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With availability of voluminous sets of observational data, an empirical paradigm to screen for drug repurposing opportunities (i.e., beneficial effects of drugs on nonindicated outcomes) is feasible. In this article, we use a linked claims and electronic health record database to comprehensively explore repurposing effects of antihypertensive drugs. We follow a target trial emulation framework for causal inference to emulate randomized controlled trials estimating confounding adjusted effects of antihypertensives on each of 262 outcomes of interest. We then fit hierarchical models to the results as a form of postprocessing to account for multiple comparisons and to sift through the results in a principled way. Our motivation is twofold. We seek both to surface genuinely intriguing drug repurposing opportunities and to elucidate through a real application some study design decisions and potential biases that arise in this context., (© 2022 The Authors. Pharmacoepidemiology and Drug Safety published by John Wiley & Sons Ltd.)

We compared healthcare expenditure over a six-month period following initiation of therapy with either venlafaxine (immediate and extended-release) or a selective serotonin reuptake inhibitor (SSRI) in depressed patients with or without anxiety. Patients beginning treatment for a new depressive episode were identified retrospectively using the administrative data of the MEDSTAT MarketScan database for the period 1994-1999. Before beginning therapy, patients prescribed venlafaxine had more non-mental illnesses (0.85 vs 0.76; p<0.01) and hospitalisations for mental illness (0.53 vs 0.29; p<0.05) than patients prescribed SSRIs. In the six months after initiating treatment, venlafaxine was associated with lower hospitalisation expenditure for non-mental illness ($177 vs $526; p<0.01) than SSRIs, although total healthcare expenditure was not significantly different. Venlafaxine was associated with a 50% decrease in the odds of hospitalisation for non-mental illness compared with SSRIs, with significantly lower inpatient expenditure.

Background: The ability to predict biologic behavior and treatment responsiveness would be a valuable asset in the multimodality approach to esophageal carcinoma. The authors examined whether alterations of the p53 gene correlate with clinicopathologic parameters, response to preoperative chemotherapy/radiotherapy, and outcome in patients with esophageal carcinoma. METHODS. Histopathologic/genetic analysis of p53 was performed on formalin fixed, paraffin embedded tissues. Tissue sections were stained immunohistochemically for p53 protein followed by topographic genotyping comprised of polymerase chain reaction amplification and direct sequencing of p53 exons 5-8. All patients received induction chemotherapy (5-fluorouracil, cisplatin, and alpha-interferon) and concurrent external beam radiotherapy (4500 centigrays) followed by resection., Results: p53 analysis performed on 42 tumors from patients with potentially resectable esophageal carcinoma revealed 25 of the 42 tumors (59.5%) to be p53 immunopositive; however, only 17 of the 42 tumors (40.5%) were proven to contain p53 point mutational damage in exons 8 (n=5), 5 (n=5), 7 (n=4), and 6 (n=3). Eight cases were weakly immunopositive and had no genotype mutation suggesting hyperexpression of normal wild-type p53. Genotyping also identified two immunonegative cases with deletion-type mutations (exons 5 and 6). Tissue samples collected before and after chemotherapy/radiotherapy exhibited fidelity in p53 mutational genotype in all cases. The presence of a p53 point mutation positively correlated with pTNM stage (P=0.003) and residual disease in the resected specimen (P=0.01). Moreover, survival of patients with p53 mutations was significantly lower than that of patients without mutations (overall survival of 21.6 months vs. 40 months; P=0.0038; and disease free survival of 14.1 months vs. 38 months; P=0.0004)., Conclusions: Histopathologic/genetic analysis is a better determinant of p53 mutational damage than immunohistochemistry alone and can be used as a prognostic marker for esophageal carcinoma. p53 genotyping may define a subset of patients who respond to chemotherapy/radiotherapy and may predict who potentially benefits from multimodality therapy.

Arterial compliance, defined as a change in dimension in response to a given change in stress, is becoming an increasingly important clinical parameter. Related concepts, such as distensibility, elasticity, and stiffness, and more traditional concepts such as resistance, afterload, and impedance need to be differentiated from compliance, although they are frequently (inappropriately) used interchangably. Many studies cannot differentiate between compliance changes due to a drug's effect on blood pressure and those due to a drug's effect on vessel wall integrity. This differentiation is important because a more physiologic therapy, one that benefits pulsatile and nonpulsatile flow, should be of greater clinical benefit than a therapy that only lowers blood pressure. A number of methods have been used to estimate compliance, but to date there is no generally agreed-on best method. There also are no longitudinal studies that relate abnormal compliance and drug effects to outcome. Nonetheless, patients at risk from a variety of disease states, such as hypertension, diabetes mellitus, and hypercholesterolemia, may benefit from earlier recognition of abnormal compliance. Earlier recognition may lead to interventions that would reduce their risk. This review includes a discussion of compliance and related estimates of blood vessel function and attempts to summarize the data currently available regarding the effects of cardioactive drugs on arterial compliance.

Electronic spirometry units were used to monitor lung transplantation recipients upon their return home. The data from 77 participants were used to develop methods to verify that the pulmonary function measurements, forced vital capacity (FVC) and forced expiratory volume in 1 s (FEV1), were reliable and valid. The standard deviation was calculated for the best daily effort on consecutive days of home spirometry. An acceptable upper limit for the standard deviation, as the measure of day-to-day reliability, was 0.20 for FVC and 0.15 for FEV1. Validity was determined by examining the mean difference (bias) between the spirometry done in the pulmonary function laboratory and the home monitoring results. The clinic values were slightly higher, with an average difference of 0.15 for FVC and 0.12 for FEV1. Therefore, the home spirometry measurements have a high degree of reliability and validity and can now be used for early detection of serious complications.

Background: Extraovarian müllerian adenocarcinoma (EOM) resembles primary ovarian carcinoma (POC) both histologically and clinically, yet little is known regarding the molecular genetic characteristics of this entity. The objective of this study was to compare the expression of three molecular markers of tumor behavior in EOMs and POCs., Methods: Forty-four patients meeting strict criteria for EOM were identified and matched to POC controls for age, stage, tumor histology and grade, cytoreductive surgery, and survival. Immunohistochemistry was used to determine overexpression of p53 and HER-2/neu. DNA content was evaluated by flow cytometry. Direct DNA sequencing of exons 5-8 of the p53 gene was performed in nine EOM tumors. Statistical comparisons were made using chi-square, Kaplan-Meier, and Mantel-Cox log rank methods., Results: Overexpression of HER-2/neu was demonstrated in 59% (26 of 44) of the EOM group versus 36% overexpression (16 of 44) in the POC controls (P = 0.05). Overexpression of p53 was noted in 48% of the EOM cases, similar to the 59% incidence observed in the control group (P = 0.29). Missense mutations were found in 9 of 9 EOM tumors showing strong p53 nuclear immunostaining. No significant difference in the incidence of aneuploidy was observed when EOM cases were compared with POC controls (65% vs. 63%). High tumor grade was strongly associated with HER-2/neu overexpression in the EOM group (P = 0.002). None of the parameters studied were predictive of prognosis within the EOM and POC groups., Conclusions: Although overexpression of p53 protein, p53 gene mutations, and abnormal DNA content were similar between EOMs and POCs, EOMs demonstrated almost twice the rate of HER-2/neu overexpression. This result suggests that distinct genetic events may be responsible for malignant transformation in EOMs versus POCs.

Background: Patients with gastric remnants resulting from partial resections have an increased risk for carcinoma. It is unclear whether adenocarcinoma arising in the gastric stump (GSca) differs from intact stomach carcinoma (Gca). The goal of this study was to examine the pathologic and molecular features of GSca and compare them with Gca., Methods: Adjacent nonmalignant areas and tumors from 14 patients who were 19-55 years postgastrectomy (mean, 32.1 years) were compared with 14 Gca by pathologic and molecular analysis. Formalin fixed, paraffin embedded specimens were immunohistochemically stained for p53 followed by topographic genotyping. Exons 5-8 were amplified by the polymerase chain reaction and directly sequenced., Results: No differences were noted between the two groups regarding gender, types of metaplasia, dysplasia, morphology, or histologic tumor type. However, a higher incidence of cystic dilatation and foveolar hyperplasia were present in GSca. p53 gene point mutations occurred in 5 of 14 (35.7%) GSca patients. GSca p53 mutations included missense point mutations (G:A transitions in four patients and G:C transversion in one patient) with allelic loss. In four of the five patients with p53 mutations, the same mutation was also observed in the adjacent area. p53 point mutations were present in 4 of 14 Gca (28.6%), in exons 5, 6, and 8. In one case, the same mutation was also detected in the adjacent nonmalignant mucosa., Conclusions: Similarities in clinical, pathologic, and molecular features between GSca and Gca suggest the possibility that they share similar mechanisms of carcinogenesis. p53 gene alterations in premalignant areas may denote a possible early role of this gene in gastric carcinoma.

Background: Clinical observations suggest that malignant astrocytomas may arise from well-differentiated, low-grade tumors that have undergone anaplastic progression or may develop de novo. Mutations that alter the function of the p53 gene product are thought to play a critical role in astrocytoma tumorigenesis. The authors studied the pattern of mutant p53 expression in astrocytomas to define its role in the formation of malignant tumors by these different pathways., Methods: Tissues from 44 astrocytomas corresponding to Grades I-IV of the World Health Organization (WHO) classification were analyzed for the presence of mutations in exons 5, 7, and 8 of the p53 gene using single strand conformation polymorphism (SSCP) and sequence analysis of DNA amplified by the polymerase chain reaction. Immunostaining for mutant p53 proteins was performed on tissues fixed in formaldehyde solution and embedded in paraffin; the tissues were from these 44 astrocytomas and another 103 astrocytomas obtained from archival material., Results: Tumors with mutant p53 genes were reliably identified by immunostaining for mutant p53 proteins. A higher percentage of astrocytomas of histologic Grades II-IV stained positively for p53 than were identified by mutational analysis. The average ages of patients with Grade III/IV astrocytomas with prominent (> 10%) p53 staining and those with sparse (< 10%) or no p53 staining were 44.5, 64.3, and 67.9 years, respectively (P < 0.0001)., Conclusions: The pattern of mutant p53 expression is consistent with a role in driving the progression of low-grade astrocytomas to more malignant tumors. These results provide a genetic basis for the clinical observation that malignant astrocytomas resulting from anaplastic progression occur in a younger patient population than do malignant astrocytomas arising de novo.

Background: New measures enabling better prediction of biologic behavior of large bowel cancer are highly desirable. One hundred ninety-four consecutive primary, recurrent, and metastatic colorectal adenocarcinomas, accessioned during 1991 at Rhode Island Hospital, were classified according to the presence and specific type of K-ras-2 point mutation., Methods: An integrated histopathologic-genetic approach was used to detect mutations starting with minute, topographically selected, tissue samples from formaldehyde-fixed, paraffin-embedded specimens., Results: Each colorectal adenocarcinoma exhibited either no or only one of seven specific types of K-ras-2 mutation. The mutation type of each primary tumor was present consistently in its metastatic deposits. Thirty-five percent of primary colorectal adenocarcinomas were found to be mutated (42 of 119). A significantly higher mutation rate (65%) was seen in lymphogenous-hematogenous metastases as a group (35 of 54; P < 0.005). By contrast, 22% of anastomotic recurrences and transcoelomic metastasis were mutated (4 of 18). Twenty-eight percent of adenocarcinomas with invasion limited to muscularis propria (Tis, T1, T2) were mutated (16 of 57), compared to 41% for more deeply invasive tumors (T3, T4; 26 of 63). When colorectal adenocarcinomas were analyzed by specific K-ras-2 mutation type, it was found that codon 13 mutated tumors did not progress to local or distant metastasis (P < 0.01). Tumors having a codon 12 valine substitution did not metastasize beyond pericolonic-perirectal lymph nodes. In contrast, colorectal cancers with codon 12 aspartic acid substitutions accounted for most of the distant hematogenous deposits (P < 0.01). Tumors with normal K-ras-2 accounted for most intraperitoneal deposits., Conclusions: Genotyping of colorectal adenocarcinoma by K-ras-2 status can identify subsets of patients likely to pursue indolent and aggressive forms of disease. The integrated histopathologic-genetic approach outlined is feasible for use in diagnostic pathology, providing information that together with clinicopathologic staging may individualize and optimize treatment.

Fifty-one women (29 to 75 years of age) with 55 cancers (ductal carcinoma in situ [DCIS] or ductal carcinoma in situ with microinvasion [DCISM] were studied by comparing biopsy specimens with mastectomy specimens. Presentation, histologic type, nuclear grade, microscopic duct counts, multicentricity, and microinvasion were correlated. Forty-seven percent of the cancers (26 of 55) were detected by mammography, 18% (ten of 55) were incidental to benign disease, and 35% (19 of 55) were palpable or exhibited nipple abnormality. Incidental tumors were all DCIS, averaged seven ducts, and showed no residual tumor during mastectomy. Mammographic lesions averaged 117 ducts (31% [eight of 26] were DCISM and 42% [11 of 26] were multicentric). Most comedocarcinomas that showed a high incidence of microinvasion were in this group. Clinical lesions averaged 110 ducts (42% [eight of 19] were DCISM and 68% [13 of 19] were multicentric). Three had nodal metastases. Mammographic and clinical tumors in the quantitative range of the incidental group (50 ducts) showed significant differences from it for all variables studied. Histologic and quantitative study of these tumors is necessary to best guide treatment. Incidental tumors, however, may only need observation.