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Background: Uncertainty about the benefit-risk ratio of regional lymph node irradiation led to varying clinical protocols. We investigated long-term late side effects after internal mammary and medial supraclavicular (IM-MS) lymph node irradiation to improve shared decision making., Methods: The multicenter European Organization for Research and Treatment of Cancer trial (ClinicalTrials.gov, NCT00002851) randomly assigned stage I-III breast cancer patients with involved axillary nodes and/or a medially located primary tumor. We analyzed late side effects both longitudinally at every follow-up and cross-sectionally at 5-year intervals. All statistical tests were 2-sided., Results: Between 1996 and 2004, 46 departments from 13 countries accrued 4004 patients. Median follow-up was 15.7 years. Longitudinal follow-up data showed cumulative incidence rates at 15 years of 2.9% (95% confidence interval [CI] = 2.2% to 3.8%) vs 5.7% (95% CI = 4.7% to 6.9%) (P < .001) for lung fibrosis, 1.1% (95% CI = 0.7% to 1.7%) vs 1.9% (95% CI = 1.3% to 2.6%) (P = .07) for cardiac fibrosis, and 9.4% (95% CI = 8.0% to 10.8%) vs 11.1% (95% CI = 9.6% to 12.7%) (P = .04) for any cardiac disease when treated without or with IM-MS lymph node irradiation. There was no evidence for differences between left- and right-sided breast cancer (Wald χ2 test of treatment by breast side interaction, P = .33 and P = .35, for cardiac fibrosis and for any cardiac disease, respectively). The cumulative incidence probabilities of cross-sectionally reported side effects with a score of 2 or greater at 15 years were 0.1% (95% CI = 0.0% to 0.5%) vs 0.8% (95% CI = 0.4% to 1.4%) for pulmonary (P = .02), 1.8% (95% CI = 1.1% to 2.8%) vs 2.6% (95% CI = 1.8% to 3.7%) for cardiac (P = .15), and 0.0% (95% CI not evaluated) vs 0.1% (95% CI = 0.0% to 0.4%) for esophageal (P = .16), respectively. No difference was observed in the incidence of second malignancies, contralateral breast cancer, or cardiovascular deaths., Conclusions: The incidence of late pulmonary side effects was statistically significantly higher after IM-MS lymph node irradiation, as were some of the cardiac events, without a difference between left- and right-sided treatments. Absolute rates and differences were very low, without increased non-breast cancer-related mortality, even before introducing heart-sparing techniques., (© The Author(s) 2021. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

At our institution, 17% of cervical conization specimens are reported as negative for dysplasia or malignancy. To identify sources of error, we reviewed 53 negative conization specimens and their prior and follow-up cytology, biopsy, and endocervical curettage specimens. Examination of deeper-level sections and p16 immunostaining were performed on all conization specimens and selected biopsy specimens. Dysplasia was detected in 26% (14/53) of conization specimens. Twenty-eight percent (15/53) of cones were truly negative, and the presurgical material had been overcalled as high-grade squamous intraepithelial lesions (HSIL). Forty-five percent (24/53) of cones were truly negative and HSIL was confirmed in the presurgical material. Of these, 11% (6/53) showed subsequent evidence of residual dysplasia and 26% (14/53) were negative on further follow-up. Deeper-level sections, p16 immunostains, and consensus review may help identify squamous dysplasia in conization specimens and may prevent the overdiagnosis of HSIL on cervical biopsies.

A young white man with new-onset central diabetes insipidus was discovered to have a posterior pituitary mass on magnetic resonance imaging. No other radiological abnormalities were noted in the anterior pituitary, infundibulum or hypothalamus. No other endocrinopathies were present: laboratory investigations showed normal basal concentrations of anterior pituitary hormones, including prolactin. The patient was suspected to have sarcoidosis affecting the posterior pituitary, because of the discovery of pulmonary sarcoidosis during his diagnostic evaluation. His symptoms of polydipsia and polyuria responded promptly to intranasal administration of 1-desamino-8-D-arginine vasopressin (DDAVP). The patient demonstrated complete regression of the posterior pituitary mass after a course of corticosteroid therapy. However, his diabetes insipidus persisted and he continues to need DDAVP treatment, currently at 12 months of follow-up. The resolution of the neurohypophysial mass was compatible with the diagnosis of pituitary sarcoidosis and this precluded the need for a transsphenoidal biopsy or surgery.

A 61-year-old man with acquired immunodeficiency syndrome (AIDS) sought care because of the onset of progressive dysphagia. He was found to have a perforated, fungating esophageal mass. The combined histologic and immunologic findings were diagnostic of Hodgkin's disease, nodular sclerosis type, lymphocyte-depleted variant, arising in the esophagus. The Reed-Sternberg cells and mononuclear variants were positive for Epstein-Barr virus (EBV) latent membrane protein (LMP1) and EBV RNA. Occasional small lymphoid cells were also positive for EBV RNA. Polymerase chain reaction studies demonstrated the presence of EBV type A without deletion of the EBV LMP1 gene. Other authors have reported an increased frequency of type B EBV and deletion of the EBV LMP1 gene in cases of human immunodeficiency virus-associated Hodgkin's disease. Hodgkin's disease arising in the esophagus is rare in immunocompetent patients. However, in the presence of AIDS, Hodgkin's disease should be considered in the differential diagnosis of patients with signs or symptoms of esophageal disease.

Background: Tumor stage, histologic grade, and regional lymph node status are currently used to obtain prognostic information about bladder cancers. However, additional prognostic indicators are needed to aid clinicians in selecting patients who would benefit most from specific therapies. A majority of studies assessing the prognostic value of measuring tumor angiogenesis (i.e., measurement of tumor microvessel densities) have found a positive association between increasing microvessel densities and worsening prognosis., Purpose: We explored the relationship between established prognostic indicators and the extent of tumor-associated angiogenesis in patients with invasive transitional cell carcinoma (TCC) of the bladder, and we determined whether tumor microvessel density measurement could be used independently to predict bladder tumor behavior., Methods: Tumor tissue was obtained from 164 patients with invasive primary TCC of the bladder. The extent of tumor-associated angiogenesis in this tissue was evaluated by immunohistochemical methods using HPCA-1, a mouse monoclonal antibody directed against the endothelial cell antigen, CD34. The number of microvessels in a 200x microscopic high-power field (hpf) containing the area of greatest neovascularization within or immediately adjacent to each tumor was determined. The patient population was then divided into three equivalently sized groups, with tumors containing low (< or = 64), intermediate (65-99), or high (> or = 100) numbers of microvessels per hpf. Kaplan-Meier product limit estimates of overall survival and the complement of cumulative incidence curves for recurrence-free survival were plotted. When analyzing survival or recurrence, the logrank test was used to compare groups of patients with and without stratification according to tumor stage. Analysis of variance was used to test for an association between microvessel density and established prognostic variables. Reported P values are from two-sided tests., Results: Microvessel density was significantly associated with disease-free (P < .0001) and overall (P = .0007) survival. The estimated probabilities of recurrence at 5 years were 19% (95% confidence interval [CI] = 8-29), 56% (95% CI = 43-69), and 68% (95% CI = 55-81) for patients with lowest, intermediate, and highest microvessel counts, respectively. Overall survival at 5 years was estimated to be 68% (95% CI = 56-81), 44% (95% CI = 30-57), and 34% (95% CI = 21-47) for the same three patient groups. Microvessel density was associated with disease progression in patients with organ-confined tumors, tumors extending through the bladder wall, and tumors that had spread to regional lymph nodes. Tumor angiogenesis was found to be an independent prognostic indicator when evaluated in the presence of histologic grade, pathologic stage, and regional lymph node status., Conclusion: Tumor angiogenesis, as determined by microvessel density measurement, is an independent prognostic indicator for patients with invasive TCC of the bladder.

Background: Axillary lymph node status has been the most important prognostic factor in operable breast carcinoma, but it does not fully account for the varied disease outcome. More accurate prognostic indicators would help in selection of patients at high risk for disease recurrence and death who are candidates for systemic adjuvant therapy. Our recent findings indicated that microvessel density (count or grade) in invasive breast carcinoma (a measure of tumor angiogenesis) is associated with metastasis and thus may be a prognostic indicator., Purpose: This study was designed to further define the relationship of microvessel density with overall and relapse-free survival and with other reported prognostic indicators in breast carcinoma., Methods: In a prospective, blinded study of 165 consecutive patients, the microvessels within primary invasive breast carcinoma were highlighted by immunocytochemical staining to detect factor VIII-related antigen. Using light microscopy, we counted microvessels per 200x field in the most active areas of neovascularization and graded microvessel density. These findings were correlated, by univariate and multivariate analyses, with overall and relapse-free survival, axillary node status, and other prognostic indicators (median follow-up, 51 months)., Results: There was a highly significant (P < or = .001) association of microvessel density with overall survival and relapse-free survival in all patients, including node-negative and node-positive subsets. All patients with breast carcinomas having more than 100 microvessels per 200x field experienced tumor recurrence within 33 months of diagnosis, compared with less than 5% of the patients with breast carcinoma having 33 or fewer microvessels per 200x field. Moreover, microvessel density was the only statistically significant predictor of overall survival among node-negative women (P < .001). Only microvessel density (P < .001) and histologic grade (P = .04) showed statistically significant correlations with relapse-free survival in the node-negative subset., Conclusions: Microvessel density in the area of the most intense neovascularization in invasive breast carcinoma is an independent and highly significant prognostic indicator for overall and relapse-free survival in patients with early-stage breast carcinoma (I or II by International Union Against Cancer criteria)., Implications: Such an indicator would be useful in selection of those node-negative patients with breast carcinoma who are at high risk for having occult metastasis at presentation. These patients could then be given systemic adjuvant therapy.

Granulomatous prostatitis and poorly differentiated prostate carcinoma can mimic each other both clinically and histologically. To develop criteria useful in resolving problem cases, the authors compared the reactivities of these conditions (nine cases of granulomatous prostatitis and six cases of poorly differentiated carcinoma) with a panel of antibodies to cytokeratin (AE1/3), prostate-specific antigen (PSA), prostatic acid phosphatase (PAP), lysozyme, antimacrophage M, and leukocyte common antigen (LCA). In granulomatous prostatitis, histiocytes were not immunoreactive for PAP, PSA, or cytokeratin; however, histiocytes reacted to lysozyme in nine of nine cases, antimacrophage M in seven of nine cases, and LCA in one of nine cases. Tumor cells from all six carcinoma cases reacted with PAP, PSA, and cytokeratin; all failed to react with lysozyme, LCA, and antimacrophage M. The authors conclude that granulomatous prostatitis and poorly differentiated carcinoma can be reliably distinguished with immunohistochemical methods.

We report two cases of unexplained, isolated, persistently increased aspartate aminotransferase activity in serum. In the first patient, this lasted for 10 years and prompted multiple hospitalizations and medical/surgical consultations. For patient two, the abnormal enzyme activity resulted in hospitalization for further evaluation of possible heart disease. In spite of extensive investigation to determine the possible reason for the abnormality, no clear clinical cause was ever discovered in either patient. Electrophoretic and immunologic evidence indicates that the enzyme was complexed to IgG in the serum of both individuals. Recognition that this complex is probably benign may obviate other patients having to undergo unnecessary hospitalization, anxiety, and expense.

A high-pressure liquid chromatographic method for the routine measurement of serum theophylline that is accurate, specific, and sensitive is presented. It is technically simple, requires only 50 microliter serum, and takes relatively little technician time. Values for theophylline in sera obtained by this method correlate well with those obtained by use of a gas-liquid chromatographic method (r = 0.980) and with values obtained by the commonly used spectrophotometric method (r = 0.939) when the latter is free of interference. The assay has been employed for two years in a routine clinical chemistry laboratory, with interassay coefficients of variation of 2.4-3.2%. Interferences have been identified at an incidence rate of 3.8% of all specimens, and interfering substances include cephazolin, chloramphenicol, sulfamethoxazole, and sulfisoxazole. A calculation technic that allows a reliable and clinically useful estimation of a range of concentrations of theophylline in the serum when these interferences are present is described. In contrast, the incidence of interferences with the spectrophotometric method is 4.9%, and in this method the interferences prevent the analysis of theophylline. Of 33 samples having interferences by use of the spectrophotometric method, the high-pressure liquid chromatographic technic yielded precise values for theophylline in 21 and reliable estimates of ranges of concentrations of theophylline in the remaining 12.

Two patients presented with hypophosphataemic osteomalacia and were subsequently found to have small tumours unusual histopathology and location causing the osteomalacia. Each tumour was found after an intensive search for occult masses. Studies of vitamin D metabolism and renal tubular function before and after surgery yielded further insight into the pathophysiology of oncogenic osteomalacia. These cases demonstrate that microscopic quantities of tumour are capable of causing the syndrome and further illustrate the high index of suspicion often necessary to locate causative tumours in patients with hypophosphataemic osteomalacia.

Five cases of benign lymphoepithelial cysts (BLCs) of the parotid gland are reported, and the histologic, aspiration cytologic, and ultrastructural findings are described in detail. These uncommon parotid lesions contain epithelium-lined cystic spaces encased by abundant lymphoid tissue with germinal centers. The epithelium was "mucoepidermoid" in three of our cases and squamous in two. Familiarity with the morphologic features of BLCs should make it possible to distinguish them from similar-appearing cystic lesions, especially low-grade cystic mucoepidermoid carcinoma and cystic types of benign lymphoepithelial lesion (so-called Mikulicz's disease). These distinctions, however, are difficult on aspiration cytology specimens.

The accuracy of Masson's trichrome stain to predict the presence of immune complexes was determined in 63 renal biopsies. When immunofluorescence was defined as the reference method, the histologic method correctly predicted the presence or absence of deposits in 70% of biopsy specimens, while electron microscopy was accurate in 79% of specimens. This difference was not statistically significant. The commonest error in our assessment of the Masson's trichrome-stained specimens was the erroneous interpretation of specimens showing minimal change nephropathy or ischemic glomerulopathy by immunofluorescence and electron microscopy. This resulted in a falsely positive diagnosis of one or another of the glomerulonephritides in 13% of cases. Thus, the routine study of renal biopsies with Masson's trichrome stain is clearly useful and should be applied with caution, but it does not replace electron-microscopic and immunofluorescence studies.

After using a cellular digestion technic to extract cells from the basement membranes of frozen kidney tissue, we used scanning electron microscopy to examine the acellular glomerular basement membranes (AGBM) and acellular tubular basement membranes (ATBM) from normal kidneys and from the kidneys of patients with lupus nephritis. This method revealed, in the AGBM, previously unrecognized three-dimensional patterns of pathologic changes. These patterns correlated with the World Health Organization (WHO) subclass of lupus nephritis and with the quantity of immune-complex deposition seen with two-dimensional microscopy. These pathologic changes included epimembranous, crater-like deformities with and without material resembling immune complexes; severely distorted, "moth-eaten" glomerular basement membrane; and the formation of secondary basement membrane within glomerular capillaries. We did not see similar abnormalities in the ATBM.