Can we accurately diagnose endometriosis without a diagnostic laparoscopy?

Endometriosis is a progressive, estrogen-dependent, chronic inflammatory disease that affects approximately 6-10% of reproductive age women. Patients usually presents with symptoms, such as non-menstrual pelvic and abdominal pain, ovulatory pain, dyspareunia, dysmenorrhea, dyschezia, and/or changes to bowel or bladder function, which can be exacerbated during ovulation or menses. Endometriosis is a leading cause of unexplained infertility, accounting for up to 50-80% of cases. Currently, altered endometrial receptivity and progesterone resistance are some of the leading theories that could explain endometriosis-related implantation failure. In the endometrium, the B-cell chronic lymphocytic leukemia/lymphoma 6 (BCL-6) protein forms a complex that binds to and inactivates regulators of the progesterone pathway, leading to progesterone resistance, aberrant decidualization, implantation failure, and recurrent miscarriages in women diagnosed with endometriosis. Surgical diagnosis consisting of laparoscopy, with or without histologic confirmation, is still considered the gold standard for diagnosis of endometriosis. Development of noninvasive screening and diagnostic tests to accurately identify patients with endometriosis has become increasing popular. A screening test for endometriosis has been developed to detect endometrial BCL-6 overexpression in asymptomatic women with unexplained infertility or recurrent pregnancy loss. Positive endometrial BCL-6 testing has been associated with recurrent miscarriages and poor in vitro fertilization outcomes. When the underlying cause of endometrial inflammation secondary to endometriosis was treated, an improvement in subsequent live birth rates was seen. Endometrial BCL-6 testing has a high positive predictive value that could help physicians and patients undergoing infertility treatment to seek surgical evaluation for endometriosis, to improve their reproductive outcomes.

Coexistence of BRAF V600E and TERT Promoter Mutations in Low-grade Serous Carcinoma of Ovary Recurring as Carcinosarcoma in a Lymph Node: Report of a Case.

Low-grade serous carcinomas only rarely coexist with or progress to high-grade tumors. We present a case of low-grade serous carcinoma with transformation to carcinosarcoma on recurrence in the lymph node. Identical BRAF V600E and telomerase reverse transcriptase promoter mutations were identified in both the original and recurrent tumor. Given that telomerase reverse transcriptase promotor mutations are thought to play a role in progression of other tumor types, the function of telomerase reverse transcriptase mutations in BRAF mutated low-grade serous carcinoma deserves investigation.

Characterization of the peripheral neuropathy associated with brentuximab vedotin treatment of Mycosis Fungoides and Sézary Syndrome.

Chemotherapy-induced peripheral neuropathy (CIPN) is common, frequently limits chemotherapy dosing, and negatively impacts quality of life. The National Cancer Institute Common Toxicity Criteria for Adverse Events (CTCAE), version 4.0, and the Total Neuropathy Score clinical version (TNSc) are both validated scores to quantify peripheral neuropathy (PN), with the TNSc being more sensitive to clinical changes. Mycosis fungoides and Sézary syndrome (MF/SS) are characterized by a chronic course, where current therapies are generally non-curative and treatment toxicities have the potential for significant lasting effects. Brentuximab vedotin (BV) is an antibody-drug-conjugate composed of an anti-CD30 monoclonal antibody linked to the microtubule-disrupting agent, monomethyl auristatin E, with a known associated CIPN. In our phase II clinical trial of BV in MF/SS, 25 (69%) of 36 patients developed PN, with 18 (50%) developing Clinically Significant PN, CTCAE v4.0 grade 2 or higher. The median time to grade 2 PN was 15 weeks (range 0.4-48) after the initial dose. By Kaplan-Meier calculation, the median time to improvement from Clinically Significant PN was 30 weeks from the last BV dose. Seventy-four percent had improvement by 24 months. We found that TNSc scores significantly correlated with CTCAE grade, with Spearman correlation coefficient 0.68 (p < 0.001). By logistic regression, for each 100 mg increase in BV total dose, the likelihood of developing Clinically Significant PN increased by 23% (95% CI 4-46%). Improved monitoring of CIPN associated with BV is of paramount importance in the MF/SS population.

Useful Parameters for Distinguishing Subcutaneous Panniculitis-like T-Cell Lymphoma From Lupus Erythematosus Panniculitis.

Some cases of subcutaneous panniculitis-like T-cell lymphoma (SPTCL) and lupus erythematosus panniculitis (LEP) demonstrate clinical and histopathologic overlap, raising the possibility that they represent opposite ends of a disease spectrum. SPTCL, however, is typically associated with greater morbidity and risk for hemophagocytic lymphohistiocytosis (HLH); therefore, diagnostic distinction is clinically important. We present the histopathologic, immunophenotypic, and molecular findings with long-term clinical follow-up of 13 patients with SPTCL (median, 64 mo follow-up) and 7 with LEP (median, 50 mo follow-up) in our multidisciplinary cutaneous oncology clinic. Six SPTCL patients developed HLH, including 2 under the age of 21 years. In the SPTCL group, 2 of 13 patients died of disease. In contrast, we had no mortality or development of HLH in our LEP cohort. We demonstrate that a limited panel (Ki-67, CD3, CD4, and CD8 immunostains) reveals foci of "Ki-67 hotspots" enriched in cytotoxic atypical CD8+ T cells in SPTCL. Ki-67 hotspots were not identified in LEP, thus aiding the distinction of SPTCL from LEP. Lymphocyte atypia combined with adipocyte rimming of CD8+ T cells within Ki-67 hotspots was also highly specific for the diagnosis of SPTCL. Hyaline lipomembranous change, B-cell aggregates, plasmacytoid dendritic cell clusters, and plasma cell aggregates favored the diagnosis of LEP but were identified in some cases of SPTCL including patients with HLH. We confirm that SPTCL and LEP can show significant histologic overlap, suggest a role for high-throughput sequencing in confirming neoplastic clones, and introduce the concept of SPTCL "Ki-67 hotspots" in evolving disease.

Genomic analysis of mycosis fungoides and Sézary syndrome identifies recurrent alterations in TNFR2.

Mycosis fungoides and Sézary syndrome comprise the majority of cutaneous T cell lymphomas (CTCLs), disorders notable for their clinical heterogeneity that can present in skin or peripheral blood. Effective treatment options for CTCL are limited, and the genetic basis of these T cell lymphomas remains incompletely characterized. Here we report recurrent point mutations and genomic gains of TNFRSF1B, encoding the tumor necrosis factor receptor TNFR2, in 18% of patients with mycosis fungoides and Sézary syndrome. Expression of the recurrent TNFR2 Thr377Ile mutant in T cells leads to enhanced non-canonical NF-κB signaling that is sensitive to the proteasome inhibitor bortezomib. Using an integrative genomic approach, we additionally discovered a recurrent CTLA4-CD28 fusion, as well as mutations in downstream signaling mediators of these receptors.

Phase II Investigator-Initiated Study of Brentuximab Vedotin in Mycosis Fungoides and Sézary Syndrome With Variable CD30 Expression Level: A Multi-Institution Collaborative Project.

PURPOSE: In contrast to Hodgkin lymphoma and systemic anaplastic large-cell lymphoma, CD30 expression of malignant lymphocytes in mycosis fungoides (MF) and Sézary syndrome (SS) is quite variable. Clinical activity and safety of brentuximab vedotin, a CD30 targeting antibody-drug conjugate, was evaluated in MF and SS. Tissue and blood biomarkers of clinical response were explored. PATIENTS AND METHODS: In this phase II study, patients with MF or SS with negligible to 100% CD30 expression levels were treated with brentuximab vedotin (1.8 mg/kg) every 3 weeks for a maximum of sixteen doses. The primary end point was overall global response rate. Secondary end points included correlation of tissue CD30 expression level with clinical response, time to response, duration of response, progression-free and event-free survivals, and safety. RESULTS: Of the 32 patients enrolled and treated, 30 patients had available efficacy evaluations. Objective global response was observed in 21 (70%) of 30 patients (90% CI, 53% to 83%). CD30 expression assessed by immunohistochemistry was highly variable, with a median CD30max of 13% (range, 0% to 100%). Those with <5% CD30 expression had a lower likelihood of global response than did those with 5% or greater CD30 expression (P < .005). CD163 positive tumor-associated macrophages, many of which coexpress CD30, were abundant in tissue. Peripheral neuropathy was the most common adverse event. CONCLUSION: Brentuximab vedotin demonstrated significant clinical activity in treatment-refractory or advanced MF or SS with a wide range of CD30 expression levels. Additional biomarker studies may help optimize rational design of combination therapies with brentuximab vedotin.

Lymph node involvement by mycosis fungoides and Sézary syndrome mimicking angioimmunoblastic T-cell lymphoma.

Clinical management of cutaneous T-cell lymphoma (CTCL) and angioimmunoblastic T-cell lymphoma (AITL) differs markedly. Diagnostic distinction is critical. Herein, we describe a series of 4 patients with clinically, molecularly, and histopathologically annotated mycosis fungoides or Sézary syndrome whose nodal disease mimicked AITL. The patients otherwise exhibited classic clinical manifestations of mycosis fungoides/Sézary syndrome preceding the onset of lymphadenopathy by 1 to 5 years. Skin biopsies revealed epidermotropic infiltrates characteristic of CTCL. Lymph node biopsies revealed dense CD4+ T-cell infiltrates that coexpressed follicular helper T-cell markers and were accompanied by proliferations of high endothelial venules and arborizing CD21+ follicular dendritic cell networks. Two patients had T-cell receptor gene rearrangement studies performed on their skin, lymph node, and peripheral blood demonstrating identical polymerase chain reaction clones in all 3 tissues. A small secondary clonal B-cell population was present in 1 patient that mimicked the B-cell proliferations known to accompany AITL and persisted on successive nodal biopsies over several years. This latter phenomenon has not previously been described in CTCL. The potential for patients to be misdiagnosed with AITL for lack of consideration of advanced-stage CTCL with nodal involvement underscores the necessity of information sharing among the various pathologists and clinicians involved in the care of each patient.

Low-dose total skin electron beam therapy as an effective modality to reduce disease burden in patients with mycosis fungoides: results of a pooled analysis from 3 phase-II clinical trials.

BACKGROUND: Standard-dose (36-Gy) total skin electron beam therapy (TSEBT) is a highly effective treatment in mycosis fungoides. However, the regimen is time-intensive and may be associated with significant toxicity. OBJECTIVE: We sought to evaluate the efficacy and tolerability associated with low-dose (12-Gy) TSEBT. METHODS: Data from 3 clinical trials using low-dose (12-Gy) TSEBT were pooled. In all trials, TSEBT-naïve patients with stage IB to IIIA mycosis fungoides were treated with TSEBT (12 Gy, 1 Gy per fraction over 3 weeks). The primary end point was clinical response rate. Secondary end points included time to response and duration of clinical benefit. RESULTS: In all, 33 patients enrolled. Eighteen were male; stages were 22 IB, 2 IIA, 7 IIB, and 2 IIIA. Overall response rate was 88% (29/33), including 9 patients with complete response. Median time to response was 7.6 weeks (3-12.4 weeks). Median duration of clinical benefit was 70.7 weeks (95% confidence interval 41.8-133.8 weeks). Toxicities from TSEBT were mild and reversible. LIMITATIONS: Conclusions are limited because of the small number of patients. CONCLUSIONS: Low-dose TSEBT provides reliable and rapid reduction of disease burden in patients with mycosis fungoides, which could be administered safely multiple times during the course of a patient's disease with acceptable toxicity profile.

Identification of Candida species associated with vulvovaginal candidiasis by multiplex PCR.

BACKGROUND: Vulvovaginal candidiasis is a common infection. The aim of this study was to identify the species of vaginal Candida isolates by using multiplex PCR technique. METHODS: 191 isolates from patients admitted to Mahdieh hospital were identified. The vaginal swab specimens were cultured on Sabouraud Dextrose Agar. The ITS1 region between the 18S and 5.8S rRNA genes and a specific DNA fragment within the ITS2 region were amplified. The multiplex PCR products were separated by electrophoresis in 2% agarose gel, visualized by staining with ethidium bromide, and photographed. Descriptive statistics, Chi-square test, and Spearman correlation were used to summarize the findings. RESULTS: C. albicans and C. glabrata were the most common species isolated from the specimens. A mix of C. glabrata and C. albicans was the most common mixed infection isolated from the samples. The analysis revealed a significant positive association between older age and infection with C. glabrata isolates (Spearman's rho = 0.89, P = 0.015). CONCLUSION: Multiplex PCR is a fast, yet reliable method to identify Candida species. C. albicans and then C. glabrata are the two most common causes of vulvovaginal candidiasis. The number of mixed fungal infections is higher among Iranian population compared to international reports.

The prevalence of menstrual pain and associated risk factors among Iranian women.

AIM: To estimate the prevalence of dysmenorrhea in Iranian women and investigate associated risk factors. MATERIAL & METHODS: In a cross-sectional study in Tehran, Iran in 2007, 381 women (81% response rate, age 16-56 years) were selected through a stratified random sample of 22 different districts and completed a questionnaire about dysmenorrhea. Descriptive statistics, spearman rank correlation statistic, and ordinal logistic regression models were used. Confounding and effect-modification were explored for each association. RESULTS: The prevalence of no, mild, moderate, and severe menstrual pain was 10%, 41%, 28%, and 22%, respectively. Older age and high intake of fruits and vegetables were protective factors for menstrual pain while women with family history of dysmenorrhea, higher stress and depression tended to have more severe pain. Body mass index, parity, smoking, and physical activity were not significantly associated with dysmenorrhea after controlling for potential confounding factors and effect modifiers. CONCLUSION: Menstrual pain is a common complaint in Iranian women. The inverse association between fruit and vegetable intake and dysmenorrhea, and reduction of stress and depression need to be further explored and considered in terms of recommendation to reduce dysmenorrhea.

Drug-use patterns in an intensive care unit of a hospital in Iran: an observational prospective study.

OBJECTIVES: the aim of this study was to evaluate drug-use patterns, investigate the factors influencing patient outcome, and determine the cost of drugs utilized in the intensive care unit (ICU). METHODS: in an observational prospective study, drug prescriptions for 113 patients admitted to the ICU of a hospital in Iran were recorded. The cost of drugs in ICU and the entire hospital was also calculated. Descriptive analysis and logistic regression were used to present the results. KEY FINDINGS: the mean age of patients was 50.3 years (SD = 20.4). The average ICU stay was 6 days. The mean length of stay was significantly lower in surgical patients compared to medical patients (odds ratio (OR) = 0.91, 95% confidence interval (CI) 0.84-0.97). Mortality rate was significantly higher among medical patients (OR = 10.5, 95% CI 3.7-29.8). There was a significant positive association between the total number of prescribed drugs or antibiotics received by patients and mortality. Patients received an average of 8.2 drugs at admission, 10.1 drugs during the first 24h and an average of 14.6 drugs over their entire stay at the icu. among drug groups, antibiotics and sedatives were most ordered drugs in icu. CONCLUSIONS: antibiotics are responsible for the majority of ICU drug costs. Appropriate selection of antibiotics in terms of type, dose and duration of therapy could tremendously reduce the expenses in hospitals without negatively influencing the quality of healthcare.

The Iranian population is graying: are we ready?

BACKGROUND: Iran has gone through sharp demographic changes in the past three decades. Presently, in Iran, there is a lack of health promotional activities targeting the elderly which can lead to a decrease in their quality of life and an increase in their disability rates. Those most vulnerable amongst the elderly are females, who have low education and low socioeconomic status. For them and others, few social services, accessible housing options and long-term care facilities exist. METHODS: Data was gathered using population projections over an 80-year period (1975 - 2055), facilitated by spectrum software prepared by the USAID/Health Policy Initiative with data source derived from projections of the United Nations, World Population Prospects. Projections derived were on the expected population, the median age of the population, population pyramids, total fertility rates, life expectancy, and dependency ratio. RESULTS: Projections showed that by the middle of this century approximately one fifth of the population will be over 60, with the median age of the population almost doubling from what it is today and the dependency ratio increasing steadily. Currently, the resources are not sufficient to address the special needs of an elderly population and are at risk for becoming even more strained over the 80 year span. CONCLUSION: Iran must begin to prepare itself for the impact that a massive ageing population will have in the ensuing years. Recommendations suggest developing policies supportive of accessible and affordable housing and care facilities, establishing community health programs that aid the elderly in continuing to live at home, and strengthening the availability of pension plans.

Fixed drug eruption resulting from fluconazole use: a case report.

INTRODUCTION: Fluconazole is a widely used antifungal agent with a possible side effect of fixed drug eruption. However, this adverse drug effect is absent from the reported list of possible side effects of fluconazole. We are presenting a rare case in our report. CASE PRESENTATION: A 25-year-old Iranian woman developed fixed drug eruptions on different sites of her body after taking five doses of fluconazole to treat vaginal candidiasis. A positive patch test, positive oral challenge test and skin biopsy were all found to be consistent with fixed drug eruption. CONCLUSION: Fluconazole is a widely prescribed drug, used mainly to treat candidiasis. Fixed drug eruption as a possible side effect of Fluconazole is not well known and thus, the lesions may be misdiagnosed and mistreated. Based on our findings, which are consistent with a number of other practitioners, we recommend adding fixed drug eruption to the list of possible side effects of fluconazole.