Unravelling actionable biology using transcriptomic data to integrate mitotic index and Ki-67 in the management of lung neuroendocrine tumors.

Pulmonary neuroendocrine tumors (NETs) are a heterogeneous family of malignancies whose classification relies on morphology and mitotic rate, unlike extrapulmonary neuroendocrine tumors that require both mitotic rate and Ki-67. As mitotic count is proportional to Ki-67, it is crucial to understand if Ki-67 can complement the existing diagnostic guidelines, as well as discover the benefit of these two markers to unravel the biological heterogeneity. In this study, we investigated the association of mitotic rate and Ki-67 at gene- and pathway-level using transcriptomic data in lung NET malignancies. Lung resection tumor specimens obtained from 28 patients diagnosed with NETs were selected. Mitotic rate, Ki-67 and transcriptomic data were obtained for all samples. The concordance between mitotic rate and Ki-67 was evaluated at gene-level and pathway-level using gene expression data. Our analysis revealed a strong association between mitotic rate and Ki-67 across all samples and cell cycle genes were found to be differentially ranked between them. Pathway analysis indicated that a greater number of pathways overlapped between these markers. Analyses based on lung NET subtypes revealed that mitotic rate in carcinoids and Ki-67 in large cell neuroendocrine carcinomas provided comprehensive characterization of pathways among these malignancies. Among the two subtypes, we found distinct leading-edge gene sets that drive the enrichment signal of commonly enriched pathways between mitotic index and Ki-67. Overall, our findings delineated the degree of benefit of the two proliferation markers, and offers new layer to predict the biological behavior and identify high-risk patients using a more comprehensive diagnostic workup.

Transcriptomic data helps refining classification of pulmonary carcinoid tumors with increased mitotic counts.

Pulmonary neuroendocrine neoplasms are classified by WHO as either typical or atypical carcinoids, large cell (LCNEC) or small cell (SCLC) neuroendocrine carcinoma based on mitotic count, morphology, and necrosis assessment. LCNEC with low mitotic count and sharing morphologic features with carcinoids are in a gray zone for classification and their rare prevalence and the paucity of studies precludes proper validation of the current grading system. In this study, we aim to investigate their clinicopathological and transcriptomic profiles. Lung resection specimens obtained from 18 patients diagnosed with carcinoids or LCNEC were selected. Four of them were characterized as borderline tumors based on a mitotic rate ranging between 10 and 30 mitoses per 2 mm2. Comprehensive morphological and immunohistochemical (IHC) evaluation was performed and tumor-based transcriptomic profiles were analyzed through unsupervised clustering. Clustering analysis revealed two distinct molecular groups characterized by low (C1) and high (C2) proliferation. C1 was comprised of seven carcinoids and three borderline tumors, while C2 was comprised of seven LCNEC and one borderline tumor. Furthermore, patients in cluster C1 had a better recurrence-free survival compared with patients in cluster C2 (20% vs 75%). Histological features, IHC profile, and molecular analysis showed that three out of four borderline tumors showed features consistent with carcinoids. Therefore, our findings convey that the current diagnostic guidelines are suboptimal for classification of pulmonary neuroendocrine tumors with increased proliferative index and carcinoid-like morphology. These results support the emerging concept that neuroendocrine tumors with carcinoid-like features and mitotic count of <20 mitoses per 2 mm2 should be regarded as pulmonary carcinoids instead of LCNEC.

Risk factors for neonatal mortality among very low birth weight neonates.

The objective of this study is to determine risk factors causing increase in very low birth way (VLBW) neonatal mortality. The medical files of all neonates weighing ≤1500 g, born in Vali-e-Asr hospital (2001-2004) were studied. Two groups of neonates (living and dead) were compared up to the time of hospital discharge or death. A total of 317 neonates were enrolled. A meaningful relationship existed between occurrence of death and low gestational age (P=0.02), low birth weight, lower than 1000 g (P=0.001), Apgar score <6 at 5th minutes (P=0.001), resuscitation at birth (P=0.001), respiratory distress syndrome (P=0.001) need for mechanical ventilation (P=0.001), neurological complications (P=0.001) and intraventricular hemorrhage (P=0.001). Regression analysis indicated that each 250 g weight increase up to 1250 g had protective effect, and reduced mortality rate. The causes of death of those neonates weighting over 1250 g should be sought in factors other than weight. Survival rate was calculated to be 80.4% for neonates weighing more than 1000 g. The most important high risk factors affecting mortality of neonates are: low birth weight, need for resuscitation at birth, need for ventilator use and intraventricular hemorrhage.

Methadone maintenance therapy outcomes in Iran.

INTRODUCTION: Because of the increasing number of injecting drug users (IDUs) in Iran and the risk of the spread of HIV infection, harm reduction programs have been considered for conventional law enforcement measures. The aim of this study was to evaluate the efficacy of methadone maintenance therapy (MMT) in IDUs and the associated health and social outcomes. MATERIAL AND METHODS: This case-control study was conducted at the Persepolis Harm Reduction Center in Tehran during the year 2006. Data were gathered from two groups of randomly chosen patients. The first group consisted of 75 IDU patients who had undergone at least 6 months of methadone treatment (the MMT group), and second group consisted of 75 newly admitted clients (the control group). Participants were assessed on their dangerous injection and sexual behaviors, social well-being, and patterns of drug use. The results were compared between the two groups. RESULTS: The mean age of participants in the two groups was almost the same (34.28 years in the control group and 35.68 years in the MMT group, p >.05). Prevalence of drug injection in the MMT group was less than that in the control group (16% vs. 100%). There was also a dramatic difference in needle and syringe sharing (40% in the control group vs. 4% in the MMT group) but not in crimes and arrests (p = .4). Those in the MMT group had a better relationship with their families, partners, coworkers, and neighbors compared with controls. There was no considerable difference in dangerous sexual behaviors between the two groups. CONCLUSIONS: Given the large number of HIV-positive cases among IDUs and considering that injection drug use is the main spreading factor for HIV, MMT would play a major role in controlling the HIV epidemic through reduction of heroin injection and the risk behaviors related to it. High inflation rate, lack of interorganization coordination, budget limitation, and no follow-up were the most important limitations of this study.

Economic burden attributable to functional bowel disorders in Iran: a cross-sectional population-based study.

OBJECTIVE: While few population-based studies on the economic burden of functional bowel disorders (FBD) have been published from developing countries like Iran, this study aimed to estimate their direct and indirect costs for five groups of patients: irritable bowel syndrome (IBS), functional constipation (FC), unspecified-FBD (U-FBD), functional abdominal bloating (FAB) and functional diarrhea (FD). METHODS: Up to 18,180 adults randomly sampled from Tehran, Iran (2006-2007) were interviewed using two questionnaires based on the Rome III criteria to detect FBD patients and to estimate their medical expenses (such as visiting the doctor, drugs, hospitalization and laboratory tests) and productivity loss in the previous 6 months. All costs were converted to dollar purchasing power parity (PPP$) to facilitate cross-country comparisons. RESULTS: The mean total 6-month costs were approximately: 160, 147, 103, 96 and 42 PPP$ for IBS, FC, U-FBD, FAB and FD, respectively. The highest proportion of drug consumption was found in IBS patients. The highest mean duration of absence from work was seen in IBS patients (2.26 days). Overall, doctor visit costs accounted for approximately 1/3 of the total costs for FBD, followed by hospitalization. A higher indirect cost of illness was found in IBS (54 PPP$), whereas it was zero in FD. CONCLUSION: The economic burden of FBD seems to be moderately high in Iran and it imposes a relatively heavy financial burden on the Iranian national health system because of its high prevalence and its impact on quality of life, productivity and waste of resources.

Economic burden of gastro-oesophageal reflux disease and dyspepsia: A community-based study.

BACKGROUND AND STUDY AIMS: Gastro-oesophageal reflux disease (GERD) and dyspepsia are common digestive disorders that inflict serious harm, burden and economic consequences on individuals worldwide. The aim of this study was to estimate the direct and indirect economic burden of GERD and dyspepsia in the whole population of Tehran, the capital of Iran. PATIENTS AND METHODS: The study was performed on a total of 18,180 adult subjects (age>18 years) taken as a random sample in Tehran province, Iran (2006-2007). A valid and reliable questionnaire was used to enquire about the symptoms of GERD, dyspepsia and the frequency of the utilization of health services including physician visits, hospitalisations and productivity loss due to GERD/dyspepsia symptoms in the preceding 6 months. RESULTS: GERD was found in 518 (41.9% males) patients and dyspepsia in 404 patients (38.9% males). Further 1007 subjects had both GERD and dyspepsia. The total direct costs of disease per patient for GERD, dyspepsia and their overlap were PPP$97.70, PPP$108.10 and PPP$101.30, respectively (PPP, purchasing power parity dollars). The total indirect cost of disease per patient was PPP$13.7, PPP$12.1 and PPP$32.7, for GERD, dyspepsia and their overlap, respectively. CONCLUSION: According to our results, hospitalisation and physician visits were the main cost of disease that could be minimised by revision of the insurance business in Iran.

Direct and indirect medical costs of functional constipation: a population-based study.

BACKGROUND: Constipation causes a large number of medical visits each year and imposes significant financial toll on healthcare systems worldwide. So the present community-based study was conducted in order to estimate attributable direct and indirect costs to functional constipation (FC) and to provide an overview of related physician visits in general population of Iran. METHODS: From May 2006 to December 2007, a total of 19,200 adult persons (aged 16 and above) were drawn randomly in Tehran province, Iran (response rate 94%). Participants who reported any gastrointestinal symptoms (2,790 persons) were referred to assigned physicians to be questioned about symptoms of functional bowel disorders according to the Rome III criteria. Direct and indirect costs to FC were calculated. Attributable costs were reported as purchasing power parity dollars (PPP$). RESULTS: Of the total 18,180 consenting participants in this study, 435 (2.4%) had FC according to Rome III criteria. Mean total cost of constipation per person was 146.84 PPP$, of which 128.68 PPP$ was related to direct costs and 18.16 PPP$ to indirect costs. Higher educated persons (189.75 PPP$), those above 64 years of age (373.42 PPP$), subjects with BMI of less than 18.5 kg/m(2) (510.84 PPP$), and widowed persons (258.50 PPP$) had the highest costs. CONCLUSIONS: This study determined that although the economic burden of FC does not seem to be substantial in comparison to other major health problems, it still exacts a substantial toll on the health system for two reasons: chronicity and ambiguity of symptoms.

Irritable bowel syndrome: a population based study.

BACKGROUND: The prevalence of irritable bowel syndrome (IBS) is relatively high, but up to now, no population based study in Iran has used the ROME III criteria. The aim of the present study was to determine the prevalence of IBS by using the ROME III criteria in the adult population of Iran. METHODS: A face to face survey was conducted in a large area of the Tehran province. IBS was diagnosed by using a validated questionnaire based on the ROME III criteria. RESULTS: The study population comprised 18,180 participants, with a female to male ratio of 1. 15.3% of participants complained of gastrointestinal (GI) symptoms, while the prevalence of IBS was estimated to be 1.1% (139 women, 59 men, p=0.000). IBS patients were more likely to be married, and older. The most common presenting symptoms of IBS were abdominal pain that was relieved by defecation (94%), change in fecal consistency (78%), and change in bowel frequency (70%). Constipation was predominant in 52% of IBS cases, diarrhea was predominant in 18%, and 8% experienced intermittent diarrhea and constipation. CONCLUSION: The prevalence of IBS is relatively low in the Iranian adult population according to the ROME III criteria. The most probable reasons are the specificity of ROME III criteria and the characteristic low prevalence of GI symptoms in the study population.