Characterizing diversity in the tumor-immune microenvironment of distinct subclasses of gastroesophageal adenocarcinomas.

BACKGROUND: Gastroesophageal adenocarcinomas (GEAs) are heterogeneous cancers where immune checkpoint inhibitors have robust efficacy in heavily inflamed microsatellite instability (MSI) or Epstein-Barr virus (EBV)-positive subtypes. Immune checkpoint inhibitor responses are markedly lower in diffuse/genome stable (GS) and chromosomal instable (CIN) GEAs. In contrast to EBV and MSI subtypes, the tumor microenvironment of CIN and GS GEAs have not been fully characterized to date, which limits our ability to improve immunotherapeutic strategies. PATIENTS AND METHODS: Here we aimed to identify tumor-immune cell association across GEA subclasses using data from The Cancer Genome Atlas (N = 453 GEAs) and archival GEA resection specimen (N = 71). The Cancer Genome Atlas RNAseq data were used for computational inferences of immune cell subsets, which were correlated to tumor characteristics within and between subtypes. Archival tissues were used for more spatial immune characterization spanning immunohistochemistry and mRNA expression analyses. RESULTS: Our results confirmed substantial heterogeneity in the tumor microenvironment between distinct subtypes. While MSI-high and EBV+ GEAs harbored most intense T cell infiltrates, the GS group showed enrichment of CD4+ T cells, macrophages and B cells and, in ∼50% of cases, evidence for tertiary lymphoid structures. In contrast, CIN cancers possessed CD8+ T cells predominantly at the invasive margin while tumor-associated macrophages showed tumor infiltrating capacity. Relatively T cell-rich 'hot' CIN GEAs were often from Western patients, while immunological 'cold' CIN GEAs showed enrichment of MYC and cell cycle pathways, including amplification of CCNE1. CONCLUSIONS: These results reveal the diversity of immune phenotypes of GEA. Half of GS gastric cancers have tertiary lymphoid structures and are therefore promising candidates for immunotherapy. The majority of CIN GEAs, however, exhibit T cell exclusion and infiltrating macrophages. Associations of immune-poor CIN GEAs with MYC activity and CCNE1 amplification may enable new studies to determine precise mechanisms of immune evasion, ultimately inspiring new therapeutic modalities.

A problem solving and decision making toolbox for approaching clinical problems and decisions.

In this paper, we begin by presenting three real patients and then review all the practical conceptual tools that have been suggested for systematically analyzing clinical problems. Each of these conceptual tools (e.g. Evidence-Based Medicine, Clinical Practice Guidelines, Decision Analysis) deals mainly with a different type or aspect of clinical problems. We suggest that all of these conceptual tools can be thought of as belonging in the clinician's toolbox for solving clinical problems and making clinical decisions. A heuristic for guiding the clinician in using the tools is proposed. The heuristic is then used to analyze management of the three patients presented at the outset.

Granulocyte-colony stimulating factor in the prevention of postoperative infectious complications and sub-optimal recovery from operation in patients with colorectal cancer and increased preoperative risk (ASA 3 and 4). Protocol of a controlled clinical trial developed by consensus of an international study group. Part three: individual patient, complication algorithm and quality manage.

GENERAL DESIGN: Presentation of a new type of a study protocol for evaluation of the effectiveness of an immune modifier (rhG-CSF, filgrastim): prevention of postoperative infectious complications and of sub-optimal recovery from operation in patients with colorectal cancer and increased preoperative risk (ASA 3 and 4). A randomised, placebo controlled, double-blinded, single-centre study is performed at an University Hospital (n = 40 patients for each group). This part presents the course of the individual patient and a complication algorithm for the management of anastomotic leakage and quality management. OBJECTIVE: In part three of the protocol, the three major sections include: The course of the individual patient using a comprehensive graphic display, including the perioperative period, hospital stay and post discharge outcome. A center based clinical practice guideline for the management of the most important postoperative complication--anastomotic leakage--including evidence based support for each step of the algorithm. Data management, ethics and organisational structure. CONCLUSIONS: Future studies with immune modifiers will also fail if not better structured (reduction of variance) to achieve uniform patient management in a complex clinical scenario. This new type of a single-centre trial aims to reduce the gap between animal experiments and clinical trials or--if it fails--at least demonstrates new ways for explaining the failures.

Evaluating the process of tailoring the global HIV/AIDS practice guidelines for use in developing countries.

OBJECTIVE: To describe a systematic procedure for adapting, or 'tailoring' the World Health Organisation's 'global guidelines for the management of HIV/AIDS in adults and children' for use in two developing countries: Malawi and Barbados. DESIGN: In order for these guidelines to achieve reproducibility, clinical flexibility, and clinical applicability, a systematic procedure is needed to tailor the guidelines to the local practice conditions of specific settings. METHODS: A group of local experts in each country used a nominal group process to modify the global program on AIDS (GPA) guidelines for local use. Semantic analysis techniques, known as clinical algorithm nosology (CAN), were used to compare the two modified guidelines with the global ones to determine the extent and type of differences between sets of guidelines. RESULTS: Standard, locally-tailored algorithm map guidelines (AMG) were developed within 4 months. CAN semantic analysis showed that guideline structure was maintained; 572/858 (66.6%) decision nodes were found to be the same in the GPA/Malawi, GPA/Barbados and Malawi/Barbados comparisons. However, different guideline versions managed patients quite differently, as evidenced by clinical algorithm patient abstraction (CAPA) scores of between 0 and 8.46 (0 = different; 8 = similar; 10 = identical). Analysis of the 197 specific differences found in these abstractions showed that 83% were in approaches to diagnosis and therapy, while the remaining 17% related to disease prevalence. CONCLUSIONS: Standard techniques involving consensus used to develop clinical guidelines can also be employed to tailor these guidelines to local settings. Semantic analysis shows that the tailoring preserves structure but may involve significant modification to the processes of clinical care that could in turn affect care outcomes.

Text-to-algorithm conversion to facilitate comparison of competing clinical guidelines.

This study aimed to test the usefulness and reliability of text-to-algorithm conversion in comparing competing clinical guidelines and defining their differences. Two pairs of competing guidelines for measles immunization, published in 1989 and 1994, were analyzed and compared. Five categories of differences were detected: differences in recommendations, excluded elements, logical inconsistencies, nonspecific phrases, and approaches to contraindications. On a scale of 0-10 (where identical=10), the overall comparison scores were 6.01 for the guidelines published in 1989 and 5.54 for the guidelines published in 1994. Text-to-algorithm conversions performed by three different persons on the 1989 guidelines were compared and found similar. Text-to-algorithm conversion is an important step in facilitating comparison of competing guidelines. It has the potential to assist in making rational and systematic choices between competing guidelines before actual field testing takes place. Physicians can use it to analyze and to learn a prose clinical guideline, to critique existing guidelines, and to simulate hypothetical patients for teaching and evaluating clinical management.

[Evaluation models for therapy planning/standardization exemplified by infection]. / Evaluationsmodelle zur Therapieplanung/Standardisierung am Beispiel der Sepsis.

Models of evaluation in therapeutic management pathways (practice guidelines, clinical algorithms) are demanded today, both by public health research and health policy. However, practical achievements are lacking. To overcome this controversy, the Lucerne Study Group on Sepsis Research was founded to develop guidelines in accordance with a series of official groups. It was shown that there was no agreement between the providers and the daily users. However, every surgeon has a firm, personal view about sepsis.

Hypnotic trance. The old and the new.

It has been a long and tumultuous journey for the practice of hypnosis. From the temples of ancient Greece to the hospitals of the 20th century, hypnosis has proven itself time and again to be an effective medical and psychological intervention. The responsibility now lies with clinicians and researchers to continue this practice into the 21st century and beyond.

Male-female differences in the relationship between obesity and lipids/lipoproteins.

OBJECTIVE: To examine the effect of gender on the relationship between obesity measures and lipids/lipoproteins. DESIGN: Cross-sectional, matched observational study of adult men and women. SUBJECTS: 225 spousal pairs from Cincinnati, Ohio (age range, 28-66 years; mean +/- SD (yr), 44.0 +/- 6.7 (men), 42.1 +/- 5.9 (women). MEASUREMENTS: Body mass measures, lipids, lipoproteins, apolipoproteins, physical activity levels, cigarette use and dietary variables. RESULTS: Correlations between the lipids/lipoproteins and body mass index (BMI) were stronger in women than in men for cholesterol (r = 0.24 vs 0.10), LDL-c (r = 0.27 vs 0.12), triglycerides (TG) (r = 0.48 vs 0.23) and the ratio cholesterol/HDL-c (r = 0.47 vs 0.28). Utilizing statistical regression models which included potentially confounding environmental factors, BMI and WHR both contributed significant information to describe cholesterol, HDL-c, TG and cholesterol/HDL-c values in women, whereas WHR alone provided information for these lipids/lipoproteins in men. CONCLUSION: The association between BMI and lipids/lipoproteins appears to be stronger in women than in men. In women, in contrast to men, BMI and WHR, measures which are easily attainable in the clinical setting, provide separate, independent information in the explanation of these lipid/lipoprotein levels.

Is consensus reproducible? A study of an algorithmic guidelines development process.

The authors evaluated the reproducibility of a clinical algorithm consensus development process across three different physician panels at a health maintenance organization. Physician groups were composed of primary care internists, who were provided with identical selections from the medical literature and first-draft "seed" algorithms on the management of two common clinical problems: acute sinusitis and dyspepsia. Each panel used nominal group process and a modified Delphi method to create final algorithm drafts. To compare the clinical logic in the final algorithms, the authors applied a new qualitative and quantitative comparison method, the Clinical Algorithm Patient Abstraction (CAPA). Dyspepsia algorithms from all physician groups recommended empiric anti-acid therapy for most patients, favored endoscopy over barium swallow, and had very similar indications for endoscopy. The average CAPA comparison score among final physician algorithms was 6.1 on a scale of 0 (different) to 10 (identical). Sinusitis algorithms from all groups proposed empiric antibiotic therapy for most patients. Indications for sinus radiographs were similar between two algorithms (CAPA = 4.9), but differed significantly in the third, resulting in lower CAPA scores (average CAPA = 1.9, P < 0.03). The clinical similarity of the algorithms produced by these physician panels suggests a high level of reproducibility in this consensus-driven algorithm development process. However, the difference among the sinusitis algorithms suggests that physician consensus groups using a consensus process that a health maintenance organization can do with limited resources will produce some guidelines that vary due to differences in interpretation of evidence and physician experience.

Physician use of a computerized medical record system during the patient encounter: a descriptive study.

The computerized medical record program, CLINIC, specifically designed at Ben-Gurion University of the Negev to be used on-line in a primary care clinic during a patient encounter by healthcare professionals, has been in use for over 6 years in two community clinics. In order to analyse the effectiveness and use of CLINIC, four physicians were video recorded during working sessions before and after the introduction of CLINIC. While using CLINIC did not change the total mean encounter time, the lengths of the encounter components and record use did change. The physicians' work style changed from a 'conversational pattern' (continuous data recording) to a 'blocked pattern' (data entry at intervals).

The clinical algorithm nosology: a method for comparing algorithmic guidelines.

Concern regarding the cost and quality of medical care has led to a proliferation of competing clinical practice guidelines. No technique has been described for determining objectively the degree of similarity between alternative guidelines for the same clinical problem. The authors describe the development of the Clinical Algorithm Nosology (CAN), a new method to compare one form of guideline: the clinical algorithm. The CAN measures overall design complexity independent of algorithm content, qualitatively describes the clinical differences between two alternative algorithms, and then scores the degree of similarity between them. CAN algorithm design-complexity scores correlated highly with clinicians' estimates of complexity on an ordinal scale (r = 0.86). Five pairs of clinical algorithms addressing three topics (gallstone lithotripsy, thyroid nodule, and sinusitis) were selected for interrater reliability testing of the CAN clinical-similarity scoring system. Raters categorized the similarity of algorithm pathways in alternative algorithms as "identical," "similar," or "different." Interrater agreement was achieved on 85/109 scores (80%), weighted kappa statistic, k = 0.73. It is concluded that the CAN is a valid method for determining the structural complexity of clinical algorithms, and a reliable method for describing differences and scoring the similarity between algorithms for the same clinical problem. In the future, the CAN may serve to evaluate the reliability of algorithm development programs, and to support providers and purchasers in choosing among alternative clinical guidelines.

Computerized algorithms and pediatricians' management of common problems in a community clinic.

In 1987, a microcomputer clinical algorithm (CA) system for constructing and using CAs for patient care was designed and implemented for six common primary care pediatrics problems. Six community clinic pediatricians agreed to use the system for several months. Length of patient's visit, completeness of data collection, antibiotic use, and appropriateness of clinical plan were measured before the computers were introduced (without CAs) and after the computers were introduced (both with and without CAs). All performance measures improved after the introduction of CAs. However, CA implementation had to be discontinued after five weeks because the CAs were too tedious for the physicians to follow during routine care. The authors conclude that CAs cannot be successfully sustained with physicians for common problems, even though their design and use can significantly improve the process of care.

Cryptosporidium in Bedouin and Jewish infants and children in southern Israel.

We conducted a 1-year prospective study in two clinics and a hospital in the Negev region of southern Israel to determine the epidemiological and clinical patterns of Cryptosporidium diarrhea among Jewish and Bedouin infants and children living in the same geographical area. A total of 612 episodes were studied: 398 in Bedouins and 214 in Jews, of which 449 occurred in patients with diarrhea and 164 in controls. Cryptosporidium was detected in 13 of 382 patients (3.4%) with diarrhea and in 1 of 138 controls (0.7%) (P = 0.078). In 5 of 13 Cryptosporidium-positive patients (38%) another pathogen was detected. No significant difference in Cryptosporidium detection rates was observed between Jews and Bedouins or between hospitalized or nonhospitalized patients. The frequency of Cryptosporidium detection did not differ significantly when three age-groups were compared (less than 6 months old, 7-12 and 13-36 months old). The rate of Cryptosporidium detection was similar among malnourished and well-nourished patients, as determined by weight-for-height percentiles. Cryptosporidium was detected more frequently during the summer months (8.3%) than during the rest of the year (1.2%) (P less than 0.001). Patients with Cryptosporidium diarrhea did not differ clinically from patients with other causes of diarrhea. However, they were characterized by the absence of fecal leukocytes. Cryptosporidium is not a rare cause of diarrhea in southern Israel. It is more prevalent during the hot and dry season and can be detected in a relatively high prevalence among very young infants. Its clinical features are indistinguishable from those of patients with non-cryptosporidial diarrhea.

A computerized medical record with direct data entry for community clinics in Israel.

CLINIC is a computerized medical record system currently being used in two primary care clinics in Israel. Clinic features direct coded data-entry by the medical personnel via a system based on categories of problems and complaints with common signs and symptoms.