Definitive local therapy for T4 prostate cancer associated with improved local control and survival.

OBJECTIVES: To evaluate patients with clinical (c)T4 prostate cancer (PCa), which represent both a heterogenous and understudied population, who often present with locally advanced disease and obstructive symptoms causing significant morbidity and mortality. We analysed whether receiving definitive local therapy influenced symptomatic and oncological outcomes. METHODS: Retrospective analysis of 154 patients with cT4 PCa treated at a single institution in 1996-2020. Systemic therapy with or without local treatment (surgery, radiotherapy [RT], or both). Uni- and multivariate analyses of associations between clinicopathological features (including obstructive symptoms) and receipt of local therapy on overall survival (OS) and disease control were done with Cox regression. RESULTS: The median follow-up time was 5.9 years. Most patients had adenocarcinoma (88%), Gleason score 9-10 (77%), and median baseline prostate-specific antigen (PSA) of 20 ng/mL; most (54%) had metastatic cT4N0-1M1 disease; 24% regionally advanced cT4N1M0, and 22% localised cT4N0M0. Local therapies were RT (n = 44), surgery (n = 28), or both (n = nine). Local therapy was associated with improved OS (hazard ratio [HR] 0.3, P < 0.001), longer freedom from local recurrence (HR 0.39, P = 0.002), less local progression (HR 0.41, P = 0.02), fewer obstructive symptoms with progression (HR 0.31, P = 0.01), and less death from local disease (HR 0.25, P = 0.002). On multivariate, local therapy was associated with improved survival (HR 0.58, P = 0.02), and metastatic disease (HR 2.93, P < 0.001) or high-risk pathology (HR 2.05, P = 0.03) was associated with worse survival. CONCLUSION: Definitive local therapy for cT4 PCa was associated with improved symptomatic outcomes and survival even among men with metastatic disease. Pending prospective evaluation, these findings support definitive treatment with local therapy for cT4 disease in select cases.

Ablative liver radiotherapy for unresected intrahepatic cholangiocarcinoma: Patterns of care and survival in the United States.

BACKGROUND: Single-institution studies have shown the oncologic benefit of ablative liver radiotherapy (A-RT) for patients with unresectable intrahepatic cholangiocarcinoma (ICC). However, adoption of A-RT across the United States and its associated outcomes are unknown. METHODS: We queried the National Cancer Data Base for nonsurgically managed patients with ICC diagnosed between 2004 and 2018. Patients were labeled A-RT for receipt of biologically effective doses (BED10 ) ≥ 80.5 Gy and conventional RT (Conv-RT) for lower doses. Associations with A-RT use and overall survival were identified using logistic and Cox regressions, respectively. RESULTS: Of 27,571 patients, the most common treatments were chemotherapy without liver RT (45%), no chemotherapy or liver RT (42%), and liver RT ± chemotherapy (13%). Use of liver RT remained constant over time. Of 1112 patients receiving liver RT with known doses, RT was 73% Conv-RT (median BED10 , 53 Gy; median, 20 fractions) and 27% A-RT (median BED10 , 100 Gy; median, 5 fractions). Use of A-RT increased from 5% in 2004 to 48% in 2018 (Ptrend < .001). With a median follow-up of 52.3 months, median survival estimates for Conv-RT and A-RT were 12.8 and 23.7 months (P < .001), respectively. On multivariable analysis, stage III and IV disease correlated with a higher risk of death, whereas chemotherapy and A-RT correlated with a lower risk. CONCLUSIONS: Although A-RT has been increasingly used, use of liver RT as a whole in the United States remained constant despite growing evidence supporting its use, suggesting continued unmet need. A-RT is associated with longer survival versus Conv-RT. LAY SUMMARY: Bile duct cancer is a rare, deadly disease that often presents at advanced stages. Single-institution retrospective studies have demonstrated that use of high-dose radiotherapy may be associated with longer survival, but larger studies have not been conducted. We used a large, national cancer registry of patients diagnosed between 2004 and 2018 to show that liver radiotherapy use remains low in the United States, despite growing evidence that patients who receive it live longer. Furthermore, we showed that patients who received high-dose radiotherapy lived longer than those who received lower doses. Greater awareness of the benefits of liver radiotherapy is needed to improve patient outcomes.

Association between leptin levels and severity of suicidal behaviour in schizophrenia spectrum disorders.

OBJECTIVE: Associations between suicidality and lipid dysregulation are documented in mental illness, but the potential role of leptin remains unclear. We examined the association between leptin and suicidal behaviour in schizophrenia, together with the influence of other clinical and biological indices. METHOD: We recruited a sample of 270 participants with schizophrenia spectrum diagnoses. Blood samples were analysed for leptin, while symptom severity was assessed by Positive and Negative Syndrome Scale (PANSS) and Inventory of Depressive Symptomatology (IDS-C). Patients' history of suicidal behaviour was categorized into three subgroups based on IDS-C suicide subscale: No suicidal behaviour, mild/moderate suicidal behaviour and severe suicidal behaviour with/without attempts. RESULTS: Mild/moderate suicidal behaviour was present in 17.4% and severe suicidal behaviour in 34.8%. Both groups were significantly associated with female gender (OR = 6.0, P = 0.004; OR = 5.9, P = 0.001), lower leptin levels (OR = 0.4, P = 0.008; OR = 0.5, P = 0.008) and more severe depression (OR = 1.2, P < 0.001; OR = 1.1, P < 0.001) respectively. Smoking (OR = 2.6, P = 0.004), younger age of onset (OR = 0.9, P = 0.003) and less use of leptin-increasing medications (OR = 0.5, P = 0.031) were associated with severe/attempts group, while higher C-reactive protein CRP (OR = 1.3, P = 0.008) was associated with mild/moderate group. CONCLUSION: Lower leptin levels were associated with higher severity of suicidal behaviour in schizophrenia.

Demethylation of induced pluripotent stem cells from type 1 diabetic patients enhances differentiation into functional pancreatic ß cells.

Type 1 diabetes (T1D) can be managed by transplanting either the whole pancreas or isolated pancreatic islets. However, cadaveric pancreas is scarcely available for clinical use, limiting this approach. As such, there is a great need to identify alternative sources of clinically usable pancreatic tissues. Here, we used induced pluripotent stem (iPS) cells derived from patients with T1D to generate glucose-responsive, insulin-producing cells (IPCs) via 3D culture. Initially, T1D iPS cells were resistant to differentiation, but transient demethylation treatment significantly enhanced IPC yield. The cells responded to high-glucose stimulation by secreting insulin in vitro The shape, size, and number of their granules, as observed by transmission electron microscopy, were identical to those found in cadaveric ß cells. When the IPCs were transplanted into immunodeficient mice that had developed streptozotocin-induced diabetes, they promoted a dramatic decrease in hyperglycemia, causing the mice to become normoglycemic within 28 days. None of the mice died or developed teratomas. Because the cells are derived from "self," immunosuppression is not required, providing a much safer and reliable treatment option for T1D patients. Moreover, these cells can be used for drug screening, thereby accelerating drug discovery. In conclusion, our approach eliminates the need for cadaveric pancreatic tissue.

Proton Therapy Mediates Dose Reductions to Brain Structures Associated With Cognition in Children With Medulloblastoma.

PURPOSE: Emerging evidence suggests proton radiation therapy may offer cognitive sparing advantages over photon radiation therapy, yet dosimetry has not been compared previously. The purpose of this study was to examine dosimetric correlates of cognitive outcomes in children with medulloblastoma treated with proton versus photon radiation therapy. METHODS AND MATERIALS: In this retrospective, bi-institutional study, dosimetric and cognitive data from 75 patients (39 photon and 36 proton) were analyzed. Doses to brain structures were compared between treatment modalities. Linear mixed-effects models were used to create models of global IQ and cognitive domain scores. RESULTS: The mean dose and dose to 40% of the brain (D40) were 2.7 and 4.1 Gy less among proton-treated patients compared with photon-treated patients (P = .03 and .007, respectively). Mean doses to the left and right hippocampi were 11.2 Gy lower among proton-treated patients (P < .001 for both). Mean doses to the left and right temporal lobes were 6.9 and 7.1 Gy lower with proton treatment, respectively (P < .001 for both). Models of cognition found statistically significant associations between higher mean brain dose and reduced verbal comprehension, increased right temporal lobe D40 with reduced perceptual reasoning, and greater left temporal mean dose with reduced working memory. Higher brain D40 was associated with reduced processing speed and global IQ scores. CONCLUSIONS: Proton therapy reduces doses to normal brain structures compared with photon treatment. This leads to reduced cognitive decline after radiation therapy across multiple intellectual endpoints. Proton therapy should be offered to children receiving radiation for medulloblastoma.

Exploratory analysis of the cervix tumoral HPV antigen-specific T-cell repertoire during chemoradiation and after brachytherapy.

BACKGROUND: Chemoradiation (CRT) may modulate the immune milieu as an in-situ vaccine. Rapid dose delivery of brachytherapy has unclear impact on T-cell repertoires. HPV-associated cancers express viral oncoproteins E6/E7, which enable tracking antigen/tumor-specific immunity during CRT. METHODS: Thirteen cervical cancer patients on a multi-institutional prospective protocol from 1/2020-1/2023 underwent standard-of-care CRT with pulsed-dose-rate brachytherapy boost (2 fractions). Cervix swabs at various timepoints underwent multiplex DNA deep sequencing of the TCR-ß/CDR3 region with immunoSEQ. Separately, HPV-responsive T-cell clones were also expanded ex vivo. Statistical analysis was via Mann-Whitney-U. RESULTS: TCR productive clonality, templates, frequency, or rearrangements increased post-brachytherapy in 8 patients. Seven patients had E6/E7-responsive evolution over CRT with increased productive templates (ranges: 1.2-50.2 fold-increase from baseline), frequency (1.2-1.7), rearrangements (1.2-40.2), and clonality (1.2-15.4). Five patients had HPV-responsive clonal expansion post-brachytherapy, without changes in HPV non-responsive clones. Epitope mapping revealed VDJ rearrangements targeting cervical cancer-associated antigens in 5 patients. The only two patients with disease recurrence lacked response in all metrics. A lack of global TCR remodeling correlated with worse recurrence-free survival, p = 0.04. CONCLUSION: CRT and brachytherapy alters the cervical cancer microenvironment to facilitate the expansion of specific T-cell populations, which may contribute to treatment efficacy.

Outcomes and toxicities in patients with diffuse-large B cell lymphoma involving the gastrointestinal tract and digestive organs.

Background: Diffuse large B-cell lymphoma (DLBCL) involving the gastrointestinal (GI) organs is rare, and real-world outcomes after combined modality therapy (CMT) with systemic therapy (ST) and radiotherapy (RT) are not well-characterized, particularly in the contemporary era. We characterized outcomes in a large cohort of GI-DLBCL patients treated with ST alone or CMT. Methods: Patients with GI-DLBCL treated at a single institution were retrospectively reviewed. Kaplan-Meier and Cox regression models estimated survival. Multivariable analyses were conducted using the Cox proportional hazards model. Results: Of 204 patients, gastric involvement was most common (63%). Most presented with early-stage disease (61%). All patients received ST and 65 patients (32%) received RT, 88% as part of first-line CMT. Median dose was 36 Gy (IQR 30.6-39.6) in 18 fractions (IQR 17-22). Median follow-up was 46 months. Five-year overall survival (OS) and progression-free survival (PFS) was 88% and 84%, respectively; complete response (CR) rate was 82%. Improved OS associated with low IPI (p=0.001), fewer chemotherapy lines (p<0.001), early stage (p<0.006), and CR (p<0.001). Survival did not differ by RT receipt (p>0.25). Only early stage and CR correlated with improved OS on multivariable analysis. Stomach-directed RT vs. RT to other sites correlated with improved PFS and OS (p<0.04). Patients with early stage DLBCL treated with CMT in the post-rituximab era had equivalent OS vs. ST alone, even with fewer chemotherapy cycles (p<0.02; median of 4 with RT vs. 6 cycles without). Fifty patients had bulky disease (≥7.5 cm), of whom 18 (36%) had early stage disease. Among patients with bulky disease, 5 (10%) developed relapse at the initial site of disease bulk. Four of the 5 patients did not receive consolidative radiation. Among these 4 patients, 3 relapsed only in their initial site of bulky disease. Of 191 patients with luminal GI-DLBCL, n=4 (2.1%) developed perforation; only one received RT. Acute Grade 3 toxicities were reported in 41.2% of patients, and 12 (5.8%) patients had late Grade 3 toxicities, 99% attributed to chemotherapy. Conclusion: GI-DLBCL patients have favorable outcomes after CMT with minimal late toxicity. CMT may be offered with abridged systemic regimens with equivalent outcomes. Stomach directed-RT may mitigate relapse risk associated with incomplete disease response or bulky disease.

Characterization of lymphopenia and correlating the risk of cytopenias with dose and BM volume irradiated in aggressive B-cell lymphoma patients bridged with radiation therapy for CAR-T cell therapy.

INTRODUCTION: The impact of bridging radiation therapy (bRT) for CAR T-cell therapy on absolute lymphocyte count (ALC) kinetics and treatment outcome is unknown. METHODS: We retrospectively reviewed adults with relapsed/refractory aggressive large B-cell lymphoma (LBCL) who received bRT prior to CD-19 CAR-T between 11/2017-4/2023. The change in ALC (ALC Δ RT) was computed by subtracting ALC pre- and post-bRT. Percent bone marrow (%BM) irradiated was calculated by estimating skeletal BM distribution. PFS, DSS, and OS were modeled via Kaplan-Meier. RESULTS: Fifty-one patients received bRT, of which 13 (25.5%) had bulky disease (≥7.5cm). The median bRT dose was 30Gy (range: 4-48Gy); 26 patients (51%) received ≥30Gy. Thirty-one patients (61%) received bRT comprehensively to all disease sites. The median cumulative %BM irradiated was 5.05% (range: 0-50%). At a median follow-up of 10.3 months (95% CI: 7.7-16.4), the 1-year OS, PFS, and DSS rates were 80% (95% CI: 66-99), 78% (64-87), and 82% (68-90), respectively. The incidence of ≥Grade 3 lymphopenia was 33% pre-RT and 68% post-RT, but recovered to 43% at the conditioning chemotherapy (CC) timepoint. There was no correlation between post-RT Grade ≥3 lymphopenia and the receipt of comprehensive bRT, combined modality bridging, ≥30Gy bRT, or bRT to ≥15% of BM (all p>0.2). Among patients with Grade 0-2 lymphopenia pre-RT, increased conversion to Grade ≥3 lymphopenia post-RT correlated with comprehensive or ≥30Gy bRT, but these factors did not impair ALC recovery at CC. There was no association between ALC Δ RT or post-RT ALC with 30 or 90 day response (p>0.25), DSS, PFS, or OS (p>0.3). CONCLUSIONS: Lymphocyte change during bRT is not associated with CAR-T outcomes. Persistent cytopenia risk following bRT is not associated with bRT to ≥30Gy, ≥15% of BM, or comprehensive coverage. While bRT can be delivered safely, we urge careful treatment planning when incorporating into pre-CAR-T regimens.

Development and implementation of optimized endogenous contrast sequences for delineation in adaptive radiotherapy on a 1.5T MR-linear-accelerator: a prospective R-IDEAL stage 0-2a quantitative/qualitative evaluation of in vivo site-specific quality-assurance using a 3D T2 fat-suppressed platform for head and neck cancer.

Purpose: To improve segmentation accuracy in head and neck cancer (HNC) radiotherapy treatment planning for the 1.5T hybrid magnetic resonance imaging/linear accelerator (MR-Linac), three-dimensional (3D), T2-weighted, fat-suppressed magnetic resonance imaging sequences were developed and optimized. Approach: After initial testing, spectral attenuated inversion recovery (SPAIR) was chosen as the fat suppression technique. Five candidate SPAIR sequences and a nonsuppressed, T2-weighted sequence were acquired for five HNC patients using a 1.5T MR-Linac. MR physicists identified persistent artifacts in two of the SPAIR sequences, so the remaining three SPAIR sequences were further analyzed. The gross primary tumor volume, metastatic lymph nodes, parotid glands, and pterygoid muscles were delineated using five segmentors. A robust image quality analysis platform was developed to objectively score the SPAIR sequences on the basis of qualitative and quantitative metrics. Results: Sequences were analyzed for the signal-to-noise ratio and the contrast-to-noise ratio and compared with fat and muscle, conspicuity, pairwise distance metrics, and segmentor assessments. In this analysis, the nonsuppressed sequence was inferior to each of the SPAIR sequences for the primary tumor, lymph nodes, and parotid glands, but it was superior for the pterygoid muscles. The SPAIR sequence that received the highest combined score among the analysis categories was recommended to Unity MR-Linac users for HNC radiotherapy treatment planning. Conclusions: Our study led to two developments: an optimized, 3D, T2-weighted, fat-suppressed sequence that can be disseminated to Unity MR-Linac users and a robust image quality analysis pathway that can be used to objectively score SPAIR sequences and can be customized and generalized to any image quality optimization protocol. Improved segmentation accuracy with the proposed SPAIR sequence will potentially lead to improved treatment outcomes and reduced toxicity for patients by maximizing the target coverage and minimizing the radiation exposure of organs at risk.

Definitive Liver Radiotherapy for Intrahepatic Cholangiocarcinoma with Extrahepatic Metastases.

Introduction: Tumor-related liver failure (TRLF) is the most common cause of death in patients with intrahepatic cholangiocarcinoma (ICC). Though we previously showed that liver radiotherapy (L-RT) for locally advanced ICC is associated with less frequent TRLF and longer overall survival (OS), the role of L-RT for patients with extrahepatic metastatic disease (M1) remains undefined. We sought to compare outcomes for M1 ICC patients treated with and without L-RT. Methods: We reviewed ICC patients that found to have M1 disease at initial diagnosis at a single institution between 2010 and 2021 who received L-RT, matching them with an institutional cohort by propensity score and a National Cancer Database (NCDB) cohort by frequency technique. The median biologically effective dose was 97.5 Gy (interquartile range 80.5-97.9 Gy) for L-RT. Patients treated with other local therapies or supportive care alone were excluded. We analyzed survival with Cox proportional hazard modeling. Results: We identified 61 patients who received L-RT and 220 who received chemotherapy alone. At median follow-up of 11 months after diagnosis, median OS was 9 months (95% confidence interval [CI] 8-11) and 21 months (CI: 17-26) for patients receiving chemotherapy alone and L-RT, respectively. TRLF was the cause of death more often in the patients who received chemotherapy alone compared to those who received L-RT (82% vs. 47%; p = 0.001). On multivariable propensity score-matched analysis, associations with lower risk of death included duration of upfront chemotherapy (hazard ratio [HR] 0.82; p = 0.005) and receipt of L-RT (HR: 0.40; p = 0.002). The median OS from diagnosis for NCDB chemotherapy alone cohort was shorter than that of the institutional L-RT cohort (9 vs. 22 months; p < 0.001). Conclusion: For M1 ICC, L-RT associated with a lower rate of death due to TRLF and longer OS versus those treated with chemotherapy alone. Prospective studies of L-RT in this setting are warranted.

Nitric oxide dioxygenation reaction by oxy-coboglobin models: in-situ low-temperature FTIR characterization of coordinated peroxynitrite.

The oxy-cobolglobin models of the general formula (NH(3))Co(Por)(O(2)) (Por = meso-tetra-phenyl and meso-tetra-p-tolylporphyrinato dianions) were constructed by sequential low temperature interaction of NH(3) and dioxygen with microporous layers of Co-porphyrins. At cryogenic temperatures small increments of NO were introduced into the cryostat and the following reactions were monitored by the FTIR and UV-visible spectroscopy during slow warming. Upon warming the layers from 80 to 120 K a set of new IR bands grows with correlating intensities along with the consumption of the ν(O(2)) band. Isotope labeling experiments with (18)O(2), (15)NO and N(18)O along with DFT calculations provides a basis for assigning them to the six-coordinate peroxynitrite complexes (NH(3))Co(Por)(OONO). Over the course of warming the layers from 140 to 170 K these complexes decompose and there are spectral features suggesting the formation of nitrogen dioxide NO(2). Upon keeping the layers at 180-210 K the bands of NO(2) gradually decrease in intensity and the set of new bands grows in the range of 1480, 1270, and 980 cm(-1). These bands have their isotopic counterparts when (15)NO, (18)O(2) and N(18)O are used in the experiments and certainly belong to the 6-coordinate nitrato complexes (NH(3))Co(Por)(η(1)-ONO(2)) demonstrating the ability of oxy coboglobin models to promote the nitric oxide dioxygenation (NOD) reaction similar to oxy-hemes. As in the case of Hb, Mb and model iron-porphyrins, the six-coordinate nitrato complexes are not stable at room temperature and dissociate to give nitrate anion and oxidized cationic complex Co(III)(Por)(NH(3))(1,2).

Comparative analysis of acute toxicities and patient reported outcomes between intensity-modulated proton therapy (IMPT) and volumetric modulated arc therapy (VMAT) for the treatment of oropharyngeal cancer.

BACKGROUND AND PURPOSE: IMPT improves normal tissue sparing compared to VMAT in treating oropharyngeal cancer (OPC). Our aim was to assess if this translates into clinical benefits. MATERIALS AND METHODS: OPC patients treated with definitive or adjuvant IMPT or VMAT from 2013 to 2018 were included. All underwent prospective assessment using patient-reported-outcomes (PROs) (EORTC-QLQ-H&N35) and provider-assessed toxicities (CTCAEv4.03). End-of-treatment and pretreatment scores were compared. PEG-tube use, hospitalization, and narcotic use were retrospectively collected. Statistical analysis used the Wilcoxon Rank-Sum Test with propensity matching for PROs/provider-assessed toxicities, and t-tests for other clinical outcomes. RESULTS: 46 IMPT and 259 VMAT patients were included; median follow-up was 12 months (IMPT) and 30 months (VMAT). Baseline characteristics were balanced except for age (p = 0.04, IMPT were older) and smoking (p < 0.01, 10.9% IMPT >20PYs, 29.3% VMAT). IMPT was associated with lower PEG placement (OR = 0.27; 95% CI: 0.12-0.59; p = 0.001) and less hospitalization ≤60 days post-RT (OR = 0.21; 95% CI:0.07-0.6, p < 0.001), with subgroup analysis revealing strongest benefits in patients treated definitively or with concomitant chemoradiotherapy (CRT). IMPT was associated with a relative risk reduction of 22.3% for end-of-treatment narcotic use. Patients reported reduced cough and dysgeusia with IMPT (p < 0.05); patients treated definitively or with CRT also reported feeling less ill, reduced feeding tube use, and better swallow. Provider-assessed toxicities demonstrated less pain and mucositis with IMPT, but more mucosal infection. CONCLUSION: IMPT is associated with improved PROs, reduced PEG-tube placement, hospitalization, and narcotic requirements. Mucositis, dysphagia, and pain were decreased with IMPT. Benefits were predominantly seen in patients treated definitively or with CRT.

Tracking embryonic hematopoietic stem cells to the bone marrow: nanoparticle options to evaluate transplantation efficiency.

BACKGROUND: As the prevalence of therapeutic approaches involving transplanted cells increases, so does the need to noninvasively track the cells to determine their homing patterns. Of particular interest is the fate of transplanted embryonic stem cell-derived hematopoietic progenitor cells (HPCs) used to restore the bone marrow pool following sublethal myeloablative irradiation. The early homing patterns of cell engraftment are not well understood at this time. Until now, longitudinal studies were hindered by the necessity to sacrifice several mice at various time points of study, with samples of the population of lymphoid compartments subsequently analyzed by flow cytometry or fluorescence microscopy. Thus, long-term study and serial analysis of the transplanted cells within the same animal was cumbersome, making difficult an accurate documentation of engraftment, functionality, and cell reconstitution patterns. METHODS: Here, we devised a noninvasive, nontoxic modality for tracking early HPC homing patterns in the same mice longitudinally over a period of 9 days using mesoporous silica nanoparticles (MSNs) and magnetic resonance imaging. RESULTS: This approach of potential translational importance helps to demonstrate efficient uptake of MSNs by the HPCs as well as retention of MSN labeling in vivo as the cells were traced through various organs, such as the spleen, bone marrow, and kidney. Altogether, early detection of the whereabouts and engraftment of transplanted stem cells may be important to the overall outcome. To accomplish this, there is a need for the development of new noninvasive tools. CONCLUSIONS: Our data suggest that multifunctional MSNs can label viably blood-borne HPCs and may help document the distribution and homing in the host followed by successful reconstitution.

Kidney function and histopathological changes in unilateral hydronephrosis with special reference to bilharzial ureter.

Fifty-six patients with unilateral hydronephrosis were the subject of this study. The patients were classified into 4 groups according to the stage of hydronephrosis as assessed by radiological criteria. Split kidney function, histopathological studies, and measurement of intraureteral pressure were performed. Urinary Bilharziasis was held responsible for obstructive nephropathy in 77% of cases. Complicating urinary infection was present in 66%. The study has shown that creatinine excretion was slightly decreased in early, moderate, and moderately advanced hydronephrosis. On the other hand, a marked lowering of urine osmolality was found even in the early stages of hydronephrosis. The hydronephrotic kidney was found to be a salt losing one only in early, moderate, and moderately advanced hydronephroses, but not in the very advanced cases. The histopathological changes were mainly tubular, but some cases showed proliferative changes in the glomeruli. Eradication of urinary Bilharziasis and early treatment of this disease would markedly contribute to the prevention of obstructive nephropathies in countries where this disease is endemic.

Neuroleptic malignant syndrome occurring in a suspected case of systemic lupus erythematosus.

The case of a 40 year old female patient of SLE who developed fatal neuroleptic malignant syndrome following administration of serenase (haloperidol) is reported. Relevant literature has been reviewed.

Unilateral inter-nuclear ophthalmoplegia in systemic lupus erythematosus.

We report a case of a 14 year old girl with SLE who developed neurological involvement in the form of posterior internuclear ophthalmoplegia (pINO). An MRI showed lesion involving pons which corroborated with the pINO.

Adrenal histoplasmosis.

A 60 year old diabetic was admitted with the history of low grade fever and weight loss of six weeks duration. After investigations, he was detected to have bilateral adrenal masses which on biopsy proved to be due to histoplasmosis. He was treated with itraconazole and made complete recovery.

Prevalence of antibodies to hepatitis C virus in hemodialysis patients and renal transplant recipients.

This work was carried out to study the prevalence of hepatitis C virus (HCV) infection, its associated risk factors and possible routes of transmission in hemodialysis patients and renal transplant recipients. Ninety five patients and 15 normal controls were included in this study. Patients were classified into 3 groups: Group I (64 hemodialysis patients), Group II (16 renal transplant recipients) and Group III (15 patients with chronic renal insufficiency on conservative treatments). Each individual was subjected to full clinical examination, estimation of serum alanine aminotransferase (ALT), testing for antibodies to hepatitis C virus (anti-HCV), screening for hepatitis B surface antigen (HBsAg), antibodies to hepatitis B surface antigen (anti-HBs) and core antigen (anti-HBc) by modified ELISA technique. Anti-HCV was found in 87.5% of hemodialysis patients, 81.25% of renal transplant patients, 53.3% of the conservative group and in 13.3% of the control group. There was a significant correlation between the presence of anti-HCV and the duration on dialysis in groups I and II (p < 0.05), while no significant correlation was detected between HCV positive cases and the number of units of transfused blood in groups I and II (p > 0.05). Serum ALT was elevated in patients with HCV infection, but there was no significant correlation between the presence of anti-HCV and elevated ALT level among the examined groups of patients (p > 0.05). The prevalence of HCV infection was not correlated with the duration of renal transplantation and the type of immunosuppressive therapy (p > 0.05). Coinfection with HBV and HCV could occur, as previous infection with HBV was demonstrated. Anti-HBc was found in 51.8%, 66.7%, 37.5% of anti-HCV positive patients in groups I, II, II respectively. Anti-HBs was detected in 24.1% and 15.4% of anti-HCV positive in groups I and II. HBsAg was found only in 4.7% of anti-HCV positive hemodialysis.

Skin deep: from dermal fibroblasts to pancreatic beta cells.

Type I diabetes (T1D) is a chronic autoimmune disease caused by pancreatic ß-cell destruction induced by autoantibodies and autoreactive T cells. After significant reduction of the ß-cell mass, diabetes sets in and can cause significant complications. It is estimated that more than 3 million Americans have T1D, and its prevalence among young individuals is progressively rising; however, the reasons for this increase are not known. Islet transplantation is recognized as the ultimate cure for T1D, but unfortunately, the severe scarcity of available islets makes it necessary to establish alternative sources of ß-cells. Our lab seeks to establish human-induced pluripotent stem cells as an unlimited, novel source of insulin-producing cells (IPCs) that are patient-specific, obviating the requirement for immunosuppression. Although several reports have emerged demonstrating successful derivation of IPCs from human pluripotent stem cells, the efficiencies of derivation are inadequate and these IPCs do not respond to glucose stimulation in vitro. We reasoned that the use of a growth factor sequestering bioscaffold and promotion of cell-cell signaling through 3D clustering would enhance the generation of functionally superior IPCs compared to those derived by 2D differentiation. Here, we discuss a novel 3D platform for the generation of highly efficient human IPCs.