Mixed effects modelling of excess mortality and COVID-19 lockdowns in Thailand.

Accurate mortality data are critical for understanding the impact of COVID-19 and learning lessons from crisis responses. But published statistics risk misrepresenting deaths due to limited testing, underreporting, and lack of subnational data, especially in developing countries. Thailand experienced four COVID-19 waves between January 2020 and December 2021, and used a color-coded, province-level system for lockdowns. To account for deaths directly and indirectly caused by COVID-19, this paper uses mixed effects modelling to estimate counterfactual deaths for 2020-2021 and construct a monthly time series of provincial excess mortality. A fixed effects negative binomial and mixed effects Poisson model both substantiate other studies' estimates of excess deaths using subnational data for the first time. Then, panel regression methods are used to characterize the correlations among restrictions, mobility, and excess mortality. The regressions show that mobility reductions modestly curbed mortality immediately upon imposition, suggesting that aversion of non-COVID deaths was a major aspect of the lockdowns' effect in Thailand. However, the estimates are imprecise. An auto-regressive distributed lag model suggests that the effect of lockdowns was through reduced mobility, but the effectiveness appears to have varied over the course of the pandemic.

Multi-disciplinary diabetic limb salvage programme in octogenarians with diabetic foot ulcers is not futile: An observational study with historical controls.

This study evaluated the effectiveness of a multi-disciplinary diabetic limb salvage programme in improving clinical outcomes and optimising healthcare utilisation in 406 patients aged ≥80 years with diabetic foot ulcers (DFUs), compared to 2392 younger patients enrolled from June 2020 to June 2021 and against 1716 historical controls using one-to-one propensity score matching. Results showed that elderly programme patients had lower odds of amputation-free survival (odds ratio: 0.64, 95% CI: 0.47, 0.88) and shorter cumulative length of stay (LOS) compared to younger programme patients (incidence rate ratio: 0.45, 95% CI: 0.29, 0.69). Compared to the matched controls, participating in the programme was associated with 5% higher probability of minor lower extremity amputation, reduced inpatient admissions and emergency visits, shorter LOS but increased specialist and primary care visits (all p-values <0.05). The findings suggest that the programme yielded favourable impacts on the clinical outcomes of patients aged≥80 years with DFUs. Further research is needed to develop specific interventions tailoring to the needs of the elderly population and to determine their effectiveness on patient outcomes while accounting for potential confounding factors.

A feasibility study on the efficacy of a patient-owned wound surveillance system for diabetic foot ulcer care (ePOWS study).

Objective: Wound image analysis tools hold promise in helping patients to monitor their wounds. We aim to perform a novel feasibility study on the efficacy of a patient-owned wound surveillance system for diabetic foot ulcer (DFU) care. Methods: This two-institutional, prospective, single-arm pilot study examined patients with DFU. An artificial intelligence-enabled image analysis app calculating the wound surface area was installed and patients or caregivers were instructed to take pictures of wounds during dressing changes. Patients were followed until wound deterioration, wound healing, or wound stability at 6 months occurred and the outcomes of interest included study adherence, algorithm performance, and user experience. Results: Between January 2021 and December 2021, 39 patients were enrolled in the study, with a mean age of 61.6 ± 8.6 years, and 69% (n = 27) of subjects were male. All patients had documented diabetes and 85% (n = 33) of them had peripheral arterial disease. A mean follow-up for those completing the study was 12.0 ± 8.5 weeks. At the conclusion of the study, 80% of patients (n = 20) had primary wound healing whilst 20% (n = 5) had wound deterioration. The study completion rate was 64% (n = 25). Usage of the app for surveillance of DFU healing, as compared to physician evaluation, yielded a sensitivity of 100%, specificity of 20%, positive predictive value of 83%, and negative predictive value of 100%. Of those who provided user experience feedback, 59% (n = 10) felt the app was easy to use, 47% (n = 8) would recommend the wound analysis app to others but only 6% would pay for the app out of pocket (n = 1). Conclusion: Implementation of a patient-owned wound surveillance system is feasible. Most patients were able to effectively monitor wounds using a smartphone app-based solution. The image analysis algorithm demonstrates strong performance in identifying wound healing and is capable of detecting deterioration prior to interval evaluation by a physician. Patients generally found the app easy to use but were reluctant to pay for the use of the solution out of pocket.

Reducing single-use cutlery with green nudges: Evidence from China's food-delivery industry.

Rising consumer demand for online food delivery has increased the consumption of disposable cutlery, leading to plastic pollution worldwide. In this work, we investigate the impact of green nudges on single-use cutlery consumption in China. In collaboration with Alibaba's food-delivery platform, Eleme (which is similar to Uber Eats and DoorDash), we analyzed detailed customer-level data and found that the green nudges-changing the default to "no cutlery" and rewarding consumers with "green points"-increased the share of no-cutlery orders by 648%. The environmental benefits are sizable: If green nudges were applied to all of China, more than 21.75 billion sets of single-use cutlery could be saved annually, equivalent to preventing the generation of 3.26 million metric tons of plastic waste and saving 5.44 million trees.

Patients, carers and healthcare providers' perspectives on a patient-owned surveillance system for diabetic foot ulcer care: A qualitative study.

Objective: Digital health has recently gained a foothold in monitoring and improving diabetes care. We aim to explore the views of patients, carers and healthcare providers (HCPs) regarding the use of a novel patient-owned wound surveillance application as part of outpatient management of patients with diabetic foot ulcers (DFUs). Methods: Semi-structured online interviews were conducted with patients, carers and HCPs in wound care for DFUs. The participants were recruited from a primary care polyclinic network and two tertiary hospitals in Singapore, within the same healthcare cluster. Purposive maximum variation sampling was used to select participants with differing attributes to ensure heterogeneity. Common themes relating to the wound imaging app were captured. Results: A total of 20 patients, 5 carers and 20 HCPs participated in the qualitative study. None of the participants have used a wound imaging app before. Regarding a patient-owned wound surveillance app, all were open and receptive to the system and workflow for use in DFU care. Four major themes emerged from patients and carers: (1) technology, (2) application features and usability, (3) feasibility of using the wound imaging application and (4) logistics of care. Four major themes were identified from HCPs: (1) attitudes towards wound imaging app, (2) preferences regarding functionality, (3) perceived challenges for patients/carers and (4) perceived barriers for HCPs. Conclusion: Our study highlighted several barriers and facilitators from patients, carers and HCPs regarding the use of a patient-owned wound surveillance app. These findings demonstrate the potential of digital health and areas to improve and tailor a DFU wound app suitable for implementation in the local population.

Protocol Considerations for In Vitro Metabolic Glycoengineering of Non-Natural Glycans.

Metabolic glycoengineering (MGE) refers to a technique where non-natural monosaccharide analogs are introduced into living biological systems. Once inside a cell, these compounds intercept a targeted biosynthetic glycosylation pathway and in turn are metabolically incorporated into cell-surface-displayed oligosaccharides, where they can modulate a host of biological activities or be exploited as tags for bioorthogonal and chemoselective ligation reactions. Over the past decade, azido-modified monosaccharides have become the go-to analogs for MGE; at the same time, analogs with novel chemical functionalities continue to be developed. Therefore, one emphasis of this article is to describe a general approach for analog selection and then provide protocols to ensure safe and efficacious analog usage by cells. Once cell-surface glycans have been successfully remodeled by MGE methodology, the stage is set for probing changes to the myriad cellular responses modulated by these versatile molecules. This manuscript concludes by detailing how one of these detection methods-flow cytometry-can be successfully utilized to quantify MGE analog incorporation and set the stage for numerous follow-up applications. © 2023 The Authors. Current Protocols published by Wiley Periodicals LLC. Basic Protocol 1: Incubation of cells with sugar analogs Support Protocol: Routine growth and maintenance of Jurkat cells Basic Protocol 2: Cell viability assays Basic Protocol 3: Periodate-resorcinol assay to measure analog uptake and incorporation into metabolic pathways Basic Protocol 4: Quantitation of cell-surface glycoconjugates.

Diabetic foot in primary and tertiary (DEFINITE) Care: A health services innovation in coordination of diabetic foot ulcer (DFU) Care within a healthcare cluster - 18-month results from an observational population health cohort study.

Diabetic Foot in Primary and Tertiary (DEFINITE) Care is an inter-institutional and multi-disciplinary team (MDT) health systems innovation programme at a healthcare cluster in Singapore. We aim to achieve coordinated MDT care across primary and tertiary care for patients with diabetic foot ulcers (DFU), within our public healthcare cluster - an integrated network of seven primary care polyclinics and two acute care tertiary hospitals (1700-bed and 800-bed) with a total catchment population of 2.2 million residents. Results from prospective DEFINITE Care is referenced against a retrospective 2013-2017 cohort, which was previously published. Cardiovascular profile of the study population is compared against the same population's profile in the preceding 12 months. Between June 2020 and December 2021, there were 3475 unique patients with DFU with mean age at 65.9 years, 61.2% male, mean baseline HbA1c at 8.3% with mean diabetes duration at 13.3 years, mean diabetes complication severity index (DCSI) at 5.6 and mean Charlson Comorbidity Index (CCI) at 6.8. In the 12-months preceding enrolment to DEFINITE Care, 35.5% had surgical foot debridement, 21.2% had minor lower extremity amputation (LEA), 7.5% had major LEA whilst 16.8% had revascularisation procedures. At 18-months after the implementation of DEFINITE Care programme, the absolute minor and major amputation rates were 8.7% (n = 302) and 5.1% (n = 176), respectively, equating to a minor and major LEA per 100000 population at 13.7 and 8.0, respectively. This represents an 80% reduction in minor amputation rates (P < .001) and a 35% reduction in major amputation rates (P = .005) when referenced against a retrospective 2013-2017 cohort, which had minor and major LEA per 100000 population at 68.9 and 12.4, respectively. As compared to the preceding 12 months, there was also a significant improvement in cardiovascular profile (glycemic and lipid control) within the DEFINITE population, with improved mean HbAc1 (7.9% from 8.4%, P < .001), low-density lipoprotein (LDL) levels (2.1 mmol/L from 2.2, P < .001), total cholesterol (3.9 mmol/L from 4.1, P < .001) and triglycerides levels (1.6 mmol/L from 1.8, P = .002). Multivariate analysis revealed a history of minor amputation in the preceding 12 months to be an independent predictor for major and minor amputation within the study period of 18 months (Hazard Ratio 3.4 and 1.8, respectively, P < .001). In conclusion, within DEFINITE care, 18-month data showed a significant reduction of minor and major LEA rates, with improved medical optimisation and cardiovascular profile within the study population.

Neutralizing Antibody Response following a Third Dose of the mRNA-1273 Vaccine among Cancer Patients.

Cancer patients are at an increased risk of morbidity and mortality from SARS-CoV-2 infection and have a decreased immune response to vaccination. We conducted a study measuring both the neutralizing and total antibodies in cancer patients following a third dose of the mRNA-1273 COVID-19 vaccine. Immune responses were measured with an enzyme-linked immunosorbent assay (ELISA) and neutralization assays. Kruskal-Wallis tests were used to evaluate the association between patient characteristics and neutralization geometric mean titers (GMTs), and paired t-tests were used to compare the GMTs between different timepoints. Spearman correlation coefficients were calculated to determine the correlation between total antibody and neutralization GMTs. Among 238 adults diagnosed with cancer, a third dose of mRNA-1273 resulted in a 37-fold increase in neutralization GMT 28 days post-vaccination and maintained a 14.6-fold increase at 6 months. Patients with solid tumors or lymphoid cancer had the highest and lowest neutralization GMTs, respectively, at both 28 days and 6 months post-dose 3. While total antibody GMTs in lymphoid patients continued to increase, other cancer types showed decreases in titers between 28 days and 6 months post-dose 3. A strong correlation (p < 0.001) was found between total antibody and neutralization GMTs. The third dose of mRNA-1273 was able to elicit a robust neutralizing antibody response in cancer patients, which remained for 6 months after administration. Lymphoid cancer patients can benefit most from this third dose, as it was shown to continue to increase total antibody GMTs 6 months after vaccination.

Prognostic and Predictive Value of PIK3CA Mutations in Metastatic Colorectal Cancer.

BACKGROUND: Comprehensive genomic profiling is used to guide the management of metastatic colorectal cancer (mCRC); however, the role of PIK3CA mutations, present in up to 20% of mCRCs, is unclear. OBJECTIVE: This study aimed to evaluate the association of PIK3CA mutations with other common mutations in mCRC and determine the prognostic and predictive value of PIK3CA mutations. PATIENTS AND METHODS: A retrospective chart review was performed on patients in the Moffitt Clinical Genomic Database with mCRC. A meta-analysis was performed to further evaluate the predictive value of PIK3CA mutations to the response to anti-epidermal growth factor receptor (EGFR) therapy. RESULTS: Among 639 patients, PIK3CA was positively correlated with KRAS mutation (r = 0.11, p = 0.006) and negatively correlated with TP53 mutation (r = - 0.18, p ≤ 0.001) and ERBB2 amplification (r = - 0.08, p = 0.046). The median overall survival (OS) of patients with PIK3CA-mutant mCRC (n = 49) was 35.5 (95% confidence interval [CI] 18.7-48.1) months vs. 55.3 (95% CI 47.5-65.6) months for PIK3CA wild-type mCRC (n = 286) [p = 0.003]. This OS difference remained significant with exon 9 and exon 20 subset analyses. There was no significant difference in response rate between patients with PIK3CA wild-type (n = 97) versus mutant (n = 9) mCRC who received anti-EGFR therapy (43% vs. 56%, p = 0.61) and no significant difference in median progression-free survival (PFS) of 10.3 versus 7.2 months (p = 0.60). However, our meta-analysis of 12 studies, including ours, using a common effect model identified that PIK3CA mutations are associated with reduced response to anti-EGFR therapy, with a relative risk of 0.56 (95% CI 0.38-0.82). CONCLUSION: Our study identified PIK3CA mutations as a poor prognostic factor, and our meta-analysis identified PIK3CA mutations as predictive of decreased response to anti-EGFR therapy in patients with mCRC.

Copy Number Alterations as Novel Biomarkers and Therapeutic Targets in Colorectal Cancer.

In colorectal cancer, somatic mutations have played an important role as prognostic and predictive biomarkers, with some also functioning as therapeutic targets. Another genetic aberration that has shown significance in colorectal cancer is copy number alterations (CNAs). CNAs occur when a change to the DNA structure propagates gain/amplification or loss/deletion in sections of DNA, which can often lead to changes in protein expression. Multiple techniques have been developed to detect CNAs, including comparative genomic hybridization with microarray, low pass whole genome sequencing, and digital droplet PCR. In this review, we summarize key findings in the literature regarding the role of CNAs in the pathogenesis of colorectal cancer, from adenoma to carcinoma to distant metastasis, and discuss the roles of CNAs as prognostic and predictive biomarkers in colorectal cancer.

Human Epidermal Growth Factor Receptor 2-Targeting Approaches for Colorectal Cancer: Clinical Implications of Novel Treatments and Future Therapeutic Avenues.

The treatment paradigm for colorectal cancer (CRC) has changed significantly over the past decade with targeted therapeutics. Human epidermal growth factor receptor 2 (HER2) amplification is seen among 3%-4% of patients with metastatic CRC (mCRC). The biological discovery of HER2 amplification in cancer cells has led to practice-changing drug development for several solid tumors, including breast, gastric, and esophageal cancers. HER2 amplification is now highly actionable in CRC with distinct therapeutic combinations, including the combination of monoclonal antibodies and HER2 receptor-specific tyrosine kinase inhibitors, as well as antibody-drug conjugates, that delivers targeted cytotoxic agents. However, it is essential to define the therapeutic role and sequence of these different combinations, some of which are already part of standard clinical practice. In this review article, we discuss recent clinical studies demonstrating the clinical benefits of each distinct therapeutic approach and their impacts on the current management of HER2-amplified mCRC. We also review ongoing clinical trials targeting the HER2 pathway in mCRC and elaborate on novel therapeutic opportunities in this space that may further define the changing paradigm of HER2-targeted therapy for CRC.

Evaluation of Antibody Response to SARS-CoV-2 mRNA-1273 Vaccination in Patients With Cancer in Florida.

Importance: Patients with cancer experience high rates of morbidity and mortality after SARS-CoV-2 infection. Immune response to mRNA-1273 vaccination across multiple cancer types and treatments remains to be established. Objective: To quantitate antibody responses after mRNA-1273 vaccination among patients with solid tumors and hematologic cancer and to assess clinical and treatment factors associated with vaccine response. Design, Setting, and Participants: This cohort study included patients with cancer who were aged 18 years or older, spoke English or Spanish, had received their first mRNA-1273 dose between January 12 and 25, 2021, and agreed to blood tests before and after vaccination. Exposures: Receipt of 1 and 2 mRNA-1273 SARS-CoV-2 vaccine doses. Main Outcomes and Measures: Seroconversion after each vaccine dose and IgG levels against SARS-CoV-2 spike protein obtained immediately before the first and second vaccine doses and 57 days (plus or minus 14 days) after the first vaccine dose. Cancer diagnoses and treatments were ascertained by medical record review. Serostatus was assessed via enzyme-linked immunosorbent assay. Paired t tests were applied to examine days 1, 29, and 57 SARS-CoV-2 antibody levels. Binding antibody IgG geometric mean titers were calculated based on log10-transformed values. Results: The 515 participants were a mean (SD) age of 64.5 (11.4) years; 262 (50.9%) were women; and 32 (6.2%) were Hispanic individuals and 479 (93.0%) White individuals; race and ethnicity data on 4 (0.7%) participants were missing. Seropositivity after vaccine dose 2 was 90.3% (465; 95% CI, 87.4%-92.7%) among patients with cancer, was significantly lower among patients with hematologic cancer (84.7% [255]; 95% CI, 80.1%-88.6%) vs solid tumors (98.1% [210]; 95% CI, 95.3%-99.5%), and was lowest among patients with lymphoid cancer (70.0% [77]; 95% CI, 60.5%-78.4%). Patients receiving a vaccination within 6 months after anti-CD20 monoclonal antibody treatment had a significantly lower seroconversion (6.3% [1]; 95% CI, 0.2%-30.2%) compared with those treated 6 to 24 months earlier (53.3% [8]; 95% CI, 26.6%-78.7%) or those who never received anti-CD20 treatment (94.2% [456]; 95% CI, 91.7%-96.1%). Low antibody levels after vaccination were observed among patients treated with anti-CD20 within 6 months before vaccination (GM, 15.5 AU/mL; 95% CI, 9.8-24.5 AU/mL), patients treated with small molecules (GM, 646.7 AU/mL; 95% CI, 441.9-946.5 AU/mL), and patients with low lymphocyte (GM, 547.4 AU/mL; 95% CI, 375.5-797.7 AU/mL) and IgG (GM, 494.7 AU/mL; 95% CI, 304.9-802.7 AU/mL) levels. Conclusions and Relevance: This cohort study found that the mRNA-1273 SARS-CoV-2 vaccine induced variable antibody responses that differed by cancer diagnosis and treatment received. These findings suggest that patients with hematologic cancer and those who are receiving immunosuppressive treatments may need additional vaccination doses.

BRAF Mutations Are Associated with Poor Survival Outcomes in Advanced-stage Mismatch Repair-deficient/Microsatellite High Colorectal Cancer.

BACKGROUND: Mismatch repair-deficient (MMR-D)/microsatellite instability-high (MSI-H) metastatic colorectal cancer (mCRC) is a unique disease entity with growing interest given the rise of young-onset CRC. Given its heterogeneous behavior and potential for highly effective treatment outcomes, we sought to identify the clinical and molecular features that offer prognostic value for MMR-D CRC. MATERIALS/METHODS: This was a retrospective cohort study of patients with metastatic CRC with MMR-D or microsatellite instability in a real-world database. Overall survival (OS) was determined by the date of metastatic disease to date of death with stratification made based on factors including BRAF and RAS mutation status, age, and MMR protein loss type. RESULTS: There were 1101 patients in the study. Patients with BRAF mutations had worse OS compared with patients with wild-type BRAF with a median survival of 18.9 months versus 33.2 months (hazard ratio [HR] 1.52, 95% confidence interval [CI]: 1.25-1.86, P < .001). Patients with age >50 were found to have decreased OS versus age ≤50 with a median survival of 21.4 months versus 38.7 months (HR 1.66, 95% CI: 1.33-2.07, P < .001). BRAF mutations and age >50 remained significant predictors of OS in multivariate analysis. CONCLUSION: BRAF mutations and age >50 are associated with worse survival outcomes for patients with MMR-D mCRC. RAS mutations and specific MMR alterations are not associated with survival outcomes.

Core Homologous Recombination Mutations and Improved Survival in Nonpancreatic GI Cancers.

INTRODUCTION: Homologous recombination mutations (HRM) have led to increased responses to platinum chemotherapy in pancreatic cancer. However, HRMs' role in nonpancreatic gastrointestinal (GI) cancers remains to be determined. Our objective was to evaluate the prognostic and predictive role of core (BRCA1, BRCA2, PALB2) and noncore HRM in nonpancreatic GI cancers receiving platinum therapy. MATERIALS AND METHODS: This study performed at Moffitt Cancer Center included metastatic nonpancreatic GI cancer patients treated with platinum therapy. All patients had either a core or noncore HRM, determined by next generation sequencing. Response rates, median progression-free survival (PFS), and median overall survival (OS) were determined and compared between core versus noncore HRM patients. RESULTS: In the study, 69 patients with one or more HRM were included: 63.8% were male, 87.0% were Caucasian, and 47.9% had colorectal cancer. Twenty-one (30.4%) patients had a core HRM and 48 (69.6%) had a noncore HRM. Among evaluable patients (n=64), there was no significant difference in objective response: 20.0% with core HRM versus 22.7% with noncore HRM responded to platinum therapy (P=0.53). Median PFS was 10.4 months versus 7.1 months for core HRM versus noncore HRM, respectively (P=0.039). Median OS was 68.9 months versus 24.3 months (P=0.026) for core HRM versus noncore HRM, respectively. CONCLUSIONS: Our study demonstrated response of core and noncore HRM to platinum therapy in metastatic nonpancreatic GI malignancies, suggesting benefit in both groups. Core HRM patients had significantly increased median OS and median PFS compared with those with noncore HRM, suggesting potential prognostic and predictive significance. Larger prospective studies are needed to confirm our findings.

TCR gene-engineered cell therapy for solid tumors.

The engineering of immune cells to target cancer cells (cellular immunotherapy) has been an exciting area of development in recent years. One type of cellular therapy, T cell receptor (TCR) gene engineered therapy, has shown particular promise in solid tumors. Through use of a heterodimer to recognize intracellular tumor antigens presented through the major histocompatibility complex (MHC), TCR T cells are able to evoke a cytotoxic response as well as a clinical response. In this review, we discuss the potential of TCR-based cellular therapies in solid tumors. While various challenges exist with this therapy, multiple clinical trials are ongoing, in attempt to mitigate these limitations.

Impact of the FilmArray meningitis/encephalitis panel on antimicrobial duration among patients with suspected central nervous system infection.

Ten controlled studies evaluated antimicrobial use following implementation of the FilmArray meningitis and encephalitis panel versus usual care. Only one-half of studies identified significant reductions in antibiotic duration, with 8/10 reporting modest reductions for acyclovir. Coupling the FilmArray meningitis and encephalitis panel with interventions by antimicrobial stewardship programs may help enhance its clinical impact.

A phase 1/2 trial of ibrutinib in combination with pembrolizumab in patients with mismatch repair proficient metastatic colorectal cancer.

BACKGROUND: MMR proficient (pMMR) colorectal cancer (CRC) is usually unresponsive to immunotherapy. Recent data suggest that ibrutinib may enhance the anti-tumour activity of anti-PD-1 immunotherapy. In this study, we evaluated the safety and efficacy of ibrutinib plus pembrolizumab in refractory metastatic CRC. METHODS: This was a phase 1/2 study in patients with refractory metastatic pMMR CRC. The primary endpoints for phases 1 and 2 were maximum tolerated dose (MTD) and disease control rate, respectively. The secondary endpoints were safety, progression-free survival (PFS) and overall survival (OS). RESULTS: A total of 40 patients were enrolled. No dose-limiting toxicity was observed, and MTD was not identified. The highest tested dose of ibrutinib, 560 mg once daily, was combined with a fixed dose of pembrolizumab 200 mg every 3 weeks for the phase 2 portion. The most common grade 3/4 treatment-related adverse events were anaemia (21%), fatigue (8%) and elevated alkaline phosphatase (8%). Among 31 evaluable patients, 8 (26%) achieved stable disease, and no objective response was observed. The median PFS and OS were 1.4 and 6.6 months, respectively. CONCLUSION: Ibrutinib 560 mg daily plus pembrolizumab 200 mg every 3 weeks appears to be well tolerated with limited anti-cancer activity in metastatic CRC. CLINICALTRIALS. GOV IDENTIFIER: NCT03332498.

Defining the current role of immune checkpoint inhibitors in the treatment of mismatch repair-deficient/microsatellite stability-high colorectal cancer and shedding light on future approaches.

Introduction: Mismatch repair deficient (MMR-D)/microsatellite instability-high (MSI-H) colorectal cancer (CRC) carries unique biologic features including high tumor mutation burden, increased amount of mutation-associated neoantigen generation, and the presence of marked tumor-infiltrating lymphocytes. Immune checkpoint inhibitor (ICI) therapy has rapidly changed the treatment algorithm of MMR-D/MSI-H CRC.Areas covered: In this review article, we discuss the recent data regarding the use of ICIs in metastatic MMR-D/MSI-H CRC patients. We also elaborated on potential biomarkers of ICI response and innovative therapeutic approaches that may prevail resistance mechanisms for the treatment of MMR-D/MSI-H colorectal cancer.Expert opinion: Pembrolizumab was recently granted approval by the FDA as first-line therapy for metastatic MMR-D/MSI-H CRC based on the results of the Keynote 177 study. The combination of nivolumab and ipilimumab will also likely be a choice for the initial therapy of MMR-D/MSI-H CRC in the near future. More therapeutic modalities with novel immunomodulatory agents as well as targeted therapy directed to immune resistance pathways are needed. The novel approaches discussed in this review article will define potential treatment options for the management of MMR-D/MSI-H CRC patients who progress on first-line ICI therapy.

Temporomandibular disorders in prospective orthodontic patients.

OBJECTIVES: To determine the prevalence and severity of temporomandibular disorders (TMDs) in prospective orthodontic patients. The association between TMDs and malocclusion severity as well as the impact of TMDs on oral health-related quality of life (OHRQoL) were also examined. MATERIALS AND METHODS: A total of 350 consecutive patients seeking orthodontic treatment were invited to participate in the study. The presence of TMDs was established with the Fonseca Anamnestic Index (FAI), while malocclusion severity and OHRQoL were evaluated using the Peer Assessment Rating (PAR) index and Oral Health Impact Profile-14 (OHIP-14), respectively. Data were analyzed using chi-square, Kruskal-Wallis, and Mann-Whitney U tests and Spearman's correlation (P < .05). RESULTS: Of the 350 patients, 164 consented to participation. Data from 26 participants were excluded because of incomplete entries, and that from 138 subjects (mean age 21.02 ± 5.45 years) were examined. TMD-related symptoms were present in two-thirds of the subjects, with 20.3% experiencing moderate/severe TMDs. While no significant difference in PAR scores were observed between the group with no TMDs and those with TMDs, subjects with TMDs had significantly higher OHIP-14 summary/domain scores than those without TMDs. Although a moderately strong correlation was observed between the FAI and summary OHIP-14 scores (rs = 0.57), no association was observed between FAI and PAR index scores. CONCLUSIONS: The prevalence of TMD-related symptoms in prospective orthodontic patients was high, emphasizing the importance of screening the masticatory system before initiating orthodontic therapy. Although the presence of TMDs was not associated with malocclusion severity, it had a significant negative impact on OHRQoL.

Phase 2 study of copanlisib in combination with gemcitabine and cisplatin in advanced biliary tract cancers.

BACKGROUND: Biliary tract cancer (BTC) has a poor prognosis despite treatment with first-line gemcitabine and cisplatin. In BTC, PI3K/AKT pathway activation has been shown to increase resistance to chemotherapy, which may be overcome with PI3K inhibition. This phase 2 study evaluated the safety and efficacy of copanlisib, a PI3K inhibitor, with gemcitabine and cisplatin in advanced BTCs. The role of PTEN expression in outcomes was also explored. METHODS: Patients with advanced/unresectable BTC received gemcitabine, cisplatin, and copanlisib as their first-line treatment. The primary endpoint was progression-free survival (PFS) at 6 months. Secondary endpoints were the response rate (RR), median overall survival (OS)/PFS, and safety profile. An assessment of PTEN expression by immunohistochemistry was also performed along with molecular profiling. RESULTS: Twenty-four patients received at least 1 dose of the study drug. The PFS rate at 6 months was 51%; the median OS was 13.7 months (95% CI, 6.8-18.0 months), and the median PFS was 6.2 months (95% CI, 2.9-10.1 months). Nineteen patients were evaluable for RR: 6 patients achieved a partial response (31.6%), and 11 (57.9%) had stable disease. The most common grade 3/4 adverse events were a decreased neutrophil count (45.83%), anemia (25%), increased lipase (25%), and hypertension (20.8%). Twenty patients had tissue evaluable for the PTEN status. The PFS for low (n = 9) and high PTEN expression (n = 11) was 8.5 and 4.6 months, respectively (P = .19). The median OS for low and high PTEN expression groups was 17.9 and 7.0 months, respectively (P = .19). CONCLUSIONS: The addition of copanlisib to gemcitabine and cisplatin does not improve PFS at 6 months. However, future studies using PTEN as a potential biomarker should be considered. LAY SUMMARY: The addition of copanlisib, a PI3K inhibitor, to standard chemotherapy for advanced biliary tract cancers was assessed for efficacy and safety. Twenty-four patients with advanced biliary tract cancer received treatment in this study. There was no difference in survival with the addition of copanlisib in comparison with standard chemotherapy. Copanlisib may be more effective and increase survival in patients with low PTEN expression levels. Further studies are needed to confirm this. No unexpected adverse events occurred.