Distribution of tumor-infiltrating-T-lymphocytes and possible tumor-escape mechanisms avoiding immune cell attack in locally advanced adenocarcinomas of the esophagus

Introduction The inflammatory microenvironment has emerged as one of the focuses of cancer research. Little is known about the immune environment in esophageal adenocarcinoma (EAC) and possible tumor-escape mechanisms to avoid immune cell attack. Patients and methods We measured T cell inflammation (CD3, CD8) in the microenvironment using a standardized software-based evaluation algorithm considering different predefined tumor areas as well as expression of MHC class 1 and PD-L1 on 75 analyzable primarily resected and locally advanced (≥ pT2) EACs. We correlated these findings statistically with clinical data. Results Patients with high amounts of T cell infiltration in their tumor center showed a significant survival benefit of 41.4 months compared to 16.3 months in T cell poor tumors (p = 0.025), although CD3 fails to serve as an independent prognostic marker in multivariate analysis. For the invasion zone, a correlation between number of T-cells and overall survival was not detectable. Loss of MHC1 protein expression on tumor cells was seen in 32% and PD-L1 expression using the combined positive score (CPS) in 21.2%. Most likely due to small numbers of cases, both markers are not prognostically relevant, even though PD-L1 expression correlates with advanced tumor stages. Discussion Our analyses reveal an outstanding, though not statistically independent, prognostic relevance of T-cell-rich inflammation in our group of EACs, in particular driven by the tumor center. For the first time, we describe that the inner part of the invasion zone in EACs shows significantly fewer T-cells than other tumor segments and is prognostically irrelevant. We also demonstrate that the loss of antigen presenting ability via MHC1 downregulation by the carcinoma cells is a common escape mechanism in EACs. Future work will need to show whether tumors with MHC class 1 loss respond less well to immunotherapy (AU)

Distribution of tumor-infiltrating-T-lymphocytes and possible tumor-escape mechanisms avoiding immune cell attack in locally advanced adenocarcinomas of the esophagus.

INTRODUCTION: The inflammatory microenvironment has emerged as one of the focuses of cancer research. Little is known about the immune environment in esophageal adenocarcinoma (EAC) and possible tumor-escape mechanisms to avoid immune cell attack. PATIENTS AND METHODS: We measured T cell inflammation (CD3, CD8) in the microenvironment using a standardized software-based evaluation algorithm considering different predefined tumor areas as well as expression of MHC class 1 and PD-L1 on 75 analyzable primarily resected and locally advanced (≥ pT2) EACs. We correlated these findings statistically with clinical data. RESULTS: Patients with high amounts of T cell infiltration in their tumor center showed a significant survival benefit of 41.4 months compared to 16.3 months in T cell poor tumors (p = 0.025), although CD3 fails to serve as an independent prognostic marker in multivariate analysis. For the invasion zone, a correlation between number of T-cells and overall survival was not detectable. Loss of MHC1 protein expression on tumor cells was seen in 32% and PD-L1 expression using the combined positive score (CPS) in 21.2%. Most likely due to small numbers of cases, both markers are not prognostically relevant, even though PD-L1 expression correlates with advanced tumor stages. DISCUSSION: Our analyses reveal an outstanding, though not statistically independent, prognostic relevance of T-cell-rich inflammation in our group of EACs, in particular driven by the tumor center. For the first time, we describe that the inner part of the invasion zone in EACs shows significantly fewer T-cells than other tumor segments and is prognostically irrelevant. We also demonstrate that the loss of antigen presenting ability via MHC1 downregulation by the carcinoma cells is a common escape mechanism in EACs. Future work will need to show whether tumors with MHC class 1 loss respond less well to immunotherapy.

Early detection and evaluation of professionalism deficiencies in medical students: one school's approach.

Since 1995, the University of California, San Francisco, School of Medicine has monitored students' professional behaviors in their third and fourth years. The authors recognized that several students with professionalism deficiencies during their clerkships had manifested problematic behaviors earlier in medical school. They also observed behaviors of concern--such as inappropriate behavior in small groups--in some first- and second-year students who could have been helped by early remediation. The authors describe the modifications to the evaluation system to bring professionalism issues to a student's attention in a new, earlier, and heightened way. In this new system for first- and second-year students, the course director of a student who has professionalism deficiencies submits a Physicianship Evaluation Form to the associate dean for student affairs, who then meets with the student to identify the problematic issues, to counsel, and to remediate. The student's behavior is monitored throughout the academic years. If the student receives two or more forms during the first two years and a subsequent form in the third or fourth year, this indicates a persistent pattern of inappropriate behavior. Then the physicianship problem is described in the dean's letter of recommendation for residency and the student is placed on academic probation. The student may be eligible for academic dismissal from school even if he or she has passing grades in all courses. The authors describe their experience with this system, discuss lessons learned, and review future plans to expand the system to deal with residents' mistreatment of students.

Ventricular aneurysm or diverticulum? Clinical differential diagnosis.

Intrathoracic ventricular aneurysms and diverticula can be differentiated by several criteria. Contractility is the only reliable parameter: aneurysms expand, whereas diverticula contract during ventricular systole.

What did we learn about early clinical experience?

This article explores the lessons learned by ten demonstration schools regarding the early clinical experience (ECE) component of the Interdisciplinary Generalist Curriculum (IGC) PROJECT: Students in ECE at these schools participated in longitudinal, one-to-one or two-on-one preceptorships with primary care physician preceptors in outpatient settings. Development of an ECE was a key component of curricular change at each of the IGC Project schools. Shattering the traditional barrier between preclinical and clinical years of the 2 + 2 medical curriculum model helped create a leading edge for innovation at each of the schools. In this article, the authors incorporated evaluation information from several sources, including the external evaluation reports of the IGC Project, final annual reports from demonstration schools, and curriculum evaluations from the coauthors' schools (the University of Colorado School of Medicine, Nova Southeastern University College of Osteopathic Medicine, and the University of California, San Francisco School of Medicine).

Teaching prevention in pediatrics.

Pediatrics has attempted to inculcate the "culture of prevention" into practice, both through anticipatory guidance in well-child care and through behavioral interventions in sick care. The effectivenesses of many components of well-child care have not been conclusively demonstrated, particularly in health education, counseling, and anticipatory guidance, nor has teaching prevention in pediatrics been thoroughly evaluated. This article reviews methods of teaching prevention in pediatrics and highlights innovative programs. Teaching programs use the wide range of approaches now common in medical education, in a variety of inpatient and outpatient sites. Programs across the country are trying new approaches to teaching traditional topics or are introducing new topics into their curricula. Examples of specific programs are given, organized by the themes of the programs. The field needs to develop in three major directions. First, there is a need to develop competencies and curricula in prevention issues of contemporary importance, including the new morbidities, cross-cultural issues, cost-effectiveness, quality of care, and practice in managed care and other community settings. Second, further work is needed to evaluate programs and measure educational outcomes. This feedback must in turn be used to redefine competencies, curricula, and programs, Third, there needs to be an accessible clearinghouse, and educational tools need to be disseminated. To be effective, a curriculum for prevention in pediatrics cannot stand alone, but must be part of a vertically and horizontally integrated curriculum. Further, creating horizontally and vertically integrated curricula in prevention teaching across disciplines should be the standard.

Influence of polarity reversal on defibrillation success with biphasic shocks and a transvenous/subcutaneous defibrillator system in a porcine animal model.

Clinical studies show that polarity reversal affects defibrillation success in transvenous monophasic defibrillators. Current devices use biphasic shocks for defibrillation. We investigated in a porcine animal model whether polarity reversal influences defibrillation success with biphasic shocks. In nine anesthetized, ventilated pigs, the defibrillation efficacy of biphasic shocks (14.3 ms and 10.8 ms pulse duration) with "initial polarity" (IP, distal electrode = cathode) and "reversed polarity" (RP, distal electrode = anode) delivered via a transvenous/subcutaneous lead system was compared. Voltage and current of each defibrillating pulse were recorded on an oscilloscope and impedance calculated as voltage divided by current. Cumulative defibrillation success was significantly higher for RP than for IP for both pulse durations (55% vs 44%, P = 0.019) for 14.3 ms (57% vs 45%, P < 0.05) and insignificantly higher for 10.8 ms (52% vs 42%, P = ns). Impedance was significantly lower with RP at the trailing edge of pulse 1 (IP: 44 +/- 8.4 vs RP: 37 +/- 9.3 with 14.3 ms, P < 0.001 and IP: 44 +/- 6.2 vs RP: 41 +/- 7.6 omega with 10.8 ms, P < 0.001) and the leading edge of pulse 2 (IP: 37 +/- 5 vs RP: 35 +/- 4.2 omega with 14.3 ms, P = 0.05 and IP: 37.5 +/- 3.7 vs RP: 36 +/- 5 omega with 10.8 ms, P = 0.02). In conclusion, in this animal model, internal defibrillation using the distal coil as anode results in higher defibrillation efficacy than using the distal coil as cathode. Calculated impedances show different courses throughout the shock pulses suggesting differences in current flow during the shock.

Pulmonary embolectomy: review of a 15-year experience and role in the age of thrombolytic therapy.

OBJECTIVE: Surgical intervention for fulminant pulmonary embolism is nowadays most commonly restricted to patients with failure of or contraindication to thrombolytic therapy. Such a second choice indication may alter operative risks or late outcome, and this was investigated in a retrospective study. MATERIAL AND METHODS: Thirty-six patients (17 male, mean age: 50.6 +/- 15.5 years) with fulminant pulmonary embolism of either the pulmonary trunk or one of the pulmonary arteries and at least one contralateral segment underwent pulmonary embolectomy on cardiopulmonary bypass during a 15-year period (1979-89: 31 patients, group I; 1990-94: 5 patients, group II). Group II included only patients who did not meet the criteria for acute thrombolysis. All patients were in strongly compromised circulatory conditions (29/36 high dose catecholamines, 20/36 mechanical ventilation, 14/36 pre-operative cardiopulmonary resuscitation). RESULTS: The perioperative mortality rate was 26% in group I (8/31 patients, 7 with pre-operative cardiac arrest) and 20% in group II (1/5 patients not related to failure of previous thrombolytic therapy). Severe but non-fatal complications occurred in six patients who fully recovered following treatment. Follow-up was completed to 93% (25/27 patients) and comprised a total of 248 patient-years (mean: 119 months). Twenty-three out of 25 patients (92%) were in functional class I or II (NYHA). No recurrent pulmonary embolism or late clinical symptoms related to embolectomy were observed. One patient died 8 years postoperatively (late mortality: 0.4% patient-year). There was no difference between group I and group II regarding perioperative mortality, complications and late results. CONCLUSIONS: Late results after pulmonary embolectomy are excellent in respect to functional class and late mortality. Early mortality is closely associated with preoperative cardiac arrest. Previous thrombolysis does not alter the perioperative risks, occurrence of complications or late outcome after surgical intervention.

Klippel-Feil anomaly combined with fetal alcohol syndrome.

Alcohol is the most frequent and most important teratogenic noxa for the embryo and fetus. It may lead to deformation of all cells and organs. A case of Klippel-Feil anomaly associated with fetal alcohol syndrome is described. The diagnosis of Klippel-Feil anomaly, even a late diagnosis made on the basis of rare deformities, is very important as the affected patients are at a high risk of alcoholism. The combination of Klippel-Feil anomaly with numerous other syndromes and deformities suggests a basic general disorder of skeletal maturation. Diverse cases of Klippel-Feil anomaly possibly originate, in reality, in an unrecognized fetal alcohol syndrome.

A computerized recall system for office practice.

A computerized system that has been in use in a small group practice since 1980 is described. Although many pediatricians have begun to use personal computers in office practice, most accounts of their experience to date relate primarily to the role of computers in facilitating administrative tasks, such as billing. The procedures involved in establishing the system are described, along with details about the nature of the programming concepts and several of the most important applications. A particular focus was to enable the computer to be used to improve the follow-up of patients with problems requiring recall visits, eg, immunizations. The results indicate that the percent of patients judged to be overdue for immunizations fell from 15.4% prior to the introduction of the computer to 1.3% and 4.3%, respectively, in the following 2 years. The proportion of children with other health problems requiring follow-up, 44.5% of the entire active practice population are also described. It is concluded that the computerized system can enhance the quality of patient care and greatly facilitate office-based research.

The organization and evaluation of a computer-assisted, centralized immunization registry.

The rationale for, and establishment of, a computer-assisted, centralized immunization registry are described. This registry was created to improve the quality and quantity of information regarding immunization status for a defined population receiving primary care from a variety of providers, principally public clinics and private practitioners. An evaluation of the feasibility of the registry after one year's function shows that 93 per cent of eligible providers initially agreed to participate and 73 per cent continue to do so. Their reports have resulted in the creation of 17,500 individual patient files. Of a prospective cohort of newborns, 23 per cent were identified as "high-risk" for overdue immunizations. After one year, the immunization rates in audited groups improved significantly. The direct cost of this registry is less than 65 cents per currently registered child per year.