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Patients with locally advanced non-small-cell lung cancer (NSCLC) who undergo concurrent chemotherapy and radiotherapy often experience synergistic toxicity, and local regional control rates remain poor. We assessed the activity and safety outcomes of primary tumour stereotactic body radiotherapy (SBRT) followed by conventional chemoradiotherapy to the lymph nodes and consolidation immunotherapy in patients with unresectable locally advanced NSCLC. In this multicentre, single-arm, phase 2 trial, patients aged 18 years and older were enrolled at eight regional cancer centres in North Carolina and South Carolina, USA. Patients were eligible if they had stage II–III, unresectable, locally advanced NSCLC (any histology), with peripheral or central primary tumours that were 7 cm or smaller, excluding central tumours within 2 cm of involved nodal disease, and an Eastern Cooperative Oncology Group performance status of 0–2. Patients who had previously received systemic therapy or radiotherapy were excluded. Participants received SBRT to the primary tumour (50–54 Gy in three to five fractions) followed by standard radiotherapy (planned up to 60 Gy in 30 2 Gy fractions) to the involved lymph nodes with concurrent platinum doublet chemotherapy (either paclitaxel 50 mg/m2 intravenously plus carboplatin area under the curve 2 mg/mL per min every 7 days for a total of six 1-week cycles or etoposide 50 mg/m2 intravenously on days 1–5 and days 29–33 plus cisplatin 50 mg/m2 intravenously on days 1, 8, 29, and 36 for two cycles of 4 weeks). An amendment to the protocol (Dec 11, 2017) permitted the administration of consolidation durvalumab at the discretion of the treating investigator. An additional protocol amendment on Jan 13, 2021, directed patients without disease progression after chemoradiotherapy to receive consolidation durvalumab (10 mg/kg intravenously on day 1 and day 15 of a 4-week cycle for up to 12 cycles or 1500 mg intravenously on day 1 of a 4-week cycle for up to 12 cycles). The primary endpoint was 1-year progression-free survival (per Response Evaluation Criteria in Solid Tumours version 1.1), assessed in all participants who received at least one fraction of SBRT and had radiological follow-up data up to 1 year. A 1-year progression-free survival rate of greater than 60% was required to reject the null hypothesis and show significant improvement in 1-year progression-free survival. One-sided exact binomial tests were used to compare the primary endpoint versus the historical control 1-year progression-free survival rate used to determine the sample size. Safety was assessed in all patients who received at least one fraction of SBRT. This study is registered with ClinicalTrials.gov, NCT03141359, and is closed to accrual. Between May 11, 2017, and June 27, 2022, 61 patients were enrolled and received at least one dose of fractionated SBRT, of whom 59 were evaluable for the primary endpoint. Median age was 67 years (IQR 61–72), 28 (46%) of 61 were female, 33 (54%) were male, 51 (84%) were White, seven (11%) were Black, and three (5%) were of other or unknown race. Of the 61 patients enrolled, 47 received at least one dose of consolidation durvalumab. As of data cutoff (July 12, 2023), median follow-up was 29·5 months (IQR 14·9–47·1). 1-year progression-free survival was 62·7% (90% CI 51·2–73·2; one-sided p=0·39, compared with the historical control rate), with 37 of 59 evaluable participants progression free and alive 1 year after enrolment (n=14 progressed, n=8 died). The most common grade 3–4 treatment-related adverse events were decreased neutrophil count (nine [15%] of 61 patients), decreased white blood cell count (five [8%]), and anaemia (four [7%]). Treatment-related serious adverse events occurred in 11 (18%) of 61 patients, which included lung infection (three [5%]), pneumonitis (two [3%]), decreased neutrophil count (two [3%]), febrile neutropenia (two [3%]), and dyspnoea, hypoxia, respiratory failure, sinus tachycardia, bronchial infection, and acute kidney injury (each in one [2%] patient). Treatment-related deaths occurred in four (7%) of 61 patients (one each of respiratory failure, respiratory failure and dyspnoea, lung infection, and pneumonitis). Although this study did not meet the primary endpoint, activity and safety profiles of primary lung tumour SBRT followed by concurrent mediastinal chemoradiotherapy were favourable compared with other modern trials treating locally advanced NSCLC with chemoradiotherapy. These findings serve as the basis for the ongoing randomised phase 3 study NRG Oncology LU008 (NCT05624996). AstraZeneca and Atrium Health Levine Cancer Institute.

BackgroundIndividuals with sickle cell disease (SCD) experience poor clinical outcomes while transitioning from paediatric to adult care. Standards for SCD transition are needed. We established a Quality Improvement (QI) Collaborative that aimed to improve the quality of care for all young adults with SCD by establishing a standardised SCD transition process. This study evaluates the implementation of the Six Core Elements (6CE) of Health Care Transition, which was a fundamental component of the cluster-randomised Sickle Cell Trevor Thompson Transition Project (ST3P-UP) study.MethodsA central QI team trained 14 ST3P-UP study sites on QI methodologies, 6CE and Got Transition’s process measurement tool (PMT). Site-level QI teams included a transition coordinator, clinic physicians/staff, patients/parents with SCD and community representatives. Sites completed the PMT every 6 months for 54 months and monthly audits of 10 randomly-selected charts to verify readiness/self-care assessments and emergency care plans.ResultsOf a possible 100, the aggregate mean (±SD) PMT score for paediatric clinics was 23.9 (±13.8) at baseline, 95.9 (±6.0) at 24 months and 98.9 (±2.1) at 54 months. The aggregate mean PMT score for adult clinics was 15.0 (±13.5) at baseline, 88.4 (±11.8) at 24 months and 95.8 (±6.8) at 54 months. The overall QI Collaborative PMT score improved by 402%. At baseline, readiness/self-care assessments were current for 38% of paediatric and 20% of adult patients; emergency care plans were current for 20% of paediatric and 3% of adult patients. Paediatric clinics had one median readiness assessment shift (76%) and four median emergency care plan shifts (65%, 77%, 79%, 84%). Adult clinics experienced three median self-care assessment shifts (58%, 63%, 70%) and two median emergency care plan shifts (57%, 70%).ConclusionsThe ST3P-UP QI Collaborative successfully embedded the 6CE of Health Care Transition into routine care and increased administration of assessments and emergency care plans for transition-aged patients with SCD.

Breast cancer treatment disparities persist and include surgical approach. This study evaluated the association of race, ethnicity, employment, and insurance status with the selected surgical approach and the effect on recurrence-free survival (RFS) and overall survival (OS) in young women with breast cancer. A retrospective review of a prospectively maintained institutional database (Sandra Levine Young Women's Breast Cancer Program) identified women aged ≤40 years diagnosed with non-metastatic breast cancer from 2010-2019 who underwent surgery. Multivariable logistic regression models and Cox proportional-hazards models were fitted. Of the 700 women, 4% were Asian, 26% Black, and 69% White. Reported ethnicity was: 67% non-Hispanic, 5% Hispanic, and 27% unknown or unreported. Clinical stage distribution was 86% early stage (0-II) and 11% stage III. Among patients with invasive cancer (n = 624), 51% were hormone receptor (HR)-positive/human epidermal growth factor receptor 2 (HER2)-negative, 21% were HR-negative/HER2-negative, 20% were HR-positive/HER2-positive, and 8% were HR-negative/HER2-positive. Local, regional, or distant recurrence occurred in 13.1% of patients who underwent lumpectomy and in 16.4% of those who underwent mastectomy ( = 0.22). Death occurred in 6.5% of patients after lumpectomy and in 10.7% of patients after mastectomy ( = 0.07). Black women were more likely to undergo lumpectomy than White women [odds ratio = 2.26; 95% confidence interval (CI), 1.49-3.43; <0.001; adjusted for ethnicity]. Private insurance was associated with improved OS (hazard ratio = 2.47; 95% CI, 1.26-4.84; = 0.003) and RFS (hazard ratio = 2.02; 95% CI, 1.28-3.20; = 0.010) compared with Medicaid. No association was noted between employment status and surgical approach, OS, or RFS. Young Black women were more likely than White women to elect the less-invasive surgery (lumpectomy). Private insurance was associated with better OS and RFS.

Introduction The role of sentinel lymph node biopsy (SLNB) when ductal carcinoma in situ with microinvasion (DCISM) is identified on core biopsy is unclear. Objective Our aim was to assess the upstage rate to invasive cancer and axillary lymph node metastasis in patients diagnosed with DCISM, and whether predictive variables could be identified that may help inform who would most likely benefit from a surgical axillary evaluation. Methods We performed a retrospective review of 70 patients diagnosed with DCISM on core biopsy. Patients with concomitant or prior invasive cancer were excluded. Demographic, clinical, radiographic, histologic, and treatment data were collected. Fisher’s exact test and univariable and multivariable logistic regression were performed to identify variables that may be associated with tumor upstaging and nodal metastasis. Time-to-event distributions were summarized using the Kaplan–Meier method. Results On final surgical pathology, 49 patients (70%) had a final diagnosis of DCISM or T1mi cancer, whereas 21 patients (30%) were upstaged to measurable invasive cancer (> 1 mm). One of 49 patients (2%) with DCISM on final pathology and 4 of 21 patients (19%) with measurable invasive cancer showed sentinel lymph node metastases. Conclusion Although the upstage rate to measurable invasive cancer in our cohort of patients with DCISM on core biopsy was 30%, findings of a positive SLNB remain low at 7%. No predictive variables were identified to inform whether the routine practice of SLNB may be omitted in some patients with DCISM.

Study Design. Retrospective review of a prospective database. Objective. Certain subset of patients undergoing surgical treatment for spinal metastasis will require a revision surgery in their disease course; however, factors predictive of revision surgery and survival outcomes are largely unknown. The goal of this study is to report on survival outcomes as well as factors predictive of revision surgery in this unique patient population. Methods. A total of 55 patients who met the inclusion criteria were included from January 2010 to December 2015. Twelve (22%) of these patients underwent a revision surgery. Patient and tumor characteristics were summarized and survival outcomes were evaluated using Kaplan-Meier methods and Cox proportional hazards regression. Results. Both the revision and the nonrevision groups were similarly matched with respect to spine disease burden, neurological status at time of initial presentation, primary malignancy types, and the use of adjuvant treatment modalities. Tumor progression (66.7%) was the most common reason for necessitating a revision followed by nonunion (16.7%), wound dehiscence (8.3%), and construct failure (8.3%). Following multivariate model selection procedures, smokers were found to have 3.5 times increased odds of undergoing revision compared to nonsmokers (p = 0.05). Analysis of survival curves showed that the median survival in the revision group was 3.0 years (95% CI: 1.5, 4.1), while the median survival in the nonrevision group was 1.5 years (95% CI: 1.1, 2.3; log-rank test, p = 0.105). Conclusion. Despite aggressive treatment, tumor progression is the most common reason for revision surgery. Smoking is an independent risk factor for revision. Revision surgery should be considered in patients when indicated as it does not appear to detrimentally affect survival.

Background We used a PCR-based approach to study the prevalence of genetic sequences related to a gammaretrovirus, xenotropic murine leukemia virus-related virus, XMRV, in human prostate cancer. This virus has been identified in the US in prostate cancer patients and in those with chronic fatigue syndrome. However, with the exception of two patients in Germany, XMRV has not been identified in prostate cancer tissue in Europe. Most putative associations of new or old human retroviruses with diseases have turned out to be due to contamination. We have looked for XMRV sequences in DNA extracted from formalin-fixed paraffin- embedded prostate tissues. To control for contamination, PCR assays to detect either mouse mitochondrial DNA (mtDNA) or intracisternal A particle (IAP) long terminal repeat DNA were run on all samples, owing to their very high copy number in mouse cells. Results In general agreement with the US prevalence, XMRV-like sequences were found in 4.8% of prostate cancers. However, these were also positive, as were 21.5% of XMRV-negative cases, for IAP sequences, and many, but not all were positive for mtDNA sequences. Conclusions These results show that contamination with mouse DNA is widespread and detectable by the highly sensitive IAP assay, but not always with less sensitive assays, such as murine mtDNA PCR. This study highlights the ubiquitous presence of mouse DNA in laboratory specimens and offers a means of rigorous validation for future studies of murine retroviruses in human disease.

Scabies is a neglected tropical disease hyperendemic to many low- and middle-income countries. Scabies can be successfully controlled using mass drug administration (MDA) using 2 doses of ivermectin-based treatment. If effective, a strategy of 1-dose ivermectin-based MDA would have substantial advantages for implementing MDA for scabies at large scale. We did a cluster randomised, noninferiority, open-label, 3-group unblinded study comparing the effectiveness of control strategies on community prevalence of scabies at 12 months. All residents from 35 villages on 2 Fijian islands were eligible to participate. Villages were randomised 1:1:1 to 2-dose ivermectin-based MDA (IVM-2), 1-dose ivermectin-based MDA (IVM-1), or screen and treat with topical permethrin 5% for individuals with scabies and their household contacts (SAT). All groups also received diethylcarbamazine and albendazole for lymphatic filariasis control. For IVM-2 and IVM-1, oral ivermectin was dosed at 200 μg/kg and when contraindicated substituted with permethrin. We designated a noninferiority margin of 5%. We enrolled 3,812 participants at baseline (July to November 2017) from the 35 villages with median village size of 108 (range 18 to 298). Age and sex of participants were representative of the population with 51.6% male and median age of 25 years (interquartile range 10 to 47). We enrolled 3,898 at 12 months (July to November 2018). At baseline, scabies prevalence was similar in all groups: IVM-2: 11.7% (95% confidence interval (CI) 8.5 to 16.0); IVM-1: 15.2% (95% CI 9.4 to 23.8); SAT: 13.6% (95% CI 7.9 to 22.4). At 12 months, scabies decreased substantially in all groups: IVM-2: 1.3% (95% CI 0.6 to 2.5); IVM-1: 2.7% (95% CI 1.1 to 6.5); SAT: 1.1% (95% CI 0.6 to 2.0). The risk difference in scabies prevalence at 12 months between the IVM-1 and IVM-2 groups was 1.2% (95% CI -0.2 to 2.7, p = 0.10). Limitations of the study included the method of scabies diagnosis by nonexperts, a lower baseline prevalence than anticipated, and the addition of diethylcarbamazine and albendazole to scabies treatment. All 3 strategies substantially reduced prevalence. One-dose was noninferior to 2-dose ivermectin-based MDA, as was a screen and treat approach, for community control of scabies. Further trials comparing these approaches in varied settings are warranted to inform global scabies control strategies. Clinitrials.gov NCT03177993 and ANZCTR N12617000738325.

Lymphatic filariasis has remained endemic in Fiji despite repeated mass drug administration using the well-established and safe combination of diethylcarbamazine and albendazole (DA) since 2002. In certain settings the addition of ivermectin to this combination (IDA) remains a safe strategy and is more efficacious. However, the safety has yet to be described in scabies and soil-transmitted helminth endemic settings like Fiji. Villages of Rotuma and Gau islands were randomised to either DA or IDA. Residents received weight-based treatment unblinded with standard exclusions. Participants were actively found and asked by a nurse about their health daily for the first two days and then asked to seek review for the next five days if unwell. Anyone with severe symptoms were reviewed by a doctor and any serious adverse event was reported to the Medical Monitor and Data Safety Monitoring Board. Of 3612 enrolled and eligible participants, 1216 were randomised to DA and 2396 to IDA. Age and sex in both groups were representative of the population. Over 99% (3598) of participants completed 7 days follow-up. Adverse events were reported by 600 participants (16.7%), distributed equally between treatment groups, with most graded as mild (93.2%). There were three serious adverse events, all judged not attributable to treatment by an independent medical monitor. Fatigue was the most common symptom reported by 8.5%, with headache, dizziness, nausea and arthralgia being the next four most common symptoms. Adverse events were more likely in participants with microfilaremia (43.2% versus 15.7%), but adverse event frequency was not related to the presence of scabies or soil-transmitted helminth infection. IDA has comparable safety to DA with the same frequency of adverse events experienced following community mass drug administration. The presence of co-endemic infections did not increase adverse events. IDA can be used in community programs where preventative chemotherapy is needed for control of lymphatic filariasis and other neglected tropical diseases.

Identification of protein-protein interactions often provides insight into protein function, and many cellular processes are performed by stable protein complexes. We used tandem affinity purification to process 4,562 different tagged proteins of the yeast Saccharomyces cerevisiae. Each preparation was analysed by both matrix-assisted laser desorption/ionization-time of flight mass spectrometry and liquid chromatography tandem mass spectrometry to increase coverage and accuracy. Machine learning was used to integrate the mass spectrometry scores and assign probabilities to the protein-protein interactions. Among 4,087 different proteins identified with high confidence by mass spectrometry from 2,357 successful purifications, our core data set (median precision of 0.69) comprises 7,123 protein-protein interactions involving 2,708 proteins. A Markov clustering algorithm organized these interactions into 547 protein complexes averaging 4.9 subunits per complex, about half of them absent from the MIPS database, as well as 429 additional interactions between pairs of complexes. The data (all of which are available online) will help future studies on individual proteins as well as functional genomics and systems biology.