Prediction of response to immune checkpoint blockade in patients with metastatic colorectal cancer with microsatellite instability.

BACKGROUND: Mismatch repair-deficient (dMMR) tumors displaying microsatellite instability (MSI) represent a paradigm for the success of immune checkpoint inhibitor (ICI)-based immunotherapy, particularly in patients with metastatic colorectal cancer (mCRC). However, a proportion of patients with dMMR/MSI mCRC exhibit resistance to ICI. Identification of tools predicting MSI mCRC patient response to ICI is required for the design of future strategies further improving this therapy. PATIENTS AND METHODS: We combined high-throughput DNA and RNA sequencing of tumors from 116 patients with MSI mCRC treated with anti-programmed cell death protein 1 ± anti-cytotoxic T-lymphocyte-associated protein 4 of the NIPICOL phase II trial (C1, NCT03350126, discovery set) and the ImmunoMSI prospective cohort (C2, validation set). The DNA/RNA predictors whose status was significantly associated with ICI status of response in C1 were subsequently validated in C2. Primary endpoint was progression-free survival by immune RECIST (iRECIST) (iPFS). RESULTS: Analyses showed no impact of previously suggested DNA/RNA indicators of resistance to ICI, e.g. MSIsensor score, tumor mutational burden, or specific cellular and molecular tumoral contingents. By contrast, iPFS under ICI was shown in C1 and C2 to depend both on a multiplex MSI signature involving the mutations of 19 microsatellites hazard ratio cohort C2 (HRC2) = 3.63; 95% confidence interval (CI) 1.65-7.99; P = 1.4 × 10-3] and the expression of a set of 182 RNA markers with a non-epithelial transforming growth factor beta (TGFB)-related desmoplastic orientation (HRC2 = 1.75; 95% CI 1.03-2.98; P = 0.035). Both DNA and RNA signatures were independently predictive of iPFS. CONCLUSIONS: iPFS in patients with MSI mCRC can be predicted by simply analyzing the mutational status of DNA microsatellite-containing genes in epithelial tumor cells together with non-epithelial TGFB-related desmoplastic RNA markers.

The effect of smoking and age on the response to first-line therapy of hidradenitis suppurativa: An institutional retrospective cohort study.

BACKGROUND: Treatment for hidradenitis suppurativa is often empiric and inadequate, and determining which patients will respond is difficult. OBJECTIVE: We sought to determine which patient factors are associated with a positive response to first-line medical therapy. METHODS: A single-center retrospective cohort study of all patients with hidradenitis suppurativa seen between January 1, 1992, and October 1, 2014, was conducted. Response to first-line medical therapy (oral/topical antibiotics, intralesional corticosteroids, and topical washes) was examined at follow-up within 6 months of initiating therapy. A multivariate binary logistic regression model was built examining response to treatment and the interplay of patient factors and treatment initiated. RESULTS: In all, 198 patients were included in the final model. Nonsmokers (odds ratio 2.634, 95% confidence interval 1.301-5.332, P = .007) and older individuals (odds ratio 1.046 for each additional year, 95% confidence interval 1.020-1.072, P < .001) were more likely to have improvement at follow-up. In addition, current smokers differed significantly from nonsmokers in several regards. LIMITATIONS: The retrospective nature of this study is a limitation, as is relying on classification of disease severity from physical examination findings in some patients. CONCLUSIONS: The results of this study suggest that clinicians may be able to more accurately predict which patients with hidradenitis suppurativa will respond to first-line medical therapy, and which patients may require therapy escalation.

The goals for successful development of treatment in gastroparesis.

BACKGROUND: Gastroparesis is a motility disorder of the stomach characterized by cardinal symptoms and delayed gastric emptying of solid food in the absence of mechanical obstruction. There is significant unmet need in its management, and essentially there are no medications approved for its treatment over four decades. PURPOSE: The objectives of this review are to develop an understanding of the goals of treatment, the evidence-based criteria for treatment success based on the current scientific understanding of gastroparesis as well as patient response outcomes, and to propose evidence-based principles for the successful development of treatments for gastroparesis. Specifically, we discuss the pathophysiologic targets in gastroparesis, eligibility criteria for clinical trial participation based on validated gastric emptying studies, and the patient response outcome measures that have been validated to appraise effects of treatment on clinically relevant outcomes. These considerations lead to recommendations regarding eligibility, design, and duration of proof-of-efficacy studies, and to endorsing the American Neurogastroenterology and Motility Society Gastroparesis Cardinal Symptom Index Daily Diary as a validated patient response outcome and to justification of the shortening of proof-of-efficacy, placebo-controlled clinical trials to 4 weeks treatment duration after a baseline period. We believe that such approaches will increase the likelihood of successful assessment of efficacy of novel approaches to treating patients with gastroparesis.

Assessing Stroke Awareness and Behavioural Response Following the National 'Act Fast' Stroke Awareness Campaign - Insights from a Cross-Sectional Survey in Qatar.

Evaluating stroke campaigns and associated behavioural changes is crucial to assess intervention effectiveness and inform future strategies. We aimed to evaluate patient's and bystanders' foreknowledge of stroke signs and symptoms and their response at stroke onset. We interviewed stroke patients using a validated questionnaire or their bystanders if the stroke patient had disabling stroke. The questionnaire was administered to 165 participants, 142 (86.1%) stroke patients and 23 (13.9%) bystanders. The mean age was 52.6 (SD = 11.7), and male-female ratio was 7:1. Among the participants, 33 (20.1%) had foreknowledge of stroke signs, and of these, 27 (16.5%) were aware of the stroke campaign in Qatar. The behavioural responses at stroke onset included; activating Emergency Medical Services (EMS) (n = 55, 33.3%), calling friends/relatives (n = 69, 41.8%), driving to hospital (n = 33, 20%), waiting for improvement in condition (n = 21, 12.7%). There was no association of ethnicity, marital status, or campaign awareness with EMS activation. Despite limited community awareness of stroke signs and campaign, help-seeking behaviour through EMS activation was generally high, underscoring the need for focused educational efforts and public health interventions.

Outcomes of responders to PD-1/PD-L1 inhibitors who discontinue therapy after sustained disease control.

BACKGROUND: PD-1/PD-L1 immune checkpoint inhibitors (ICIs) are widely used in the treatment of metastatic malignancies. Judiciously balancing disease control (DC) against development of immune-related adverse events (irAE) remains a crucial aspect of treatment. The effect of treatment discontinuation after sustained disease control (SDC) is unknown. The purpose of this analysis was to evaluate outcomes of responders to ICI who discontinue treatment after a minimum of 12 months (SDC). METHODS: We retrospectively reviewed the database of the University of New Mexico Comprehensive Cancer Center (UNMCCC) between 2014 and 2021 and identified patients who had received ICI. Patients with metastatic solid tumors who had stopped ICI therapy after achieving SDC [stable disease, partial response, complete response (SD, PR, CR)] were selected and outcomes reviewed from their electronic health records. RESULTS: We identified 204 patients who were treated with ICI for various solid cancers. Forty-four patients (21.6%) met the criteria, of whom 35 with follow-up data were included in the final analysis; including 11 melanoma, 5 non-small cell lung, 4 head & neck, 8 renal, 4 urothelial, 1 anal, 1 Merkel cell carcinoma, and 1 liposarcoma. Patients were divided into two groups: those who stopped ICI due to an irAE [irAE group, n = 14, median treatment time (MTT), 16.6 mo] and those who stopped due to other reasons (eg completion of 2 years of therapy, n = 20, non-cancer related surgery, n = 1) (non-irAE group, n = 21, MTT, 23.7 mo). Among the irAE group, the most common irAE included pneumonitis, rash, transaminitis, and fatigue. As of data cutoff date, 9 of 14 (64%) patients continued to show SDC. Only 5 of 14 (36%) patients in this group experienced progression of disease (PD), with 1 of 2 patients achieving DC (median follow-up of 19.2 mo after last dose of treatment, range 3-50.2 mo). Among the non-irAE group, 13 of 21 (62%) continued to have SDC. Eight of 21 (38%) experienced PD after stopping treatment, 7 of whom received ICI rechallenge, with 2 of 7 achieving DC (median follow-up of 22.2 mo, range 3.6-54.8 mo). At a median follow-up of 21.3 mo from stopping ICI therapy (range, 3-54.8 mo), 10 patients (71%) from the irAE group and 13 (61.9%) from the non-irAE group are in DC and have not experienced PD. CONCLUSIONS: We demonstrate that 22 (66%) patients experienced SDC, regardless of cancer type or development of irAE. After including patients who were re-challenged with ICI due to PD, 25 (71%) remain in DC. Future prospective malignancy-specific trials are warranted to evaluate optimal treatment duration.

Experiences of patients undergoing IVF treatment during the COVID-19 pandemic.

OBJECTIVE: To assess the willingness of patients with infertility to continue with their in vitro fertilization (IVF) treatment during the COVID-19 pandemic. METHODS: This cross-sectional survey was conducted in the reproductive, endocrine, and infertility medicine department (REIMD) at King Fahad Medical City (KFMC), Riyadh, Saudi Arabia. Patients that were planned to undergo IVF treatment at REIMD were contacted and asked about whether they would like to start IVF treatment during the COVID-19 pandemic from August 2020 to August 2021. Data was analyzed using the SPSS version 24. Statistics obtained as means and standard deviations from continuous variables correlated with the Chi-square test and results were considered significant at p≤0.05. RESULTS: Of the 400 participants, 245 (61.25%) were between the ages of 30-39 years. About 42.75% (n=171) of the patients had 6-10 years of infertility, and 18% (n=72) had at least one pregnancy but no living children. While 64.7% (n=259) of the participants responded on the first call, 83% (n=332) agreed to continue their treatment. Of those, 13% (n=43) preferred to book appointments as soon as possible; 29.8% (n=99) preferred booking within three months; while 57.2% (n=190) chose to book after three months. From our sample, 86.8% (n=59) were afraid to contract the virus and the choice to delay the IVF treatment correlated with the patient's age (p<0.001) and duration of infertility (p=0.007). CONCLUSIONS: The COVID-19 pandemic affected IVF treatment courses, and many patients were afraid to be infected during this pandemic.

Patients Response to Interventional Care for Chronic Pain Study (PRICS): A Cross-Sectional Survey of Community-Based Pain Clinics in Ontario, Canada.

BACKGROUND: Non-image guided injection treatments ("nerve blocks") are commonly provided in community pain clinics in Ontario for chronic non-cancer pain (CNCP) but remain controversial. AIM: We explored patients' perspectives of nerve blocks for CNCP. METHODS: We administered a 33-item cross-sectional survey to patients living with CNCP pain attending four community-based pain clinics in Ontario, Canada. The survey captured demographic information and asked about patient experiences with nerve blocks. RESULTS: Among 616 patients that were approached, 562 (91%) provided a completed survey. The mean age of respondents was 53 (SD 12), 71% were female, and the majority (57%) reported living with CNCP for more than a decade. Fifty-eight percent had been receiving nerve blocks for their pain for >3 years, 51% on a weekly frequency. Since receiving nerve blocks, patients self-reported a median improvement in pain intensity of 2.5 points (95% CI -2.5 to -3.0) on an 11-point numeric rating scale and 66% reported stopping or reducing prescription medications, including opioids. The majority who were not retired (62%) were receiving disability benefits and were unable to work in any capacity. When asked what impact cessation of nerve blocks would have, most employed patients (52%) reported they would be unable to work, and the majority indicated their ability to function across multiple domains would decrease. CONCLUSION: Our respondents who received nerve blocks for CNCP attribute important pain relief and functional improvement to this intervention. Randomized trials and clinical practice guidelines are urgently needed to optimize the evidence-based use of nerve blocks for CNCP.

Tumor mutation burden in the prognosis and response of lung cancer patients to immune-checkpoint inhibition therapies.

Immune checkpoint inhibition (ICI) therapies have reshaped the therapeutic landscape in lung cancer management, providing first-time improvements in patient response, prognosis, and overall survival. Despite their clinical effectiveness, variability in treatment responsiveness, as well as drug resistance, have led to a compelling need for predictive biomarkers facilitating the individualized selection of the most efficient therapeutic approach. Significant progress has been made in the identification of such biomarkers, with tumor mutation burden (ΤΜΒ) appearing as the leading and most promising predictive biomarker for the efficacy of ICIs in non-small cell lung cancer (NSCLC) among other tumors. Anti-PD-1/PD-L1 and anti-CTLA-4 antibodies have been extensively studied and clinically utilized. However, the overall efficiency of these drugs remains unsatisfactory, urging for the investigation of novel inhibitors, such as those targeting LAG-3, TIM-3, TIGIT and VISTA, which could be used either as a monotherapy or synergistically with the PD-1/PD-L1 or CTLA-4 blockers. Here, we investigate the role of TMB and cancer neoantigens as predictive biomarkers in the response of lung cancer patients to different ICI therapies, specifically focusing on the most recent immune checkpoint inhibitors, against LAG-3, TIM-3, TIGIT and VISTA. We further discuss the new trends in immunotherapies, including CAR T-cell therapy and personalized tumor vaccines. We also review further potential biomarkers that could be used in lung cancer response to immunotherapy, such as PD-L1+ IHC, MSI/dMMR, tumor infiltrating lymphocytes (TILs), as well as the role of the microbiome and circulating tumor DNA (ctDNA). Finally, we discuss the limitations and challenges of each.

Plasma Markers for Therapy Response Monitoring in Patients with Neuroendocrine Tumors Undergoing Peptide Receptor Radionuclide Therapy.

BACKGROUND: Pretherapeutic chromogranin A, alkaline phosphatase (ALP), or De Ritis ratio (aspartate aminotransferase/alanine aminotransferase) are prognostic factors in patients with metastatic neuroendocrine tumors (NET) undergoing peptide receptor radionuclide therapy (PRRT). However, their value for intratherapeutic monitoring remains unclear. We evaluated if changes in plasma markers during PRRT can help identify patients with unfavorable outcomes. METHODS: A monocentric retrospective analysis of 141 patients with NET undergoing PRRT with [177Lu]Lu-DOTATOC was conducted. Changes in laboratory parameters were calculated by dividing the values determined immediately before each cycle of PRRT by the pretherapeutic value. Patients with low vs. high PFS were compared with the Wilcoxon rank-sum test. RESULTS: Progression, relapse, or death after PRRT was observed in 103/141 patients. Patients with low PFS showed a significant relative ALP increase before the third (p = 0.014) and fourth (p = 0.039) cycles of PRRT. Kaplan-Meier analysis revealed a median PFS of 24.3 months (95% CI, 20.7-27.8 months) in patients with decreasing ALP values (Δ > 10%) during treatment, 12.5 months (95% CI, 9.2-15.8 months) in patients with increasing ALP values (Δ > 10%), and 17.7 months (95% CI, 13.6-21.8 months) with stable ALP values (Δ ± 10%). CONCLUSIONS: Based on these exploratory data, a rise in plasma ALP might indicate disease progression and should be interpreted cautiously during therapy.

Understanding patient and physician responses to various cost-sharing programs for prescription drugs in South Korea: A multilevel analysis.

Introduction: Patient and/or physician responses are a pivotal issue in designing rational cost-sharing programs under health insurance systems. Objectives: This study aims to understand patient and/or physician responses to cost-sharing programs designed for prescription drugs in South Korea. Methods: As a framework, we took advantage of a tiered cost-sharing program, including from copayment to coinsurance (threshold 1) and reduced coinsurance (threshold 2). Given the hierarchical structure of prescriptions nested within patients, we utilized a multilevel analysis to assess effects of various cost-sharing programs on patient and/or physician responses using National Health Insurance claims data from 2018. Results: We found that a tiered cost-sharing program was effective in changing the behaviors of patients and/or physicians. Threshold 1 was found to be more effective than threshold 2 in changing their behaviors. At the prescription level, sensitivity to cost-sharing programs was associated with prescribed days of treatment and locations of prescription. In a similar vein, sensitivity to cost-sharing programs was associated with gender and age group of patients. Conclusion: A simplified cost-sharing program with extended intervals should be considered to rationalize cost-sharing programs. Specifically, a cost-sharing program designed for long-term prescriptions for chronic diseases together with an emphasis on cost transparency is required to better guide price-conscious decisions by patients and/or physicians.

Drug susceptibility testing of circulating lung cancer cells for personalized treatment.

The presence of Circulating tumor cells (CTCs) has been proven to be correlated with disease progression and the patient's response to treatment. However, the culture of CTCs for clinical utility is still a big challenge. We have developed a short-term method that enables CTCs culture and provides an opportunity to monitor drug susceptibility testing in individual patients. In a proof-of-concept study, we established a unique method using Matrigel® coated in 96 well plate to enable cancer cell clusters to attach and proliferate. The culture method using Matrigel® provides in vitro conditions and improves the attachment and differentiation of anchorage-dependent epithelial cells proliferation and mimics the tumor microenvironment. We further treated the cells attached to Matrigel® with the same drug regimen as the patient has undergone. Around 30.7% of the CTCs were viable after the drug treatment. We also correlated the decrease in cell viability after drug treatment with the reduction in the pleural effusion of the patient as seen by the images obtained from CT scans pre-and post-treatment. Moreover, as per the RECIST criterion, the patient had exhibited a positive response to the treatment. The short-term culturing of CTC along with the drug susceptibility testing offers a novel method to predict patient response to the treatment and could be utilized for screening suitable drug combinations for personalized treatment.

Model Calibration of Pharmacokinetic-Pharmacodynamic Lung Tumour Dynamics for Anticancer Therapies.

Individual curves for tumor growth can be expressed as mathematical models. Herein we exploited a pharmacokinetic-pharmacodynamic (PKPD) model to accurately predict the lung growth curves when using data from a clinical study. Our analysis included 19 patients with non-small cell lung cancer treated with specific hypofractionated regimens, defined as stereotactic body radiation therapy (SBRT). The results exhibited the utility of the PKPD model for testing growth hypotheses of the lung tumor against clinical data. The model fitted the observed progression behavior of the lung tumors expressed by measuring the tumor volume of the patients before and after treatment from CT screening. The changes in dynamics were best captured by the parameter identified as the patients' response to treatment. Median follow-up times for the tumor volume after SBRT were 126 days. These results have proven the use of mathematical modeling in preclinical anticancer investigations as a potential prognostic tool.

Genomic landscape of the immunogenicity regulation in skin melanomas with diverse tumor mutation burden.

Skin melanoma cells are tightly interconnected with their tumor microenvironment (TME), which influences their initiation, progression, and sensitivity/resistance to therapeutic interventions. An immune-active TME favors patient response to immune checkpoint inhibition (ICI), but not all patients respond to therapy. Here, we assessed differential gene expression in primary and metastatic tumors from the TCGA-SKCM dataset, compared to normal skin samples from the GTEx project and validated key findings across 4 independent GEO datasets, as well as using immunohistochemistry in independent patient cohorts. We focused our attention on examining the expression of various immune receptors, immune-cell fractions, immune-related signatures and mutational signatures across cutaneous melanomas with diverse tumor mutation burdens (TMB). Globally, the expression of most immunoreceptors correlated with patient survival, but did not differ between TMBhigh and TMBlow tumors. Melanomas were enriched in "naive T-cell", "effector memory T-cell", "exhausted T-cell", "resting Treg T-cell" and "Th1-like" signatures, irrespective of their BRAF, NF1 or RAS mutational status. Somatic mutations in IDO1 and HLA-DRA were frequent and could be involved in hindering patient response to ICI therapies. We finally analyzed transcriptome profiles of ICI-treated patients and associated their response with high levels of IFNγ, Merck18, CD274, CD8, and low levels of myeloid-derived suppressor cells (MDSCs), cancer-associated fibroblasts (CAFs) and M2 macrophages, irrespective of their TMB status. Overall, our findings highlight the importance of pre-existing T-cell immunity in ICI therapeutic outcomes in skin melanoma and suggest that TMBlow patients could also benefit from such therapies.

Advanced Vision Analyzer-Virtual Reality Perimeter: Device Validation, Functional Correlation and Comparison with Humphrey Field Analyzer.

Purpose: To evaluate the Advanced Vision Analyzer (AVA; Elisar Vision Technology) and to compare pointwise threshold sensitivity and functional correlation of Elisar Standard Algorithm (ESA) with the Swedish Interactive Threshold Algorithm (SITA) of the Humphrey Field Analyzer (HFA; Carl Zeiss Meditec, Inc). Design: Prospective, cross-sectional, observational case series. Participants: One hundred sixty eyes (85 control participants, 75 glaucoma patients) for functional assessment, 15 eyes for test-retest variability (TRV), 107 eyes for blind spot trial (45 normal eyes, 62 glaucoma eyes) were recruited consecutively. A separate group of participants was chosen for each assessment. Methods: All participants underwent ESA and SITA Standard 24-2 testing, and 1 eye of each participant was selected randomly. Intraclass correlation coefficient (ICC), Bland-Altman, linear regression, mean bias (MB), and proportional bias analyses were quantified and assessed. Threshold measurements, TRV, and blind spot location accuracy were compared with those of the HFA. Main Outcome Measures: Pointwise threshold sensitivity, sectoral mean sensitivity (MS), mean deviation (MD), pattern standard deviation (PSD), TRV, blind spot location, average test time were computed, and data were correlated. Results: The mean time required to perform a field test with the AVA was 7.08 ± 1.55 minutes and with HFA was 6.26 ± 0.54 minutes (P = 0.228). The MS difference between AVA and HFA was -2.2 ± 2.3 dB in healthy participants (P < 0.001) and -2.6 ± 3.5 dB in participants with glaucoma (P < 0.001). The correlation coefficients for pointwise threshold values were moderately to strongly correlated for both the devices (r = 0.68-0.89). For MS, the overall ICC value was 0.893 (P < 0.001) with MB of 2.48 dB and a limits of agreement (LOA) of 10.90 (range, 7.93 to -2.97). For TRV, response variability decreased with an increase in sensitivity and increased with eccentricity. Blind spot location was accurate, and global indices of testing methods correlated well. Conclusions: The AVA effectively captures threshold values for each point in the visual field. Adequate functional correlation suggests substantial equivalence between the AVA (ESA) and HFA (SITA Standard), implying that AVA may allow accurate assessment of visual field.

Progress and Challenges in Precise Treatment of Tumors With PD-1/PD-L1 Blockade.

Immune checkpoint inhibitors target the inhibitory receptors on T cells to reinstate their antitumor ability and have shown significant efficacy in treating various cancers. However, because of tumor heterogeneity and many other uncover reasons, the objective response rate for programmed death 1 and programmed death-ligand 1 (PD-1/PD-L1) blockade is only 20 to 30%; its response rate in solid tumors is relatively low, and different degrees of side effects have occurred. There are still many unknown factors affecting the therapeutic effectiveness of PD-1/PD-L1 blockade. Additionally, screening the responding tumor patients accurately and improving the response rate and efficacy are huge challenges for tumor precise treatment. Here, we attempt to summarize the recent progress in response prediction and combined application of PD-1/PD-L1 blockade and briefly discuss the methods and evaluations combined with PD-1/PD-L1 blockade to improve the implementation of precision immunotherapy.

Breast Cancer: Evaluating Tumor Estrogen Receptor Status with Molecular Imaging to Increase Response to Therapy and Improve Patient Outcomes.

Current statistics show there are 3.5 million women in the United States living with breast cancer today, and approximately 330,000 new cases are diagnosed each year. Of these new cases, 81% are invasive cancers. About 41,000 women die from breast cancer each year. Thankfully, survival rates have increased over the years; however, an accurate diagnosis and treatment plan remain essential for patient survival and longevity. Sometimes breast cancer patients present their medical oncologist with a clinical dilemma on how their particular breast cancer should be treated, especially when standard options fail. Some breast cancer tumors respond to treatment, whereas others do not. Knowing the type of breast tumor a patient has, its estrogen receptor site status, and how it might respond to therapy are vital to effectively and successfully treating the patient, ultimately improving outcomes and overall survival rates. A potential new PET tracer, 18F-fluoroestradiol (currently under Food and Drug Administration review for approval), may be a valuable tool for noninvasive evaluation of the estrogen receptor site status of a patients' primary tumor and secondary metastatic lesions. Imaging estrogen receptor sites is like obtaining a whole-body biopsy that can localize all estrogen-positive lesions in the body, enabling an effective treatment plan to be established for each patient. Estrogen-receptor-site imaging may be beneficial when a tumor is in an inaccessible location or is otherwise difficult to biopsy. Over the years, nuclear medicine has played a crucial role in providing medical oncologists with information helpful for accurately diagnosing and treating patients. With advances in both camera technology and radiopharmaceutical development, the information that nuclear medicine can provide has improved, allowing more accurate treatment and management of patients.

The diagnostic moment: A study in US primary care.

This paper conceptualizes the act of diagnosis in primary care as a 'diagnostic moment,' comprising a diagnostic utterance in a 'diagnostic slot,' together with a patient response. Using a dataset of 201 treated conditions drawn from 255 video recorded medical visits with 71 physicians across 33 clinical practices in the Western United States, we investigate the incidence of diagnostic moments, aspects of their verbal design, and patient responsiveness. We find that only 53% of treated conditions in the dataset are associated with a diagnostic moment. Physicians present 66% of these diagnoses as hedged or otherwise doubtful, and deliver 30% of them without gazing at the patient. In the context of these diagnostic moments, patients are non- or minimally responsive 59% of the time. These findings underscore the different significance that may be accorded diagnosis in primary care in contrast to care in other medical contexts. The paper concludes that the analysis of sequences of action which empirically realize diagnosis are underrepresented in the sociology of diagnosis, and that better understanding of the diagnostic moment would enhance our understanding of diagnostic processes in primary care.

Optimized Prediction of Extreme Treatment Outcomes in Ovarian Cancer.

Ovarian cancer is the fifth leading cause of death among female cancers. Front-line therapy for ovarian cancer is platinum-based chemotherapy. However, the response of patients is highly nonuniform. The TCGA database of serous ovarian carcinomas shows that ~10% of patients respond poorly to platinum-based chemotherapy, with tumors relapsing in seven months or less. Another 10% or so enjoy disease-free survival of three years or more. The objective of the present research is to identify a small number of highly predictive biomarkers that can distinguish between the two extreme responders and then extrapolate to all patients. This is achieved using the lone star algorithm that is specifically developed for biological applications. Using this algorithm, we are able to identify biomarker panels of 25 genes (of 12,000 genes) that can be used to classify patients into one of the three groups: super responders, medium responders, and nonresponders. We are also able to determine a discriminant function that can divide the entire patient population into two classes, such that one group has a clear survival advantage over the other. These biomarkers are developed using the TCGA Agilent platform data and cross-validated on the TCGA Affymetrix platform data, as well as entirely independent data from Tothill et al. The P-values on the training data are extremely small, sometimes below machine zero, while the P-values on cross-validation are well below the widely accepted threshold of 0.05.