Stage I Breast Cancer in the Modern Era: A Retrospective Cohort Study of 328 Patients Diagnosed from 2002 to 2006 with a 14-Year Median Follow-Up.

INTRODUCTION: This study aimed to evaluate the long-term outcomes of stage I breast cancer (BC) patients diagnosed during the current era of screening mammography, immunohistochemistry receptor testing, and systemic adjuvant therapy. METHODS: A retrospective cohort study was conducted on 328 stage I BC patients treated consecutively in a single referral center with a follow-up period of at least 12 years. The primary endpoints were invasive disease-free survival (IDFS) and overall survival (OS). The influence of tumor size, grade, and subtype on the outcomes was analyzed. RESULTS: Most patients were treated by lumpectomy, sentinel node biopsy, and adjuvant endocrine therapy, and most (82%) were of subtype luminal A. Adjuvant chemotherapy was administered to 25.6% of our cohort. Only 24 patients underwent gene expression testing, which was introduced toward the end of the study period. Mean IDFS was 14.64 years, with a 15-year IDFS of 75.6%. Mean OS was 15.28 years with a 15-year OS of 74.9%. In a Cox multivariate analysis, no clinical or pathologic variable impacted on OS and only tumor size (<1 cm vs. 1-2 cm) impacted significantly on IDFS. During follow-up, 20.1% of the cohort developed second primary cancers, including BC. The median time to diagnosis of a second BC was 6.49 years. CONCLUSION: The study results emphasize the importance of long-term follow-up and screening for subsequent malignancies of patients with stage I BC and support the need for using prognostic and predictive indicators beyond the routine clinicopathological characteristics in luminal A patients.

Longitudinal change in symptoms of depression, anxiety and post-traumatic stress disorder during the COVID-19 pandemic among Mexican college students.

Longitudinal studies suggest the psychological difficulties precipitated by the COVID-19 pandemic have gradually declined, but our understanding of the factors that predict change in mental health is limited. We evaluated the mental health of Mexican college students during the early stage of the pandemic and 4 months later, as well as predictors of change in students' mental health. Participants were 648 students (71% women, Mage = 21.46) from a private University in Northern Mexico who completed online surveys from May 2020 to September 2020. Students' self-reported levels of mental health symptoms (depression, anxiety and post-traumatic stress disorder) significantly decreased from May to September. Poor physical health, more COVID-related worry and higher initial levels of peer social support predicted less change in psychological symptoms. On the other hand, more hours of sleep per night and a pre-existing mental health diagnosis predicted steeper decreases in symptoms. Findings suggest reductions in mental health difficulties that are consistent with theoretical frameworks of resilience among Mexican college students. In addition, results underscore the interplay between physical, psychological and social functioning, and the need for continued monitoring of mental health and intervention efforts that address physical health, sleep and pandemic-related worry in University settings.

Neoadjuvant therapy with doxorubicin-cyclophosphamide followed by weekly paclitaxel in early breast cancer: a retrospective analysis of 200 consecutive patients treated in a single center with a median follow-up of 9.5 years.

PURPOSE: We analyzed outcomes of doxorubicin-cyclophosphamide (AC) followed by weekly paclitaxel as neoadjuvant chemotherapy (NAC) for breast cancer (BC), in an everyday practice with long-term follow-up of patients. METHODS: All patients (n = 200) who received the AC-paclitaxel combination as NAC for BC at the Soroka University Medical Center from 2003 to 2012 were included in this retrospective cohort study. AC was administered on an every 3-week schedule (standard dose) until May, 2007 (n = 99); and subsequently every 2-week dose dense (dd) (n = 101). Clinical pathologic features, treatment course, and outcome information were recorded. Complete pathologic response (pCR) was analyzed according to BC subtype, dose regimen, and stage. RESULTS: Median age was 49 years; 55.5% and 44.5% of patients were clinically stage 2 and 3, respectively. Standard dose patients had more T3 tumors. Subtypes were human epidermal growth factor receptor-2 (HER2)-positive 32.5% (of whom 82% received trastuzumab), hormone receptor-positive/HER2-negative 53%, and triple negative 14.5%. Breast-conserving surgery (BCS) was performed in 48.5% of patients; only 9.5% were deemed suitable for BCS prior to NAC. Toxicity was acceptable. The overall pCR rate was 26.0% and was significantly higher in the dd group and HER2-positive patients. With a median follow-up of 9.51 years median event-free survival (EFS) and overall survival (OS) are 10.85 years and 12.61 years, respectively. Patients achieving pCR had significantly longer EFS and OS. CONCLUSION: NAC for BC with AC-paclitaxel can be safely administered in the "real-world' setting with high efficacy. Current efforts are aimed at increasing rates of pCR and identifying patients who may benefit from additional therapy or conversely, de-escalated treatment.

Assessment of parathyroid gland cellularity by digital slide analysis.

BACKGROUND: Computer-aided examination of digital tissue images has attracted attention in recent years. Application in the field of parathyroid pathology has not been studied previously. It holds a potential to assist in the examination of parathyroid gland adenoma or hyperplasia. OBJECTIVES: To explore parathyroid cell detection of slide images by digital tissue analysis and compare the results to standard human processing. METHODS: 47 incisional biopsies of healthy appearing parathyroid glands were evaluated for their cellularity level. First, by the standard examination using microscopy by three independent pathologists. We compared the mean cellularity grading of the pathologists to the output of a computerized cell detection software. RESULTS: A disagreement was found between the standard human cellularity grading and the digital analysis output. However, the digital analysis reaches a 94% specificity and 48% sensitivity to predict high cellularity (>60% parenchymal cells). CONCLUSIONS: Digital analysis of parathyroid tissue can be used as a tool for hypercellularity elimination, therefore assisting in the diagnosis of parathyroid cell hyperplasia. Additional studies using more advanced algorithms are necessary for further precision enhancement.

P16, Ki67, P53, and WT1 Expression in Uterine Smooth Muscle Tumors: An Adjunct in Confirming the Diagnosis of Malignancy in Ambiguous Cases.

The diagnosis of uterine smooth muscle tumors is sometimes difficult, as these tumors may show worrisome features, suspicious for but not diagnostic of malignancy. The recommended immunohistochemical panel in this setting is currently under debate. In this study, we aimed to find a panel of immunohistochemical stains that would be helpful in determining the correct diagnosis in ambiguous uterine smooth muscle tumors, with an emphasis on investigating the possible usefulness of the WT1 antibody. Uterine leiomyomas were found to be immunoreactive with WT1. Since a previous study reported on the lack of immunoreactivity of uterine leiomyosarcomas with WT1, we speculated that WT1 might be useful in this setting. We retrospectively reviewed the medical charts and slides of 91 patients: 22 with leiomyosarcoma, 15 with smooth muscle tumor of uncertain malignant potential, and 54 with leiomyoma. Immunohistochemical stains for WT1, p16, p53, and Ki67 were performed on each case. We found that immunoreactivity with p16 and Ki67 (>40% and >10% of the tumor cells, respectively) and loss of nuclear expression of WT1 (<10% of the tumor cells) were significantly more common in leiomyosarcomas (all P<0.001). Mutated p53 immunohistochemical staining pattern was significantly more prevalent in leiomyosarcomas than in leiomyomas (P<0.001). Thus, in diagnostically challenging uterine smooth muscle tumors, we recommend using an immunohistochemical panel composed of Ki67, p16, p53, and WT1. A positive result in either of the former 2 (p16 >40% and/or Ki67 >10%) has the strongest association with leiomyosarcoma (sensitivity: 95.5%, specificity=88.9%, positive predictive value=77.8%, negative predictive value=98.0%).

Trisomy 7 as sole aberration in peripheral ameloblastoma of the mandible.

Peripheral ameloblastoma (PA) is a rare, extraosseous odontogenic tumor with histologic features similar to those of the more common intraosseous ameloblastoma. The exact nature and tumorigenesis of PA are unclear. Although there are some reports on the cytogenetics of intraosseous ameloblastoma, to the authors' knowledge, there are no studies on the cytogenetic analysis of PA. The cytogenetic analysis of a PA occurring in the gingiva of a 56-year-old man is presented. Trisomy 7 was the only cytogenetic aberration.

Social isolation dysregulates endocrine and behavioral stress while increasing malignant burden of spontaneous mammary tumors.

In a life span study, we examined how the social environment regulates naturally occurring tumor development and malignancy in genetically prone Sprague-Dawley rats. We randomly assigned this gregarious species to live either alone or in groups of five female rats. Mammary tumor burden among social isolates increased to 84 times that of age-matched controls, as did malignancy, specifically a 3.3 relative risk for ductal carcinoma in situ and invasive ductal carcinoma, the most common early breast cancers in women. Importantly, isolation did not extend ovarian function in late middle age; in fact, isolated animals were exposed to lower levels of estrogen and progesterone in the middle-age period of mammary tumor growth, with unchanged tumor estrogen and progesterone receptor status. Isolates, however, did develop significant dysregulation of corticosterone responses to everyday stressors manifest in young adulthood, months before tumor development, and persisting into old age. Among isolates, corticosterone response to an acute stressor was enhanced and recovery was markedly delayed, each associated with increased mammary tumor progression. In addition to being stressed and tumor prone, an array of behavioral measures demonstrated that socially isolated females possessed an anxious, fearful, and vigilant phenotype. Our model provides a framework for studying the interaction of social neglect with genetic risk to identify mechanisms whereby psychosocial stressors increase growth and malignancy of breast cancer.

Personal well-being and financial threats in Peruvian adults: The mediating role of financial well-being.

Crises negatively affect the economy of a country, increasing financial risk, as they affect work activities and the well-being of the population. This study aimed to examine the mediating role of financial well-being in the relationship between personal well-being and financial threats. A predictive cross-sectional study was conducted. The variables analyzed were personal well-being, financial threats, and financial well-being. A total of 416 Peruvian adults from the three regions of Peru participated. The mean age was M = 35.36, SD = 8.84, with a range of 19-62 years. To represent the statistical mediation model, a structural equation model (SEM) was used. The analysis showed that the variables were significantly related (p < 0.001). The theoretical model indicated a perfect mediation, also obtaining a good fit, χ 2(168) = 394.3, CFI = 0.931, RMSEA = 0.057, SRMR = 0.062. The study showed that personal well-being serves as a basis for promoting financial well-being and this contributes to the reduction of financial threats.

High parathyroid hormone levels after parathyroidectomy for parathyroid adenoma are not related to the cellularity of the remaining glands.

BACKGROUND: Patients with primary hyperparathyroidism (PHPT) treated surgically occasionally have normalized calcium, but persistently high parathyroid hormone (PTH). We hypothesized that a possible explanation for this phenomenon is an underlying hyperplasia rather than adenoma. METHODS: Retrospective cohort of patients who underwent parathyroidectomy for PHPT with biopsy of a normal-appearing parathyroid gland were included. Cellularity level of each biopsy and of the adenoma's rim was determined. RESULTS: Forty-seven patients were included. Of them, 19 (40%) had postoperative normocalcemia but elevated PTH. There was no correlation between cellularity either in the rim or of the normal-appearing parathyroid gland and postoperative PTH. The postoperative high PTH group had higher preoperative PTH (P = 0.001) and larger adenomas (P = 0.025). CONCLUSIONS: High PTH levels after successful parathyroidectomy in patients with primary hyperparathyroidism do not appear to result from underlying hyperplasia. A possible alternative explanation is that these patients have a higher preoperative burden of disease.

Administration of glucocorticoids to ovarian cancer patients is associated with expression of the anti-apoptotic genes SGK1 and MKP1/DUSP1 in ovarian tissues.

PURPOSE: To prevent chemotherapy-related side effects, synthetic glucocorticoids, for example, dexamethasone, are routinely administered to patients with ovarian cancer. However, preclinical data implicate glucocorticoids in suppressing chemotherapy-mediated apoptosis in epithelial tumors. The anti-apoptotic mechanisms underlying this increased survival have been shown to require up-regulation of prosurvival genes, including serum and glucocorticoid-regulated kinase 1 (SGK1) and map kinase phosphatase 1 (MKP1)/dual specificity phosphatase 1 (DUSP1). Despite abundant preclinical data, there are no correlative studies in patients. We therefore evaluated anti-apoptotic gene expression in tumor samples from patients randomized to dexamethasone or normal saline. EXPERIMENTAL DESIGN: Eighteen patients were randomized before exploratory laparotomy for suspected ovarian cancer. Dexamethasone or normal saline was administered i.v. following anesthesia. Ovarian and omental tumor samples were collected intra-operatively before and after infusion. Samples were analyzed for histology and glucocorticoid receptor expression by immunohistochemistry. SGK1 and MKP1/DUSP1 mRNA levels were determined using quantitative real-time PCR. RESULTS: Ten patients were evaluable. At 30 min postinfusion, tumor samples from five patients receiving dexamethasone revealed an average SGK1 mRNA induction of 6.1-fold (SEM, +/-2.6) compared with only 1.5-fold (SEM, +/-0.4) in tumor samples from five patients receiving normal saline (P = 0.028). Average MKP1/DUSP1 mRNA expression was increased by 8.2-fold (SEM, +/-2.9) following dexamethasone versus 1.1-fold (SEM, +/-0.4) following normal saline (P = 0.009). All samples expressed glucocorticoid receptor. CONCLUSION: Glucocorticoid administration to patients is associated with rapid up-regulation of SGK1 and MKP1 expression in ovarian tumors. This finding supports the hypothesis that pharmacologic doses of glucocorticoids may decrease chemotherapy effectiveness in ovarian cancer patients through increased anti-apoptotic gene expression.

Glucocorticoid receptor expression in breast cancer associates with older patient age.

Breast cancer can be classified according to estrogen (ER), progesterone (PR), and HER2 receptor expression. Recent evidence suggests that activation of the glucocorticoid receptor (GR) contributes to breast cell survival, although the incidence of GR expression in primary human breast tumors is not well established. We therefore evaluated ER, PR, HER2, and GR by immunohistochemistry from 231 patients and found that while African American (AA) patient tumors were much more likely to be ER negative compared to tumors from non-AA patients, GR expression was significantly higher in tumors from patients >or=50 regardless of ancestry. Prospective examination of GR expression in tumors should be considered to determine whether GR contributes to long-term clinical outcome.

Measles virus: evidence for association with lung cancer.

In recent years the frequency of nonsmokers among lung cancer patients has increased to 10% to 15%. The measles virus has rarely been evoked as an etiological agent in malignant tumors and its role in carcinogenesis remains doubtful. It has been suggested that measles virus phosphoprotein may inhibit ubiquitination of Pirh2, which has been reported to be overexpressed in lung carcinoma and is responsible for degrading the cell cycle regulator p53. The authors conducted a clinicopathological study of newly diagnosed patients with non-small cell lung carcinoma of all stages seen in a 10-year period. Immunohistochemical studies for measles virus antigens, p53, and Pirh2 were performed using the avidin-biotin peroxidase complex. The authors found expression of measles virus antigens in 54 of 65 cases of non-small cell lung carcinoma. This finding is associated with the older age of the patients and with expression of Pirh2. The presence of Pirh2 itself was associated with improved survival.

FDG PET/CT of Mediastinal Epithelioid Hemangioendothelioma.

Epithelioid hemangioendothelioma is a rare low- to intermediate-grade malignant vascular neoplasm with a variable clinical course and currently no standardized treatment. We present a case of a 65-year-old woman diagnosed as having mediastinal epithelioid hemangioendothelioma, a location which is very exceptional. FDG PET/CT was more sensitive than CT for staging, revealing intense FDG uptake in the primary tumor and in the metastatic disease. Despite high FDG uptake, the disease was stable with no further specific treatment. Only few reports utilizing FDG PET/CT are available; review of the literature on this subject is included.

Reciprocal affiliation among adolescent rats during a mild group stressor predicts mammary tumors and lifespan.

OBJECTIVE: Although the detrimental physical health effects of social isolation have been known for three decades, the answers to how and why social relationships generally improve health remain elusive. Social relationships are not always beneficial, and we examined a structural dimension that may bring about their salubrious effects: affiliative reciprocity during a stressor. METHODS: In a lifespan study, female rats lived with their sisters and were tested for temperament, affiliative reciprocity during an everyday stressor at puberty, corticosterone response to a stressor, mammary tumor development and diagnosis, and death. RESULTS: Rats that affiliated more reciprocally during a mild group stressor survived longer (p = .0005), having exhibited a lower corticosterone peak in response to an acute novel stressor in late adulthood (p = .0015), and longer time to the development of spontaneous mammary tumors (p = .02). These effects could not be explained solely by the number of affiliative interactions or individual temperament. Indeed, affiliative reciprocity and neophobia were independent and predicted mortality additively (p = .0002). CONCLUSIONS: Affiliative reciprocity during a stressor, a structural quality of social interactions, protected females from early mammary tumor development (the primary pathology in Sprague-Dawley rats) and early all-cause mortality. Conversely, lack of reciprocity (whether disproportionately seeking or receiving attempted affiliation) was as potent a risk factor as neophobia. Thus a social role increased risk additively with individual temperament. Our data indicate that affiliative reciprocity functions as a buffer for everyday stressors and are likely mediated by attenuated reactivity of the hypothalamic-pituitary-adrenal axis.

Primary aortoduodenal fistula: Pitfalls and success in the endoscopic diagnosis.

Primary aortoenteric fistula is a rare but catastrophic cause of gastrointestinal bleeding. The diagnosis of primary aortoenteric fistula is difficult to make and is usually accompanied by a very high level of clinical suspicion. It should be considered in any elderly patient presenting with upper gastrointestinal bleeding in the context of a known abdominal aortic aneurysm. Prompt surgical intervention is necessary. We present the case of a 78-year-old man with a history of atherosclerotic abdominal aortic aneurysm which is presented with massive upper gastrointestinal bleeding due to a primary aortoduodenal fistula. Initial misdiagnosis led to a delay in treatment and the patient succumbed to the illness.

The epidemiology of primary biliary cirrhosis in southern Israel.

BACKGROUND: The epidemiology of primary biliary cirrhosis has changed significantly over the last decade, with a trend towards increasing prevalence in many places around the world. OBJECTIVES: To determine the overall prevalence of PBC in southern Israel and the specific rates for different immigrant groups between January 1993 and October 2004. METHODS: Multiple case-finding methods were used to identify all cases of PBC in the study region. Age-adjusted prevalence rates were compared among the different immigrant groups. RESULTS: A total of 47 cases of PBC were identified with an overall prevalence of 55 cases per million. All patients were women, and all except for a Bedouin Arab were Jewish. Foreign-born patients comprised 70% of our PBC cohort even though they represent only 45.4% of the regional population. This predominance of immigrants did not change when the rates were adjusted for age (P < 0.001). The prevalence rates were 40, 177, and 58 cases per million for those born in Israel, North Africa or Asia, and Eastern Europe, respectively. The age-specific prevalence rate for women older than 40 years varied from 135 cases per million among those born in Israel to 450 among immigrants from Eastern Europe and the former USSR to 700 cases per million among immigrants from North Africa and Asia. CONCLUSIONS: The prevalence of PBC in southern Israel is similar to that reported from some European countries. The rate is much higher among Jews than Arabs and among immigrants to Israel compared to native Israelis.

Microscopic colitis.

Microscopic colitis is an idiopathic chronic inflammatory bowel disease presenting with watery diarrhea. While colonoscopy and radiology findings are normal, the colon shows striking pathologic findings, including lymphocytic colitis and collagenous colitis. The clinical course is usually benign with sustained remission. Recent medical evidence shows that bismuth and budesonide are effective treatments.

Cell-free DNA as a potential marker to predict carbon tetrachloride-induced acute liver injury in rats.

PURPOSE: Finding an optimal biomarker for the noninvasive evaluation of acute liver injury (ALI) may be of great value in predicting clinical outcomes and investigating potential treatments. We investigated cell-free DNA (CFD) as a potential biomarker to predict carbon tetrachloride-induced ALI in rats. METHODS: Forty-five Sprague-Dawley rats were randomly assigned to three groups. ALI was induced by carbon tetrachloride via a nasogastric tube at 1, 2.5, or 5 ml/kg of a 50 % solution. Fifteen additional rats underwent a sham procedure. Blood samples were drawn at time t which was 0 (baseline), 3, 6, 12, 24, 48, 72, 96, and 120 h for the measurements of CFD, glutamate-pyruvate transaminase (GPT), glutamate-oxaloacetate transaminase (GOT), and total bilirubin. Prothrombin time and histology were examined at 24 and 120 h following injection of 5 ml/kg carbon tetrachloride in 18 additional rats and in 10 control rats. RESULTS: CFD levels in rats subjected to carbon tetrachloride-induced ALI were significantly increased in all blood samples starting at 12 h after the induction of ALI (p < 0.001), reaching peak levels at 24 h. Blood GOT, GPT, and total bilirubin were elevated in all blood samples starting at 3 h after the induction of ALI (p < 0.0001), reaching peak levels by 48 h. A positive correlation was demonstrated between CFD levels and GOT (R (2) = 0.92), GPT (R (2) = 0.92), and total bilirubin (R (2) = 0.76). CFD levels correlated with liver damage seen on histological examination, as well as predicted liver damage, at 24 h after ALI. CONCLUSIONS: CFD may be a useful biomarker for the prediction and measurement of ALI. There is no evidence to suggest that CFD is superior to other available noninvasive biomarkers.

Autoimmune hepatitis in southern Israel: a 15-year multicenter study.

OBJECTIVE: In this study we aimed to assess the incidence, prevalence and clinical outcomes of patients with autoimmune hepatitis (AIH) in southern Israel. METHODS: Case-finding methods and population-based administrative data were used to evaluate the epidemiology and prognostic factors of AIH from 1995 to 2010. RESULTS: During the study period, the average annual prevalence and incidence of AIH in southern Israel were 11.0/100000 and 0.67/100000, respectively. We identified 100 AIH cases with a mean age of 47.9 years, including 95 women and five men. Type 1 AIH was found in 77 cases, and liver fibrosis and cirrhosis were found in 73.4% and 22.3% of all patients who underwent liver biopsy. In all, 98 patients were treated with a combination of steroids and azathioprine or steroids alone (prednisone and azathioprine in 71, budesonide and azathioprine in 11, prednisone or budesonide alone in six and ten, respectively). Complete remission was recorded in 56 patients, whereas partial response or failure of treatment was noted in 42 patients. In multivariate analysis the independent predictors of remission were the degree of liver fibrosis (mild vs bridging fibrosis (F3) and cirrhosis [F4]) (P=0.003) and level of albumin (P=0.031). The estimated 1-year and 10-year survival for AIH were 96.5% and 89.7%, respectively. CONCLUSIONS: The prevalence of AIH in Israel is quite similar to that of other European Caucasian populations, with a relatively long-term good prognosis, despite a low rate of response to immunosuppressive therapy.

Primary biliary cirrhosis in Southern Israel: a 20 year follow up study.

BACKGROUND: The epidemiology of primary biliary cirrhosis (PBC) in Israel is unknown. We aimed to determine the epidemiology, long-term survival and outcomes of PBC in Southern Israel from 1990 to 2010. METHODS: Case-finding methods and population-based administrative data were used to estimate and evaluate the incidence, prevalence and prognostic factors of outcome in our PBC cohort. RESULTS: 138 cases of PBC were identified. The average annual prevalence of PBC was 255 cases per million. The overall age/sex-adjusted annual incidence of PBC was 10 cases per million from 1990 through 1999 and 20 cases per million from 2000 to 2010. Among 138 incident cases with a total follow-up of 960 persons-years from diagnosis, 30 patients (21.7%) died. Survival in PBC patients was significantly lower than that of the age/sex-matched Israeli population. Mortality was significantly increased in patients with an initial MELD score greater than 8 (P<0.001), with portal hypertension (P<0.001), and in non-responders to ursodeoxycholic acid (UDCA) therapy according to Barcelona criteria (P=0.005). Out of 138 patients, 95 patients (68.0%) responded to UDCA therapy according to Barcelona and Paris criteria. None of the responders died during the follow-up period as opposed to 30 out of 43 (69.8%) of non-responders. In multivariate analysis the factors associated with response to UDCA were: albumin levels above 3.5 g/dL (P<0.001) and lower degree of fibrosis per liver biopsy (P=0.003). CONCLUSIONS: This study addresses the increasing burden of PBC in Israel and confirms the importance of some clinical and therapeutic factors as predictors of long-term prognosis.