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.

Biochemical correlates of hypnoanalgesia in arthritic pain patients.

Self-reported levels of pain, anxiety, and depression, and plasma levels of beta-endorphin, epinephrine, norepinephrine, dopamine, and serotonin were measured in 19 arthritic pain patients before and after hypnosis designed to produce pain reduction. Correlations were found between levels of pain, anxiety, and depression. Anxiety and depression were negatively related to plasma norepinephrine levels. Dopamine levels were positively correlated with both depression and epinephrine levels and negatively correlated with levels of serotonin. Serotonin levels were positively correlated with levels of beta-endorphin and negatively correlated to epinephrine. Following hypnotherapy, there were clinically and statistically significant decreases in pain, anxiety, and depression and increases in beta-endorphin-like immunoreactive material.

Rotavirus diarrhea in Jewish and Bedouin children in the Negev region of Israel: epidemiology, clinical aspects and possible role of malnutrition in severity of illness.

We conducted a 1-year prospective study in the Negev region of southern Israel to determine the epidemiologic and clinical patterns of rotavirus diarrhea. A total of 605 patients were studied, 392 Bedouins and 213 Jews, 441 of whom had diarrhea (449 episodes) and 164 did not. Rotavirus was the most common organism detected in children with diarrhea (63 of 444; 14%) but was rarely found in controls (3 of 163; 2%) (P less than 0.001). In 22% (12 of 54) of the rotavirus-positive patients, at least one other organism was also detected. The rate of rotavirus detection decreased as age increased, from 18% in the first year to 8% in the third year of life. Hospitalization with rotavirus diarrhea occurred more frequently in the summer. However, during winter, when diarrhea was less prevalent in the community, the proportion of cases associated with rotavirus was higher. Compared with controls, malnourished children were more likely to be hospitalized. However, rotavirus was detected in similar proportions among well-nourished and malnourished cases with diarrhea. The most prevalent rotavirus serotype was type 1 (in 69%), followed by types 4 and 2 (18 and 13%, respectively). We estimated that during the study period, approximately 2% of all Bedouin infants vs. only 0.2% of Jewish infants were hospitalized with rotavirus disease in their first year of life. Clinical signs and symptoms and stool appearance were not useful in predicting rotavirus detection. Malnutrition seems to be an important indicator of disease severity, which may explain why the toll of rotavirus-associated morbidity and mortality is particularly high among children in developing countries.

Rheumatology algorithms for primary care physicians.

Primary care physicians were trained on three rheumatology topics to assess the effectiveness of an educational strategy for continuing medical education. Algorithm training was shown to be at least as effective as that based on standard prose monographs. Both training groups improved their knowledge of patient management skills but there were no statistically significant differences between groups in the amount learned. When algorithms were used to design text materials, the designed texts required less study time than did the annotated clinical algorithms alone. That difference was significant for the shoulder pain materials (P less than 0.05) but not for the osteoporosis materials. The ratio of knowledge gained to study time was significantly higher for the algorithm group on the low back pain topic (P less than 0.05) but not for the other topics. Taped interview problems tests were studied as a method for assessing patient management skills related to problem-specific indicator conditions and were found to produce interrater reliability greater than 0.80 on five of the six tests.

Criteria map audit of scorpion envenomation in the Negev, Israel.

A criteria map audit is a medical record audit in which quality of care is evaluated according to algorithmically arranged criteria. Thus, a particular criterion is applied to the patient record only if other criteria have been met. For example, if a stung child's condition is severe but not life threatening and if he has had a positive skin test for antivenom sensitivity then he should receive antivenom only after receiving adrenaline and hydrocortisone. We used a modified criteria map audit to determine both the clinical picture of scorpion envenomation and quality of care process in 94 children. Related outcomes of care measured included mortality, persistent morbidity, allergic reaction to scorpion antivenom and length of stay in hospital. Scorpion stings in the Negev region are usually due to the yellow scorpion, L. quinquestriatus, and usually occur in the summer months on the extremities in exposed male children under 10. The clinical picture is more severe when the scorpion is yellow, when the child is younger and when the sting is on the trunk or head. Symptoms apparently mediated by the central nervous system (2.6 findings/child) were more frequent than parasympathetic symptoms (2.3 findings/child). Treatment with antivenom and specific therapy for complications led to very low persistent morbidity and mortality in symptomatic cases, but was also accompanied by a longer hospital stay (64% equal to or greater than 3 days) than for asymptomatic cases (18% equal to or greater than 3 days). Testing for antivenom sensitivity was omitted in an unacceptably high percentage of cases (69%) and its omission led to an allergic reaction in 4 out of 40 cases (10%). Inadequacy in treatment of 7 secondary clinical problems ranged from 71% for hypertension to 29% for seizures (mean 46%). Persistent morbidity was negligible and mortality was 1.2%. We conclude that criteria map audit can be used to describe the clinical and epidemiological picture of a clinical problem while at the same time providing an audit of the process of care.

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.

It's how you say it: physicians' vocal behavior.

The present study was designed to assess evaluations of physicians interacting with patients via the telephone. Observers used ten adjective scales which resulted in three variables: empathic, dominant, and calm. Thirty doctor-patient interactions were presented in two different communication modes: audio-only and typed transcript-only. As predicted, female listeners rated doctors as more empathic, dominant, and calm, and communication modes were significantly different with audio segments rated as more empathic, dominant and calm. Middle phases of the conversation also were evaluated more positively than greeting phases. Significant interactions between temporal phase and mode indicated that audio segments were interpreted more positively during middle phases. Also, female listeners were more sensitive to audio segments. Physicians' amplitude and speech rate were positively correlated with dominance.

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.

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.

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.

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).

Acne management. Primary care physician or dermatologist?

The question of who should treat acne patients--primary care physicians or dermatologists--is debatable. To determine physicians' attitudes toward, and referral patterns in, acne management, the authors conducted two studies. According to results of the first study, primary care physicians were less likely than dermatologists to feel referral was necessary for acne management. Primary care physicians felt that they should treat most patients with less severe (comedonal and papulopustular) acne and were neutral about referral of patients with nodulocystic acne. Dermatologists were neutral about referral of patients with less severe acne and recommended referral for most patients with nodulocystic acne. Results of the second study showed that almost all patients with less severe acne and most patients with nodulocystic acne were managed by primary care physicians. The authors feel that primary care physicians can and should handle most cases of acne without referral.

Symptomatic dermographism.

Urticaria is caused by physical factors in almost 12 percent of cases. These factors include pressure. Dermographism is the appearance of whealing and erythema within minutes where skin has been exposed to pressure or mechanical irritation. Symptomatic dermographism is present when "normal" pressures, such as those encountered in the activities of daily living, cause urticaria. Individuals with symptomatic dermographism can be shown to have a lower pressure threshold for the production of dermographism than normal individuals. A case of symptomatic dermographism is presented, and the differential diagnosis is discussed.

Urticaria in a family practice.

A review of the charts of 79 patients with urticaria was conducted in a residency-based family practice center. All patients seen with urticaria in 7 years who were identified by the practice-data retrieval system were included in the review. The annual incidence of urticaria was 0.27 percent. Female patients predominated (76 percent), and 70 percent of the cases lasted less than 6 weeks. A personal history of atopy was more common in acute urticaria than in urticaria lasting longer than 6 weeks (P less than .05). No causes were identified in 54 percent of the cases. Association with zomepirac and symptomatic dermographism were each noted in three cases. Diagnostic tests were performed in 17 percent of cases, and consultation or referral occurred in 15 percent. Treatment usually included antihistamines (89 percent). The coded diagnosis was judged by the chart reviewers to be incorrect or inadequately supported in 28 of the 108 charts (26 percent) coded urticaria. In 25 charts coded for other skin disorders, three cases (12 percent) of urticaria were noted by the chart reviewers. Coding errors involving digit transposition were noted in three of 1,044 cases. Diagnostic error, incorrect coding by nonphysicians or by physicians not familiar with the coding system, or even clerical error may be a significant problem in this type of study.