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Background: Surgery is an indispensable component of a functional healthcare system. To date there is limited information regarding how many people die during the perioperative period globally. This study describes a protocol for a systematic review and multilevel meta-regression to evaluate time trends regarding the odds of perioperative mortality among adults undergoing a bellwether surgical procedure while accounting for higher order clustering at the national level., Methods: Published studies reporting the number of perioperative deaths from bellwether surgical procedures among adults will be identified from MEDLINE, Embase, Cochrane CENTRAL, LILACS and Global Index Medicus. The primary outcome will be the rate of perioperative mortality across time and the secondary outcome will be investigating cause of death over time as a proportion of overall perioperative mortality. Two reviewers will independently conduct full text screening and extract the data. Disagreements will first be resolved via consensus. If consensus cannot be reached a third reviewer will be included to arbitrate. Due to human resource limitations, a risk of bias appraisal will not be conducted. From the included studies a multilevel meta-regression will be constructed to synthesize the results. This model will conceptualize patients as nested in studies which are in turn nested within countries while taking into account potential confounding variables at all levels., Discussion: The systematic review and multilevel meta-regression that will be conducted based on this protocol will provide synthesized global evidence regarding the trends of perioperative mortality. This eventual study may help policymakers and other key stakeholders with benchmarking surgical safety initiatives as well as identify key gaps in our current understanding of global perioperative mortality., Trial Registration: Systematic review registration: PROSPERO registration number 429040., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 McIntyre et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background and Objectives: The current Grading of Recommendations, Assessment, Development and Evaluation (GRADE) system instructs appraisers to evaluate whether individual observational studies have sufficiently adjusted for confounding. However, it does not provide an explicit, transparent, or reproducible method for doing so. This article explores how implementing causal graphs into the GRADE framework can help appraisers and end-users of GRADE products to evaluate the adequacy of confounding control from observational studies., Methods: Using modern epidemiological theory, we propose a system for incorporating causal diagrams into the GRADE process to assess confounding control., Results: Integrating causal graphs into the GRADE framework enables appraisers to provide a theoretically grounded rationale for their evaluations of confounding control in observational studies. Additionally, the inclusion of causal graphs in GRADE may assist appraisers in demonstrating evidence for their appraisals in other domains of quality of evidence beyond confounding control. To support practical application, a worked example is included in the supplemental material to guide users through this approach., Conclusion: GRADE calls for the explicit and transparent appraisal of evidence in the process of evidence synthesis. Incorporating causal diagrams into the evaluation of confounding control in observational studies aligns with the core principles of the GRADE framework, providing a clear, theory-based method for the adequacy of confounding control in observational studies., Competing Interests: Declaration of competing interest None., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Genetic analysis is a critical component in the male infertility workup. For male infertility due to oligospermia/azoospermia, standard guidelines recommend karyotype and Y-chromosome microdeletion analyses. A karyotype is used to identify structural and numerical chromosome abnormalities, whereas Y-chromosome microdeletions are commonly evaluated by multiplex PCR analysis because of their submicroscopic size. Because these assays often require different Vacutainer tubes to be sent to different laboratories, ordering is prone to errors. In addition, this workflow limits the ability for sequential testing and a comprehensive test result. A potential solution includes performing Y-microdeletion and numerical chromosome analysis-the most common genetic causes of oligospermia/azoospermia-by chromosomal microarray (CMA) and reflexing to karyotype as both assays are often offered in the cytogenetics laboratory. Such analyses can be performed using one sodium heparin Vacutainer tube sample. To determine the effectiveness of CMA for the detection of clinically significant Y-chromosome microdeletions, 21 cases with known Y microdeletions were tested by CytoScan HD platform. CMA studies identified all known Y-chromosome microdeletions, and in 11 cases (52%) identified additional clinically important cytogenetic anomalies, including six cases of 46, XX males, one case of isodicentric Y, two cases of a dicentric Y, and three cases of terminal Yq deletions. These findings demonstrate that this testing strategy would simplify ordering and allow for an integrated interpretation of test results., (Copyright © 2020 Association for Molecular Pathology and American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.)

The non-receptor tyrosine kinase Src activation plays a role in the malignant progression of breast cancer, including development of endocrine therapy resistance and survival of bone metastases. This study investigated whether adding Src kinase inhibitor dasatinib to aromatase inhibitor (AI) therapy improved outcomes in estrogen receptor (ER)-positive, HER2-negative metastatic breast cancer (MBC). Postmenopausal patients with ER-positive, HER2-negative MBC (0-1 prior chemotherapies and no prior AI for MBC) were eligible for this non-comparative, parallel group, phase-II study. Patients were randomized to letrozole (2.5 mg/day PO) alone or with dasatinib (100 mg/day PO). Patients with disease progression on letrozole alone could crossover to dasatinib plus continued letrozole. The primary endpoint was clinical-benefit-rate (CBR; complete response + partial response + stable disease ≥6 months). A total of 120 patients were randomized. The CBR of 71% (95% CI 58-83%) was observed with letrozole + dasatinib versus the projected CBR of the combination of 56%. The CBR of 66% (95% CI 52-77%) with letrozole alone also exceeded the projected CBR of 39% with letrozole alone. The CBR was 23% in the crossover arm of letrozole plus dasatinib in patients progressing on letrozole alone. Median progression-free survival with the combination was 20.1 months and 9.9 months with letrozole alone. Letrozole plus dasatinib was well tolerated, although 26% of patients required dasatinib dose reductions. In this non-comparative phase-II trial, the CBR of 71% and the median PFS of 20.1 months with letrozole + dasatinib are encouraging and suggest that dasatinib may inhibit the emergence of acquired resistance to AI therapy., Competing Interests: Competing interestsDrs. Paul, Vukelja, Holmes, Blum, McIntyre, Lindquist, Sanchez, Goldschmidt, Wang and Asmar reported no conflicts of interest. Dr. Osborne participated in advisory boards for Agendia and Guardant. Dr. Goldschmidt has received honoraria and speaker’s fees from Amgen, Eli Lilly, Bristol-Myers Squibb, and Genentech. Dr. O’Shaughnessy has been a consultant for Bristol-Myers Squibb, Agendia, Lilly, Novartis, Pfizer, Genentech, Roche, Merck, Odonate, Arch Oncology, CytomX, Genomic Health, Puma, Synthon, AstraZeneca, Abbvie, Nektar, Halozyme, Eisai, Celgene, Seattle Genetics, Amgen, Jounce, Pharmamar, Grail, 2X Oncology, Myriad, Biothera, Tempus, Oncomed, Carrick, Tocagen, Dompe, Kyoma Kirin, Loxo Oncology, Hengrui, Almac, Celldex, Immunomedics. Dr. Strauss is employed by and owns stock in Bristol-Myers Squibb., (© The Author(s) 2019.)

Background: Mammalian target of rapamycin (mTOR) inhibitor-associated stomatitis (mIAS) is a frequent adverse event (AE) associated with mTOR inhibitor therapy and can impact treatment adherence. The objectives are to evaluate two steroid-based mouthrinses for preventing/ameliorating mIAS in patients with metastatic breast cancer (MBC) treated with everolimus., Materials and Methods: This prospective, randomized phase II study enrolled 100 postmenopausal patients with hormone receptor-positive MBC within the US Oncology Network who were initiating therapy with an aromatase inhibitor + everolimus (AIE; 10 mg/day). Patients were randomized to prophylactic therapy with one of two oral rinses (Arm 1: Miracle Mouthwash [MMW] 480 mL recipe: 320 mL oral Benadryl [diphenhydramine; Johnson & Johnson, New Brunswick, NJ, USA], 2 g tetracycline, 80 mg hydrocortisone, 40 mL nystatin suspension, water; or Arm 2: prednisolone [P] 15 mg/5 mL oral solution, 1.8% alcohol). Patients were instructed to swish/expectorate 10 mL of the assigned rinse for 1-2 minutes four times daily starting with day 1 of AIE treatment, for the first 12 weeks., Results: A total of 100 patients received treatment (49 MMW; 51 P). The incidence of stomatitis/oral AEs during the first 12 weeks was 35% ( n  = 17/49) and 37% (19/51) in the MMW and P arms, respectively. The incidence of grade 2 oral AEs was 14% (7/49) and 12% (6/51) with MMW or P, respectively. There were two grade 3 oral AEs (MMW arm) and no grade 4 events. There was one everolimus dose reduction (MMW) and six dose delays (four MMW, two P) and one dose reduction + delay (MMW) during the first 12 weeks of treatment. No patients stopped steroid mouthwash therapy because of rinse-related toxicity., Conclusion: Prophylactic use of steroid-containing oral rinses can prevent/ameliorate mIAS in patients with MBC treated with AIE. MMW + hydrocortisone is an affordable option, as is dexamethasone oral rinse., Implications for Practice: This prospective phase-II study showed that two steroid-containing mouthrinses substantially reduced incidences of all-grade and grade ≥2 stomatitis and related oral adverse events (AEs), and the number of everolimus dose-delays and/or dose-reduction in metastatic breast cancer (MBC) patients receiving everolimus treatment plus an aromatase inhibitor. Both oral rinses were well tolerated and demonstrated similar efficacy. Prophylactic use of steroid mouth rinse provides a cost-effective option that substantially decreases the incidence and severity of mammalian target of rapamycin (mTOR) inhibitor-associated stomatitis and related oral AEs as well as the need for dose modification in MBC patients undergoing treatment with an mTOR inhibitor., Competing Interests: Disclosures of potential conflicts of interest may be found at the end of this article., (© AlphaMed Press 2019.)

Omega-3 long-chain polyunsaturated fatty acids (n-3 LCPUFA) have several health benefits. In particular, low n-3 LCPUFA status is associated with cardiovascular disease (CVD) and led to the development of the omega-3 index that is the proportion of eicosapentaenoic acid and docosahexaenoic acid in the erythrocyte membranes, as a marker of CVD risk. Most methods used to measure the omega-3 index are laborious and time consuming. Therefore, the aim of this study was to develop a high-throughput method for the extraction and measurement of erythrocyte fatty acids and the omega-3 index. For sample extraction and quantification, two methods were used; a single-step extraction, degradation, and derivatization method by Lepage and Roy, followed by gas chromatography flame ionization detection (GC-FID), which is commonly used and a high-throughput method using an automated methyl tert-butyl ether extraction followed by electrospray ionization mass spectrometry. Both methods were first applied to the analysis of known concentrations of synthetic phospholipid (PL) mixtures to determine recovery and precision prior to their application in the analysis of human erythrocytes. The range of recoveries over five synthetic PL mixtures were 86.4-108.9% and the coefficient of variation was <10% (within-run) and ≤15.2% (between-run). Both methods showed high correlation (R = 0.993) for the omega-3 index and there was no systematic bias in the detection of omega-3 index using either method. The new high-throughput method described here offers considerable advantages in terms of simplicity and throughput compared to the GC-FID method and provides additional information on molecular PL concentrations., (© 2018 AOCS.)

We aimed to increase pathologic complete response (pCR) in patients with invasive breast cancer by adding preoperative capecitabine to docetaxel following 5-fluorouracil, epirubicin, cyclophosphamide (FEC) (with trastuzumab for patients with HER2-positive disease) and to evaluate 5-year disease-free survival (DFS) associated with this preoperative regimen. Chemotherapy included four cycles of FEC100 (5-fluorouracil 500 mg/m 2 , epirubicin 100 mg/m 2 , cyclophosphamide 500 mg/m 2 IV on Day 1 every 21 days) followed by 4 21-day cycles of docetaxel (35 mg/m 2  days 1 and 8) concurrently with capecitabine (825 mg/m 2 orally twice daily for 14 days followed by 7 days off) (wTX). For HER2-positive patients, treatment was modified by decreasing epirubicin to 75 mg/m 2 and adding trastuzumab (H) in standard doses (FEC75-H →wTX-H). The study objective was to achieve a pCR rate in the breast and axillary lymph nodes of 37% in patients with HER2-negative breast cancer and of 67% in patients with HER2-positive breast cancer treated with preoperative trastuzumab. A total of 186 patients were enrolled on study. In an intent-to-treat analysis, the pCR rate was 31% (37/118, 95% CI: 24-40%) in the HER2-negative patients, 24% (15/62, 95% CI: 14-37%) in ER-positive/HER2-negative patients, 39% (22/56, 95% CI: 27-53%) in the ER-negative/HER2-negative patients, and 46% (29/63, 95% CI: 34-48%) in the HER2-positive patients. The pCR rate in the 40 trastuzumab-treated patients was 53% (21/40, 95% CI: 38-67%). Grade 3 and 4 adverse events included neutropenia, leukopenia, diarrhea, and hand-foot skin reactions. One trastuzumab-treated patient developed grade 3 cardiotoxicity, and 4 others experienced grade 1-2 decrements in left ventricular function; all five patients' cardiac function returned to their baseline upon completion of trastuzumab. At 5 years, disease-free survival was 70% in the HER2-negative population (78% in ER-positive/HER2-negative and 62% in the ER-negative/HER2-negative patients) and 80% in the HER2-positive patients (87% in the trastuzumab-treated HER2-positive patients). At 5 years, overall survival was 80% in the HER2-negative population (88% in ER-positive/HER2-negative and 71% in the ER-negative/HER2-negative patients) and 86% in the HER2-positive patients (94.5% in the trastuzumab-treated HER2-positive patients). FEC100 (FEC75 with trastuzumab) followed by weekly docetaxel plus capecitabine, with or without trastuzumab is a safe, effective preoperative cytotoxic regimen. However, the addition of capecitabine to docetaxel following FEC, with or without trastuzumab, did not increase pCR rates nor 5-year DFS over the rates that have been reported with standard preoperative doxorubicin/cyclophosphamide (AC) followed by paclitaxel, with or without trastuzumab. Therefore, the use of capecitabine as part of preoperative chemotherapy is not recommended., (© 2018 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Background: To define protein molecular characteristics of tumor cells prior to, and immediately following, preoperative human epidermal growth factor receptor 2 (HER2)-targeted therapy that correlate with pathologic complete response (pCR) or non response (no pCR) to preoperative HER2-directed therapy and chemotherapy., Methods: This open-label, phase II study randomized patients with HER2-positive stage II or III invasive breast cancer to trastuzumab, lapatinib, or both, 2 weeks prior to and during chemotherapy with FEC75 for 4 courses; then paclitaxel 80 mg/m2 weekly for 12 courses, then surgery. Core needle biopsies were collected at baseline and after 2 weeks of anti-HER2 therapy prior to chemotherapy. Data were correlated with pCR, defined as absence of invasive tumor in breast and lymph nodes., Results: Of 100 enrolled patients, the analysis population included those who had surgery and received ≥75% chemotherapy (78% [n=78]). pCRs by arm are: trastuzumab (n=26), 54% [n=14]; lapatinib (n=29), 45% [n=13]; trastuzumab plus lapatinib (n=23), 74% [n=17]). Paired biopsy specimens were available for 49 patients (63%). Tumor cells of patients with pCR in the trastuzumab or lapatinib treatment arms showed nonphosphorylated FOXO, phosphorylated Stat5, and sparse signal-transduction protein network crosstalk representing different patterns of connections with PI3K and autophagy proteins compared with no pCR., Conclusion: In this exploratory study, pCR with preoperative anti-HER2 therapy and chemotherapy correlated with the levels and phosphorylation status of specific baseline signal pathway proteins in tumor cells. These data may provide candidate biomarkers to stratify initial treatment and potential combination therapies for future study. Tissue preservation technology introduced here makes this procedure widely feasible., Trial Registration: ClinicalTrials.gov: NCT00524303.

Palliation is the primary goal in metastatic breast cancer (MBC), and safe, efficacious, new single-agent options are needed. Pemetrexed, an antifolate, inhibits several folate-dependent enzymes involved in purine biosynthesis. The primary goal of this study was to determine the objective response rate in patients with advanced or MBC given pemetrexed as a first-line, dose-dense, every 2-week chemotherapy. Women with HER2-negative advanced or MBC, without prior cytotoxic treatment for this stage of disease, were treated with intravenous pemetrexed 600 mg/m² on Day 1 of each 14-day cycle. Standard dexamethasone, folic acid, and vitamin B(12) premedications were given. 37 patients enrolled; 36 received ≥ 1 dose of pemetrexed and 35 were evaluable for response. Median age of patients was 61.4 years, 76% were hormone receptor positive (ER+ and/or PR+). Prior treatment included adjuvant chemotherapy (57%) and/or endocrine (65%). Patients received a median of 6 cycles of pemetrexed (range, 1-21). Based on 35 evaluable patients, the overall response rate (ORR) was 26% (1 CR and 8 PR), and the clinical benefit rate (CR+ PR+ stable disease [SD] ≥ 6 months) was 40%. Median progression-free survival (PFS) was 4.1 months (range, <1-22.4). Median overall survival (OS) was 18.9 months (range, <1-27.7). Grades 3-4 treatment-related toxicities included: neutropenia (36%), leukopenia (17%), fatigue (14%), and anemia (14%). Grade 1/2 alopecia was seen in 8% of patients. This phase II study of dose-dense, single-agent pemetrexed showed moderate activity in the first-line setting with acceptable toxicity and no significant alopecia.

Cisplatin and carboplatin have antitumor activity in breast cancer. Satraplatin, an orally bioavailable platinum analog, offers a potential alternative to intravenous chemotherapy. We conducted a multicenter phase II study of this agent as first- or second-line treatment of metastatic breast cancer. Satraplatin 80 mg/m(2) was taken PO Days 1-5 q 21 days in cycles 1 and 2, and if tolerated, increased to 100 mg/m(2) for subsequent cycles. Restaging studies to assess response were performed after every 2 cycles. Between November 2005 and March 2006, 40 patients were enrolled. Baseline characteristics: 48% prior adjuvant chemotherapy, 60% prior chemotherapy for MBC; median age, 62 years (ranges 43-83), 58% ER+/PR+, 23% ER+/PR-, 18% ER-/PR-/HER2-, and 5% HER2+. In 31 patients with measurable disease, there were two partial responses (PR; 6%; 95% CI 0, 15.2); and four patients (13%) had SD > or =6 months for a clinical benefit rate of 19%. Among the subanalysis of seven triple-negative patients with measurable disease, there were 2 SD and 2 PD. Median survival was 15 months and median progression-free survival was 2.7 months. The most common grade 3-4 toxicities were neutropenia (28%) and thrombocytopenia (25%). AEs leading to treatment discontinuation were nausea (n = 3), thrombocytopenia (n = 3), fever (n = 2), and vomiting (n = 2). This phase II study demonstrates oral satraplatin has limited activity as a single agent for MBC. Satraplatin, at a lower dose used in this study, could be combined with other chemotherapy agents in future trials in breast cancer.

Purpose: The combination of doxorubicin and cyclophosphamide (AC) is a standard adjuvant chemotherapy regimen. Studies of docetaxel and cyclophosphamide (TC) in metastatic breast cancer (MBC) showed promise in MBC. In 1997, we initiated a randomized adjuvant trial of TC compared with standard-dose AC with a primary end point of disease-free survival (DFS)., Patients and Methods: Patients were eligible if they had stage I to III operable invasive breast cancer with complete surgical excision of the primary tumor. Between June 1997 and December 1999, 1,016 patients were randomly assigned to four cycles of either standard-dose AC (60 and 600 mg/m2, respectively; n = 510) or TC (75 and 600 mg/m2, respectively; n = 506), administered intravenously every 3 weeks as adjuvant chemotherapy. Radiation therapy (as indicated) and tamoxifen, for patients with hormone receptor-positive disease, were administered after completion of chemotherapy., Results: Both treatment groups (TC and AC) were well balanced with respect to major prognostic factors. Patients were observed through 2005 for a median of 5.5 years. At 5 years, DFS rate was significantly superior for TC compared with AC (86% v 80%, respectively; hazard ratio [HR] = 0.67; 95% CI, 0.50 to 0.94; P = .015). Overall survival rates for TC and AC were 90% and 87%, respectively (HR = 0.76; 95% CI, 0.52 to 1.1; P = .13). More myalgia, arthralgia, edema, and febrile neutropenia occurred on the TC arm; more nausea and vomiting occurred on the AC arm as well as one incident of congestive heart failure., Conclusion: At 5 years, TC was associated with a superior DFS and a different toxicity profile compared with AC.

We carried out a questionnaire survey in a Semi-urban General Practice in Renfrewshire to evaluate patients' knowledge and understanding of changes to General Practitioner services six months after implementation of 'The 1990 Contract'. The survey assessed the point prevalence of patients' knowledge in an opportunity sample. A total of 237 patients attending morning surgery during one week in September 1990 were asked to complete a short questionnaire. Despite 38% of respondents declaring they were aware of the changes, only 10% of the respondents showed evidence of understanding of the changes. There was a lack of perceived usefulness of Well Person Checks despite a relatively good understanding of what this involves. Most of the recent changes in General Practice were perceived as being useful or extremely useful to patients after they had been explained. It is suggested that further publicity with careful targeting and explanation is required before the public can make appropriate and effective use of these changes.

Essential thrombocythemia is typically a disorder of adults in the sixth or seventh decade of life and is characterized by frequent thrombohemorrhagic complications. In young patients, the optimal management of complications is controversial. We studied 56 young adults (33 female and 23 male patients) with a diagnosis of essential thrombocythemia. The mean duration of follow-up was 4.68 years. The mean platelet count at diagnosis was 1,328,000/mm3. Platelet aggregation studies in 21 patients demonstrated hypoaggregation to epinephrine; spontaneous platelet aggregation was present in 4. At diagnosis, 39 patients were asymptomatic, and thrombocytosis was discovered incidentally. Throughout follow-up (up to 20 years), 24 patients remained asymptomatic. Thrombotic complications developed in 24 patients; they were life-threatening in only 3. The most common vaso-occlusive symptoms were migraine headache (in 12 patients) and erythromelalgia (in 3). Minor hemorrhagic complications occurred in six patients, and none was life-threatening. Serious complications (one cerebral and two myocardial infarctions) occurred in three patients, all of whom recovered. Two deaths occurred, neither of which was attributable to essential thrombocythemia. The treatment regimens used were chemotherapy in 9 patients, antiaggregating agents in 7, radioactive phosphorus in 1, the newer platelet-lowering agent anagrelide in 10, and only observation in 29. No treatment-related acute leukemias developed. This series of young patients with essential thrombocythemia, the largest to date, demonstrates a low incidence of life-threatening complications and a favorable long-term prognosis. Therapeutic recommendations should remain conservative, and potential leukemogens should be avoided unless serious complications develop. Anagrelide may be useful in young patients with thrombocythemia who are symptomatic.