses, particularly studies exploring biologic or genetic mechanisms, are needed to further elucidate and reduce racial disparities in cardiotoxicity.

PurposeAsymptomatic decline in left ventricular ejection fraction (LVEF) or heart failure (HF) occurs in up to 25% of patients treated with trastuzumab and can result in incomplete breast cancer therapy. The cardiac safety of continuing trastuzumab in patients with asymptomatic LVEF decline is unknown. We report the cardiac outcomes of patients treated with trastuzumab after a significant asymptomatic LVEF decline.MethodsPatients with HER2-positive breast cancer and asymptomatic LVEF decline to < 50% during trastuzumab were identified from an institutional echocardiogram database. Patients who received trastuzumab with a LVEF < 50% were classified as the continued group, whereas patients who had trastuzumab held until LVEF improved to ≥ 50% or who had trastuzumab permanently discontinued were classified as the interrupted group. Cardiac events were defined as HF (New York Heart Association class III–IV) or cardiovascular death.ResultsSixty patients were included; the median age was 54 years. In 23 patients who continued trastuzumab, 14 (61%) tolerated trastuzumab without a cardiac event, 6 (26%) developed worsening LVEF (range 25–42%) leading to trastuzumab discontinuation, and three (13%) developed a cardiac event (1 HF, 2 possible/probable cardiovascular deaths). In 37 patients with interrupted trastuzumab, 15 (41%) were re-challenged with trastuzumab after LVEF improved to > 50%, 21 (57%) were not re-challenged, and one (3%) developed HF. More patients in the continued trastuzumab group had metastatic disease (39% vs. 5%, p = 0.002). The final LVEF after median follow-up of 633 days was similar between patients with trastuzumab continuation versus interruption (54% vs. 56%, p = 0.29).ConclusionContinuation of trastuzumab after an asymptomatic LVEF decline to < 50% in patients who are expected to benefit from additional anti-HER2 therapy is a promising approach that warrants further investigation.

Trastuzumab improves outcomes among patients with HER2-positive breast cancer but is associated with a risk of treatment-induced cardiotoxicity (TIC). It is unclear how frequently TIC leads to trastuzumab interruption outside of prospective trials, and how TIC is managed in clinical practice. Patients with HER2-postive breast cancer receiving adjuvant trastuzumab from 2005 to 2010 were identified ( n  = 608). We evaluated the incidence, risk factors, and management of trastuzumab interruption due to TIC. In total, 488 (80 %) patients were treated with anthracycline prior to trastuzumab. Trastuzumab was interrupted in 108 (18 %) patients. Cumulative trastuzumab dose was lower in the interrupted group (median 86 vs. 108 mg/kg, p  < 0.0001). The most common reason for interruption was TIC (66 of 108 patients): 20 had symptomatic heart failure and 46 had asymptomatic left ventricular ejection fraction (LVEF) decline. Patients with trastuzumab interruption for TIC were older (54 vs. 50 years, p  = 0.014) with lower LVEF before anthracycline (63 vs. 67 %, p  < 0.0001) and trastuzumab (62 vs. 67 %, p  < 0.0001) therapy. Mean LVEF at baseline, TIC diagnosis, and follow-up after trastuzumab interruption was 63, 45, and 55 %, respectively. Thirty-three of 66 patients with TIC were re-challenged with trastuzumab, and five patients had recurrent LVEF decline. In clinical practice, trastuzumab interruption is common and most often due to TIC, with most patients receiving anthracycline prior to trastuzumab. Cardiac dysfunction improves after trastuzumab interruption but may not fully recover to baseline. Strategies to minimize cardiotoxicity and treatment interruption should be investigated to prevent persistent left ventricular dysfunction in affected patients.