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Supplementary fig 3 Tumor Regression Grade versus Baseline p-ERK score in Tumor Tissue

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Purpose: Pancreatic ductal adenocarcinoma (PDAC) is an aggressive cancer with a 5-year survival rate Experimental Design: Peripheral blood was collected from 73 patients presenting with previously untreated metastatic PDAC. Extensive immunologic profiling was conducted to assess relationships between OS and the level of soluble plasma biomarkers or detailed immune cell phenotypes as measured by flow cytometry.Results: Higher baseline levels of the immunosuppressive cytokines IL6 and IL10 were strongly associated with poorer OS (P = 0.008 and 0.026, respectively; HR = 1.16 and 1.28, respectively), whereas higher levels of the monocyte chemoattractant MCP-1 were associated with significantly longer OS (P = 0.045; HR = 0.69). Patients with a greater proportion of antigen-experienced T cells (CD45RO+) had longer OS (CD4 P = 0.032; CD8 P = 0.036; HR = 0.36 and 0.61, respectively). Although greater expression of the T-cell checkpoint molecule CTLA-4 on CD8+ T cells was associated with significantly shorter OS (P = 0.020; HR = 1.53), the TIM3 molecule had a positive association with survival when expressed on CD4+ T cells (P = 0.046; HR = 0.62).Conclusions: These data support the hypothesis that baseline immune status predicts PDAC disease course and overall patient survival. To our knowledge, this work represents the largest cohort and most comprehensive immune profiling of treatment-naïve metastatic PDAC patients to date. Clin Cancer Res; 22(10); 2565–74. ©2015 AACR.

Purpose:This first-in-human phase I study (NCT 01417546) evaluated the safety profile, optimal immunologic/biological dose (OID/OBD), and immunogenicity of the combination of two peptide B-cell epitope vaccines engineered to represent the trastuzumab- and pertuzumab-binding sites. Although trastuzumab and pertuzumab have been approved for clinical use, patients often develop resistance to these therapies. We have advanced a new paradigm in immunotherapy that focuses on humoral responses based on conformational B-cell epitope vaccines.Patients and Methods:The vaccine is comprised of two chimeric HER-2 B-cell peptide vaccines incorporating a “promiscuous T-cell epitope.” Patients were immunized with the vaccine constructs emulsified with nor-muramyl-dipeptide adjuvant in a water-in-oil Montanide ISA 720VG vehicle. Eligible patients with metastatic and/or recurrent solid tumors received three inoculations every 3 weeks.Results:Forty-nine patients with a median of 4 prior lines of chemotherapy received at least 1 vaccination. Twenty-eight patients completed the 3 vaccination regimens. Six patients received 1 six-month boost after the regimen, and one patient received 7 six-month boosts. No serious adverse reactions or dose-limiting toxicities were observed. The vaccine was well tolerated with dose level 2 as the recommended phase II dose. The most common related toxicity in all patients was injection-site reactions (24%). Two patients had a partial response, 14 had stable disease, and 19 had progressive disease.Conclusions:The study vaccine is safe, exhibits antitumor activity, and shows preliminary indication that peptide vaccination may avoid therapeutic resistance and offer a promising alternative to monoclonal antibody therapies.

Supplementary fig 1 Flowchart for trial design

Supplementary fig 2 Schema for trial design

Table S1. Antibodies used for flow cytometry Table S2. Monte Carlo cross-validation of continuous measure markers. Table S3. Monte Carlo cross-validation of dichotomous measure markers. Table S4. Pancreatic cancer patient circulating immune cell frequencies Figure S1. Overall survival does not predict plasma MCP-1 levels

Table showing next generation sequencing of tumor samples

This file contains supplemental materials, tables, and figures.

Supplementary fig 5 Degree of Reduction (%) in Tumor pERK Levels From Baseline to After Trametinib Monotherapy and Correlation With pCR

Supplementary fig 4 Baseline p-ERK score in Tumor Tissue Correlated to RAS/RAF Mutation Status

Purpose:The RAS/RAF/MEK/ERK signaling pathway is critical to the development of colorectal cancers, and KRAS, NRAS, and BRAF mutations foster resistance to radiation. We performed a phase I trial to determine the safety of trametinib, a potent MEK1/2 inhibitor, with 5-fluorouracil (5-FU) chemoradiation therapy (CRT) in patients with locally advanced rectal cancer (LARC).Patients and Methods:Patients with stage II/III rectal cancer were enrolled on a phase I study with 3+3 study design, with an expansion cohort of 9 patients at the MTD. Following a 5-day trametinib lead-in, with pre- and posttreatment tumor biopsies, patients received trametinib and CRT, surgery, and adjuvant chemotherapy. Trametinib was given orally daily at 3 dose levels: 0.5 mg, 1 mg, and 2 mg. CRT consisted of infusional 5-FU 225 mg/m2/day and radiation dose of 28 daily fractions of 1.8 Gy (total 50.4 Gy). The primary endpoint was to identify the MTD and recommended phase II dose. IHC staining for phosphorylated ERK (pERK) and genomic profiling was performed on the tumor samples.Results:Patients were enrolled to all dose levels, and 18 patients were evaluable for toxicities and responses. Treatment was well tolerated, and there was one dose-limiting toxicity of diarrhea, which was attributed to CRT rather than trametinib. At the 2 mg dose level, 25% had pathologic complete response. IHC staining confirmed dose-dependent decrease in pERK with increasing trametinib doses.Conclusions:The combination of trametinib with 5-FU CRT is safe and well tolerated, and may warrant additional study in a phase II trial, perhaps in a RAS/RAF-mutant selected population.

Background: The 2 approved somatostatin analogs (SSAs) in the first-line treatment of advanced, well-differentiated gastroenteropancreatic neuroendocrine tumors (GEP-NETs) are octreotide long-acting release (Sandostatin LAR) and somatuline depot (Lanreotide). The study’s objective was to compare progression-free survival (PFS) and overall survival (OS) of patients (pts) with GEP-NETs treated with somatuline or octreotide LAR. Pts and Methods: Pts with advanced well-differentiated GEP-NET who received either SSA at Emory University between 1995 and 2019 were included after institutional review board approval. The primary end point was PFS, defined as time to disease progression (according to the Response Evaluation Criteria in Solid Tumors, version 1.1, or clinical progression) or death. The secondary end point was OS. Kaplan-Meier curves were generated, and log-rank tests were conducted to compare the survival outcomes. Results: A total of 105 pts were identified. The mean age was 62.1 years (SD ± 11.8). The male-to-female ratio was 51:54. The majority (N = 69, 65.7%) were white. Most pts had grade 2 (G2) disease (N = 44, 41.9%). Primary location was small bowel in 58 (55.2%), pancreas in 27 (25.7%), and other in 20 (19.0%). Functional tumors were defined in 32 pts distributed equally between the 2 groups. Distribution of treatment was similar in the 2 groups, with 54 receiving octreotide LAR and 51 receiving somatuline depot. The median PFS for the octreotide LAR and somatuline depot groups was 12 months (95% CI, 6–18 months) and 10.8 months (95% CI, 6–15.6 months), respectively, and the difference was not statistically significant (p = 0.2665). For pts with G1 disease, the median PFS for the octreotide LAR and somatuline depot was 8.4 versus 32.4 months, respectively, and the difference was not statistically significant (p = 0.159). For G2 disease, the difference in median PFS between octreotide LAR and somutaline depot groups was statistically significant (12 vs. 7.2 months, respectively; p = 0.0372). The mean follow-up time for octreotide LAR was 21.6 months versus 11.3 months for somatuline depot. Conclusions: Overall, there was no difference in PFS between octreotide LAR and somatuline depot for pts with well-differentiated, metastatic GEP-NETs. A prospective study is worth designing selecting for G.

Metastatic colorectal cancer (mCRC) is the second most common cause of cancer-related death worldwide. In the mid-1980s, the median overall survival (OS) for patients with mCRC ranged from 10 to 12 months from the time of initial diagnosis. In more recent studies, this median has more than doubled and is commonly reported at more than 25 to 30 months. These improvements are due, in large part, to the introduction of multiple novel agents during the last 3 decades. Despite these improvements, however, nearly all patients treated with palliative chemotherapy will eventually develop resistance and ultimately succumb to progression of metastatic disease. Understanding the mechanisms by which malignant cells evade treatment could unlock novel therapeutic strategies that overcome resistance and improve survival. In this review, we will discuss some of the drivers of therapeutic resistance in patients with mCRC and present some novel strategies to overcome resistance.

Background Immune checkpoint inhibitor (ICI) therapy is highly effective in metastatic mismatch repair-deficient (MMR-D) colorectal cancer (CRC). In this study, we evaluated molecular and clinical predictors of ICI response in MMR-D CRC. Materials and Methods Patient databases at four cancer institutions were queried. The Fisher exact test was performed to test the association of clinical and molecular markers. The Kaplan-Meier method was used to estimate progression-free survival (PFS) and compared by the log-rank test. Twelve- and 24-month PFS rates were compared by the Z test. Results A total of 60 patients with CRC with MMR-D/microsatellite instability-high who previously received ICIs were identified. Patients with liver metastasis had a lower overall response rate as compared with other sites of metastasis (36.4% vs. 68.7%; p = .081). Patients with MLH1/PMS2 loss had worse 1-year and 2-year PFS rates compared with patients with MSH2/MSH6 loss (84.2% vs. 57.8% and 78.2% vs. 54.2%, respectively; p < .001). There were improved 1-year and 2-year PFS rates in patients with wild-type BRAF when compared with patients with BRAF V600E mutation (73.3% vs. 40%, and 73.3% vs. 26.7%; respectively; p < .001). Patients aged >65 had significantly worse PFS rates as compared with patients aged ≤65 (p < .001). Conclusion BRAF V600E mutation, MLH1 and/or PMS2 loss, as well as age >65 years and liver metastasis, may be predictive of duration of ICI response in patients with MMR-D CRC. Larger cohorts are needed to confirm our findings. Implications for Practice The results of this study reveal clinically important biomarkers that potentially predict immune checkpoint inhibitor response in patients with mismatch repair-deficient colorectal cancer.

About 10-20% of patients with anal squamous cell carcinoma (SCCa) present with metastatic disease and are usually treated with systemic chemotherapy. However, primary tumor control is crucial as local failure is associated with significant morbidity. Using the largest cohort to date, we report the impact of local therapy on survival among patients with metastatic anal SCCa.Data were collected from US hospitals that contributed to the National Cancer Database (NCDB) between 2004 and 2015. Patients who did not receive palliative systemic chemotherapy were excluded from analysis. Univariate (UVA) and multivariable analyses (MVA) were performed to identify factors associated with patient outcome. Kaplan-Meier analysis and Cox proportional hazards models were used to evaluate the association between tumor/patient characteristics and overall survival (OS).A total of 1,160 patients were identified over the 12 years of study. Median age was 57 years. Majority were female (64.9%), non-Hispanic Whites (79.1%) and had Charlson-Deyo Score of 0 (83.6%). Most common metastatic sites were liver (25.9%), lung (11.6%) and bone (8.5%). More than 79% of the patients had received radiation to the primary site, and 10.4% underwent surgical resection for local control. Use of local therapy correlated closely with OS on MVA (HR 0.66; 0.55-0.79; P0.001), with a 12-month and 5-year OS rates of 72.8% and 25.7% respectively, compared with 61.1% and 14.6% for patients treated with chemotherapy only. Poor prognostic factors included male gender (HR 1.44; 1.24-1.67; P0.001), age70 years (HR 1.28; 1.02-1.62; P=0.034), lack of health insurance (HR 1.32; 1.02-1.71; P=0.034), and cloacogenic zone location (HR 4.02; 1.43-11.30; P=0.008). There was no benefit from abdominoperineal resection (mOS =19.7 months; HR 1.05; 0.48-2.29; P=0.909), but both local resection of the primary (mOS =24.8 months, HR 0.48; 0.29-0.80; P=0.005) and palliative radiation (mOS =22.6 months; HR 0.66; 0.55-0.79; P0.001) were associated with improved OS.In addition to systemic therapy, resection of the primary tumor or palliative radiation improved OS in patients with anal SCCa. Patients unlikely to benefit from local control were those70 years of age, male, lack of health insurance and cloacogenic carcinoma.

Background Purpose: The combination of a mammalian target of rapamycin inhibitor and lenalidomide showed enhanced preclinical cytotoxicity. We conducted a phase 1 study in advanced solid tumour patients to assess safety, efficacy and pharmacodynamic (PD) outcomes. Methods We employed a 3+3 dose escalation design to establish the safety and recommended phase 2 doses (RP2D) of daily everolimus and lenalidomide in patients with advanced solid tumours. The starting doses were 5 and 10 mg, respectively, with planned escalation to maximum single-agent doses of 10 and 25 mg in the absence of dose-limiting toxicity. PD endpoints of lymphocyte subsets and immune cytokines were assessed in peripheral blood using multiparameter flow cytometry and LUMINEX assay. Efficacy was evaluated by cross-sectional imaging after every two cycles of treatment. Results The study enrolled 44 patients, median age of 58 years and 28 males (63.6%). The RP2D was established as 10 and 25 mg daily continuously for everolimus and lenalidomide. Common (>5%) grade ≥3 adverse events included rash (19%), neutropenia (19%), hypokalaemia (11%) and fatigue (9%). Best efficacy outcomes in 36 evaluable patients were partial response in 5 (13.8%), stable disease in 24 (55.8%) and progressive disease in 7 (19.4%) patients. PD assessment revealed significant association of cytokine levels (interleukin-2 (IL2), IL21 and IL17), baseline activated and total CD8+ lymphocytes and change in B cell lymphocytes and activated NK cells with clinical benefit. Conclusions The study demonstrated the safety of everolimus and lenalidomide with promising efficacy signal in thyroid and adenoid cystic cancers. Clinical Trial Registration NCT01218555

Purpose: Concurrent inhibition of mTOR and PI3K led to improved efficacy in preclinical models and provided the rationale for this phase I study of everolimus and buparlisib (BKM120) in patients with advanced solid tumor. Patients and Methods: We used the Bayesian Escalation with Overdose Control design to test escalating doses of everolimus (5 or 10 mg) and buparlisib (20, 40, 60, 80, and 100 mg) in eligible patients. Pharmacokinetic assessment was conducted using blood samples collected on cycle 1, days 8 and 15. Pharmacodynamic impact on mTOR/PI3K pathway modulation evaluated in paired skin biopsies collected at baseline and end of cycle 1. Results: We enrolled 43 patients, median age of 63 (range, 39–78) years; 25 (58.1%) females, 35 (81.4%) Caucasians, and 8 (18.6%) Blacks. The most frequent toxicities were hyperglycemia, diarrhea, nausea, fatigue, and aspartate aminotransferase elevation. Dose-limiting toxicities observed in 7 patients were fatigue (3), hyperglycemia (2), mucositis (1), acute kidney injury (1), and urinary tract infection (1). The recommended phase II dose (RP2D) for the combination was established as everolimus (5 mg) and buparlisib (60 mg). The best response in 27 evaluable patients was progressive disease and stable disease in 3 (11%) and 24 (89%), respectively. The median progression-free survival and overall survival were 2.7 (1.8–4.2) and 9 (6.4–13.2) months. Steady-state pharmacokinetic analysis showed dose-normalized maximum concentrations and AUC values for everolimus and buparlisib in combination to be comparable with single-agent pharmacokinetic. Conclusions: The combination of everolimus and buparlisib is safe and well-tolerated at the RP2D of 5 and 60 mg on a continuous daily schedule.

Background: Neuroendocrine neoplasms (NENs) are a heterogeneous group of neoplasms that span from well-differentiated neuroendocrine tumors (NETs) to highly aggressive neoplasms classified as neuroendocrine carcinomas (NECs). The genomic landscape of NENs has not been well studied. The aim of this study is to confirm the feasibility of next generation sequencing (NGS) testing circulating tumor DNA (ctDNA) in patients with NENs and characterize common alterations in the genomic landscape. Results: Of the 320 NEN patients, 182 (57%) were male with a median age of 63 years (range: 8-93) years. Tumor type included pancreatic NET (N = 165, 52%), gastrointestinal NEC (N = 52, 16%), large cell lung NEC (N = 21, 7%), nasopharyngeal NEC (N = 16, 5%) and NEC/NET not otherwise specified (N = 64, 20%). ctDNA NGS testing was performed on 338 plasma samples; 14 patients had testing performed twice and 2 patients had testing performed three times. Genomic alterations were defined in 280 (87.5%) samples with a total of 1,012 alterations identified after excluding variants of uncertain significance (VUSs) and synonymous mutations. Of the 280 samples with alterations, TP53 associated genes were most commonly altered (N = 145, 52%), followed by KRAS (N = 61, 22%), EGFR (N = 33, 12%), PIK3CA (N = 30, 11%), BRAF (N = 28, 10%), MYC (N = 28, 10%), CCNE1 (N = 28, 10%), CDK6 (N = 22, 8%), RB1 (N = 19, 7%), NF1 (N = 19, 7%), MET (N = 19, 7%), FGFR1 (N = 19, 7%), APC (N = 19, 7%), ERBB2 (N = 16, 6%) and PTEN (N = 14, 5%). Conclusions: Evaluation of ctDNA was feasible among individuals with NEN. Liquid biopsies are non-invasive methods that can provide personalized options for targeted therapies in NEN patients. Patients and Methods: Molecular alterations in 338 plasma samples from 320 patients with NEN were evaluated using clinical-grade NGS of ctDNA (Guardant360®) across multiple institutions. The test detects single nucleotide variants in 54-73 genes, copy number amplifications, fusions, and indels in selected genes.

Introduction Immune-related adverse event (IRAE) onset may represent a clinical biomarker for anti-programmed cell death protein 1 (PD-1) antibody response based on emerging evidence from patients with various advanced malignancies. This phenomenon has not been previously reported in a multidisease cohort of patients with gastrointestinal (GI) cancer with Food and Drug Administration (FDA)-approved indications to receive immune checkpoint inhibitor therapy. Materials and Methods The study was a multicenter retrospective cohort analysis of 76 patients with GI cancer who had received anti-PD-1 antibodies for FDA-approved indications. The primary and secondary outcomes of the study were progression-free survival (PFS) and overall survival (OS) in patients based upon IRAE presence, respectively. PFS and OS were estimated by the Kaplan-Meier method; a Cox proportional-hazards model adjusted for IRAE onset, patient age, and enrolling institution was used to analyze outcomes. Results Median PFS and OS were prolonged in patients who experienced IRAEs compared with those who did not experience them (PFS: not reached [NR] vs. 3.9 months [hazard ratio (HR) 0.13, 95% confidence interval (CI) 0.05–0.3, p < .001]; OS: NR vs. 7.4 months [HR 0.11, 95% CI 0.03–0.36, p < .001]). Among patients who experienced IRAEs, there were no significant differences in PFS and OS by either initial IRAE severity, management, or time to onset. Conclusion Patients with gastrointestinal cancer who experienced IRAEs while on anti-PD-1 antibodies demonstrated significant improvements in PFS and OS compared with their counterparts who did not develop IRAEs. Although these findings add to results from studies in other tumor types, larger prospective studies are needed prior to clinical adoption of IRAE onset as a biomarker for immune checkpoint inhibitor response. Implications for Practice Predictive clinical biomarkers for immune checkpoint inhibitor response have been understudied in the field of immuno-oncology. Immune-related adverse event onset appears to be one such biomarker. Across tumor types, immune-related adverse event onset has been associated with response to anti-programmed cell death protein 1 (PD-1) antibodies. The results of this study demonstrate this for the first time in patients with gastrointestinal cancer receiving anti-PD-1 antibodies. Before immune-related adverse event onset can be adopted clinically as a predictive biomarker for immune checkpoint inhibitor response, however, larger prospective studies are needed to better understand the nuances between immune-related adverse event characteristics (severity, site, management, timing of onset) and immune checkpoint inhibitor effectiveness.

Background Sarcopenia and inflammation have been associated with poor survival in patients with cancer. We explored the combined effects of these variables on survival in patients with cancer treated with immunotherapy. Methods We performed a retrospective review of 90 patients enrolled on immunotherapy‐based phase I clinical trials at Emory University from 2009 to 2017. Baseline neutrophil‐to‐lymphocyte ratio, monocyte‐to‐lymphocyte ratio, and platelet‐to‐lymphocyte ratio (PLR) were used as surrogates of inflammation. The skeletal muscle index (SMI) was derived from the skeletal muscle density calculated from baseline abdominal computed tomography images. Optimal cutoffs for continuous inflammation biomarkers and SMI were determined by bias‐adjusted log‐rank test. A four‐level risk stratification was used to create low‐risk (PLR, The interaction between chronic inflammation and body composition is particularly important in the era of immunotherapy, considering that immune checkpoint inhibitors rely on the host immune system for their efficacy. This article reports on the combined effects of inflammation and sarcopenia on clinical outcomes in patients with solid tumors treated with immunotherapy‐based regimens.

BACKGROUND Body mass index (BMI) is used to define obesity, but it is an imperfect measure of body composition. In the current study, the authors explored the association between types of fat and survival in patients treated with immunotherapy. METHODS A retrospective analysis of 90 patients who were treated with immunotherapy on phase 1 clinical trials at the Winship Cancer Institute in Atlanta, Georgia, from 2009 through 2017 was performed. Overall survival (OS) and progression-free survival (PFS) were used to measure clinical outcomes. Baseline BMI and radiographic images at the middle of the third lumbar vertebrae were obtained. Fat densities were calculated and converted to indices (subcutaneous fat index [SFI], intermuscular fat index [IFI], and visceral fat index [VFI]) after dividing by height in meters squared. Risk groups were created using recursive partitioning and the regression trees method for SFI and IFI, which were selected by stepwise variable selection among all fat-related variables. The Cox proportional hazards model and Kaplan-Meier method were used for the association with OS and PFS. RESULTS The majority of patients (59%) were male and diagnosed with melanoma (33%) or gastrointestinal cancers (22%). The median BMI was 27.4 kg/m2 , the median SFI was 62.78, the median IFI was 4.06, and the median VFI was 40.53. Low-risk patients (those with an SFI ≥73) had a significantly longer OS (hazard ratio, 0.20; 95% CI, 0.09-0.46 [P

BACKGROUND Hepatitis C (HCV) is the primary etiology of hepatocellular carcinoma (HCC) in the US multidisciplinary disease management teams (DMT) that optimize oncologic care. The impact of DMT for HCC in safety-net hospitals is unknown. METHODS Patients diagnosed with HCC from 2009 to 2016 at Grady Memorial Hospital (GMH) were included. The primary aim was to evaluate referrals to care, receipt of therapy, and overall survival (OS) after DMT formation. Screening patterns of HCV patients for HCC were also examined. RESULTS Of 204 HCC patients, median age was 58 years, with 81% male, 83% black. 46% presented with stage 4 disease, 53% had treatment with median OS 9.8 months. DMT formation was associated with increased referrals to surgery (49% vs 30%; P = .02), liver-directed therapy (58% vs 31%; P = .001), and radiation (13% vs 3%; P = .019). Patients were also more likely to get treatment (59% vs 41%; P = .026), with improved median OS (30.7 vs 4.9 months; P

Metastatic colorectal cancer (CRC) with a mismatch repair-deficiency (MMR-D)/microsatellite instability-high (MSI-H) phenotype carries unique characteristics such as increased tumour mutational burden and tumour-infiltrating lymphocytes. Studies have shown a sustained clinical response to immune checkpoint inhibitors with dramatic clinical improvement in patients with MSI-H/MMR-D CRC. However, the observed response rates range between 30% and 50% suggesting the existence of intrinsic resistance mechanisms. Moreover, disease progression after an initial positive response to immune checkpoint inhibitor treatment points to acquired resistance mechanisms. In this review article, we discuss the clinical trials that established the efficacy of immune checkpoint inhibitors in patients with MSI-H/MMR-D CRC, consider biomarkers of the immune response and elaborate on potential mechanisms related to intrinsic and acquired resistance. We also provide a perspective on possible future therapeutic approaches that might improve clinical outcomes, particularly in patients with actionable resistance mechanisms.

Sixty years after its enactment, the Women’s Charter remains lauded as a landmark piece of legislation in Singapore. Through its provisions, this legislative Act affirmed the rights of women, protected vulnerable women and girls, outlined the rights and responsibilities of married persons, and mandated that all non-Muslim marriages were henceforth to be monogamous. This article examines the historical developments that led to the introduction of this unprecedented “women’s Bill of Rights” by the PAP (People’s Action Party) government in 1961. Whilst extant literature credits its origins to the lobbying efforts of the Singapore’s Council of Women formed in 1952, this article argues for the need to adopt a broader contextual perspective to better account for the development of this “revolutionary” Bill between 1952 and 1961. Furthermore, earlier attempts at marriage reform, such as the 1950 Age of Marriage Bill spearheaded by the Singapore Progressive Party’s John Laycock, have curiously been overlooked in the larger narrative of women’s rights and social reform in Singapore. This article thus seeks to remedy this gap in our knowledge and to provide a fuller understanding of Singapore’s civil society in the post-war era, leading up to the introduction of the Women’s Charter. Soixante ans après sa promulgation, la Charte des femmes est encore saluée comme un texte législatif historique à Singapour. Par ses dispositions, cet Acte législatif affirmait les droits des femmes, protégeait femmes et jeunes filles vulnérables, définissait les droits et les responsabilités des personnes mariées et imposait que tous les mariages non musulmans soient désormais monogames. Cet article examine les développements historiques qui ont conduit, en 1961, à l'introduction par le gouvernement du PAP (Parti d’action populaire) de cette « déclaration des droits des femmes » sans précédent. Alors que la littérature existante attribue ses origines aux efforts de lobbying du Conseil des femmes de Singapour, créé en 1952, cet article défend la nécessité d'adopter une approche contextuelle plus large pour mieux expliquer l’origine de cette loi révolutionnaire. En effet, les tentatives antérieures de réforme du mariage, telles que le projet de loi sur l'âge du mariage de 1950 mené par John Laycock, membre du Parti progressiste de Singapour, ont curieusement été négligées dans le récit plus général des droits des femmes et de la réforme sociale à Singapour. Cet article cherche donc à combler cette lacune dans nos connaissances et à proposer une appréhension plus complète du rôle de la société civile de Singapour dans l'immédiat après-guerre, jusqu'à l'introduction de la Charte des femmes.

Objectives Despite multiple trials demonstrating that procalcitonin (PCT) is an effective tool for antibiotic stewardship, inconsistent application in real-world settings continues to fuel controversy regarding its clinical utility. We sought to determine rates of concordance between PCT results and antibiotic prescribing in hospitalized patients. Methods We performed a retrospective review of all inpatient encounters at an academic tertiary care health system with a PCT result between February 2017 and October 2019. Concordant prescribing was defined as starting or continuing antibiotics following an elevated PCT (>0.5 ng/mL) finding and withholding or stopping antibiotics following a low PCT (< 0.1 ng/mL) finding. Results Antibiotic prescribing decisions were discordant from the PCT level in 32.5% of our sample. Among patients not receiving antibiotics at the time of testing, 25.9% (430 of 1,662) were prescribed antibiotics despite a low PCT result. Among patients already receiving antibiotics, treatment was continued despite a low PCT level in 80.4% (728 of 906) of cases. Enhanced decision support tools introduced during the study period had no impact on PCT use for antibiotic decisions. Conclusions Overall concordance between PCT results and antibiotic use is relatively low in a real-world setting. The potential value of PCT for antibiotic stewardship may not be fully realized.

The treatment of locally advanced rectal cancer has improved over the years owing to advancements in surgical techniques and chemoradiation, developing into a multidisciplinary approach that has contributed to markedly reduced rates of local recurrence. Despite these advances, however, distant metastatic recurrence continues to be the main cause of rectal cancer-related death. Unfortunately, the former standard of care of neoadjuvant chemoradiation followed by surgery and adjuvant chemotherapy is still associated with significant morbidity and distant relapse rates. Many trials have studied the optimal sequence, timing, and duration of the individual components of treatment, more recently shifting both chemoradiation and systemic chemotherapy to the preoperative setting in an approach termed total neoadjuvant therapy (TNT). Some of the potential advantages of TNT include improved adherence to treatment, early treatment of micrometastases, and tumor downstaging, with the possibility of observation instead of surgery for those patients with a complete clinical response. This review provides the historical context for the shift to TNT in the treatment paradigm and discusses the critical clinical trials supporting the newer strategy. It also addresses the recent focus on the personalization of care that TNT makes possible by allowing the selective omission of radiation therapy and nonoperative management with a watch-and-wait strategy.

BackgroundHigh-risk features, such as T4 disease, bowel obstruction, poorly/undifferentiated histology, lymphovascular, perineural invasion, and MethodsUnivariate (UVA) and multivariate (MVA) Cox proportional hazards (Cox-PH) models were built to assess the association between clinical and demographic characteristics and overall survival. Kaplan–Meier survival curves were generated with log-rank tests to evaluate the association between adjuvant chemotherapy in high-risk and low-risk cohorts separately.ResultsA total of 2,293 stage II CC patients have dMMR/MSI-H; of those, 29.5% (n = 676) had high-risk features. The high-risk dMMR/MSI-H patients had worse overall survival [5-year survival and 95%CI, 73.2% (67.3–78.1%) vs. 80.3% (76.7–83.5%), p = 0.0001]. In patients with stage II dMMR/MSI-H CC, the high-risk features were associated with shorter overall survival (OS) along with male sex, positive carcinoembryonic antigen, Charlson–Deyo score >1, and older age. Adjuvant chemotherapy administration was associated with better OS, regardless of the high-risk features in dMMR/MSI-H (log-rank test, p = 0.001) or not (p = 0.0006). When stratified by age, the benefit of chemotherapy was evident only in patients age ≥65 with high-risk features.ConclusionHigh-risk features are prognostic in the setting of dMMR/MSI-H stage II CC. Adjuvant chemotherapy may improve survival specifically in patients ≥65 years and with high-risk features.

Performance on an emotional stop-signal task designed to assess emotional response inhibition has been associated with Negative Urgency and psychopathology, particularly self-injurious behaviors. Indeed, difficulty inhibiting prepotent negative responses to aversive stimuli on the emotional stop-signal task (i.e. poor negative emotional response inhibition) partially explains the association between Negative Urgency and non-suicidal self-injury. Here, we combine existing data sets from clinical (hospitalised psychiatric inpatients) and non-clinical (community/student participants) samples aged 18–65 years ( N = 450) to examine the psychometric properties of this behavioural task and evaluate hypotheses that emotional stop-signal task metrics relate to distinct impulsive traits among participants who also completed the UPPS-P ( n = 223). We specifically predicted associations between worse negative emotional response inhibition (i.e. commission errors during stop-signal trials representing negative reactions to unpleasant images) and Negative Urgency, whereas commission errors to positive stimuli – reflecting worse positive emotional response inhibition – would relate to Positive Urgency. Results support the emotional stop-signal task’s convergent and discriminant validity: as hypothesised, poor negative emotional response inhibition was specifically associated with Negative Urgency and no other impulsive traits on the UPPS-P. However, we did not find the hypothesised association between positive emotional response inhibition and Positive Urgency. Correlations between emotional stop-signal task performance and self-report measures were the modest, similar to other behavioural tasks. Participants who completed the emotional stop-signal task twice ( n = 61) additionally provide preliminary evidence for test–retest reliability. Together, findings suggest adequate reliability and validity of the emotional stop-signal task to derive candidate behavioural markers of neurocognitive functioning associated with Negative Urgency and psychopathology.

INTRODUCTION AND OBJECTIVE: Androgen deprivation therapy (ADT) can help maintain remission in advanced prostate cancer (PCa) patients with bone metastases, however, growth and metastatic spread often recur. To address the need for more predictive pre-clinical research platforms and to identify new targets and therapies for bone metastatic castration-resistant prostate cancer (CRPC). METHODS: We used patient-derived xenograft (PDX) tumors from bone metastatic prostate cancer patients to establish threedimensional (3D) organoids and investigated their response to ADT by either withholding di-hydro-testosterone (no DHT) or treating with enzalutamide. Cyst/spheroid quantitation, immunohistopathology, cell viability assay, qRT-PCR, RNA sequencing, gene set enrichment analysis (GSEA) and live cell cycle tracking using Fucci2BL were performed in PDXs: PCSD1, PCSD13 and PCSD25 and compared to PCa Cell lines: P, DU145 and LNCaP. RESULTS: ADT resulted in CRPC spheroids with CK5D CK8D cells, up-regulated stem-cell transcription factors, steroidogenic and neurogenic pathways and down-regulated AR-target genes, interferon, cell cycle, cell division and circadian pacemaker pathways. Enzalutamide-treated spheroids transitioned to G0 and AR protein was decreased but not AR mRNA. Moreover, ADT decreased both ACE2 and TMPRSS2, host cell viral entry factors for the severe acute respiratory syndrome (SARS) SARS-CoV-2. CONCLUSIONS: In organoids, or mini-tumors, established from prostate cancer bone metastasis PDXs, a novel type of dormant ADT-resistant cell with specific gene changes emerged which may be targeted in order to eradicate dormant metastases before they can progress. This study identified a new dormant CRPC basal-luminal hybrid prostate cancer cell and gene signature which may be therapeutically targeted to eradicate dormant CRPC bone metastases in order to prevent disease recurrence. ADT also reduced the cell factors required for SARS-CoV-2 or its variants to infect its host cells and thus may reduce COVID-19 disease severity. The PDX organoid models can be used to screen for therapies that target the dormant CRPC cells and that reduce ACE2 and TMPRSS2 expression to suppress viral load of SARS-CoV-2 and its variants.

Background HCC variants are rare primary hepatic tumors. The aim of this study is to compare clinical characteristics and outcomes of HCC variants with pure HCC. Methods Patients diagnosed between 2004 and 2013 with ICD-O-3 8180/3 and 8170/3-8175/3 were identified from the National Cancer Database. Univariate and multivariate survival analyses were conducted to analyze the association between histology and overall survival (OS). Results 80,280 patients were identified; pure HCC 78,461 (97.7%), fibrolamellar (FLHCC) 310 (0.4%), scirrhous 161 (0.2%), spindle cell 72 (0.1%), clear cell 487 (0.6%), pleomorphic 23 (0.0%), and combined HCC and cholangiocarcinoma (mixed HCC) 766 (1.0%). 76.7% were male and 72% Caucasian. Liver transplant was performed in 10.1% of pure HCC, 14.5% of mixed HCC, 16.2% of scirrhous, 6.9% of spindle cell, 8.8% of clear cell, 8.7% of pleomorphic, and 3.2% of FLHCC (p

Purpose: This first-in-human phase I study (NCT 01417546) evaluated the safety profile, optimal immunologic/biological dose (OID/OBD), and immunogenicity of the combination of two peptide B-cell epitope vaccines engineered to represent the trastuzumab- and pertuzumab-binding sites. Although trastuzumab and pertuzumab have been approved for clinical use, patients often develop resistance to these therapies. We have advanced a new paradigm in immunotherapy that focuses on humoral responses based on conformational B-cell epitope vaccines. Patients and Methods: The vaccine is comprised of two chimeric HER-2 B-cell peptide vaccines incorporating a “promiscuous T-cell epitope.” Patients were immunized with the vaccine constructs emulsified with nor-muramyl-dipeptide adjuvant in a water-in-oil Montanide ISA 720VG vehicle. Eligible patients with metastatic and/or recurrent solid tumors received three inoculations every 3 weeks. Results: Forty-nine patients with a median of 4 prior lines of chemotherapy received at least 1 vaccination. Twenty-eight patients completed the 3 vaccination regimens. Six patients received 1 six-month boost after the regimen, and one patient received 7 six-month boosts. No serious adverse reactions or dose-limiting toxicities were observed. The vaccine was well tolerated with dose level 2 as the recommended phase II dose. The most common related toxicity in all patients was injection-site reactions (24%). Two patients had a partial response, 14 had stable disease, and 19 had progressive disease. Conclusions: The study vaccine is safe, exhibits antitumor activity, and shows preliminary indication that peptide vaccination may avoid therapeutic resistance and offer a promising alternative to monoclonal antibody therapies.