bluuebunny/crossref_metadata_2025_split huggingface dataset:
Circulating tumor DNA (ctDNA) to detect neuroendocrine prostate cancer genomic and DNA methylation changes.
Authors: Beltran Himisha , Romanel Alessandro , Conteduca Vincenza , Casiraghi Nicola , Sigouros Michael , Franceschini Gian Marco , Fedrizzi Tarcisio , Ku sheng-Yu , Alonso Alicia , Mosquera Juan Miguel , Dann Emma , Sboner Andrea , Xiang Jenny , Elemento Olivier , Nanus David M. , Tagawa Scott T. , Benelli Matteo , Demichelis Francesca 
Published: February 2020

8 Background: Loss of androgen receptor signaling dependence occurs in approximately 20% of treatment resistant prostate cancers, and this may manifest as transformation to castration resistant neuroendocrine prostate cancer (CRPC-NE). The diagnosis of CRPC-NE relies on a metastatic tumor biopsy, which is invasive for patients. Here we study ctDNA as an approach to identify CRPC-NE-associated genomic and epigenomic changes. We also use this as a tool to understand tumor heterogeneity and clonal dynamics that occurs during CRPC-NE progression. Methods: 64 patients with metastatic prostate cancer (10 hormone naive, 35 castration resistant adenocarcinoma (CRPC-Adeno), 17 CRPC-NE) were prospectively enrolled for matched metastatic biopsy and blood collection. Twenty-four had multiple time-points, for total of 69 plasma and 98 metastatic tissues. Whole exome sequencing (WES) and whole genome bisulfite sequencing(of subset) of ctDNA,germline DNA, and metastatic biopsies were performed. Results: Overall there was high concordance of alterations between ctDNA and patient-matched metastasis, though this was highest in CRPC-NE. There was also less heterogeneity across patients with CRPC-NE. Alteration frequencies were consistent with published tissue-based studies with AR alterations enriched in CRPC-Adeno and TP53and RB1loss enriched in CRPC-NE ctDNA. The prognostic significance of these alterations differed based on histologic subtype. Allele-specific copy number analysis and serial sampling allowed for the detection and tracking of clonal and subclonal tumor cell populations. cfDNA methylation was reflective of methylation patterns in biopsies and detected CRPC-NE-associated epigenetic changes.A targeted set combining genomic ( TP53, RB1, CYLD, AR) and epigenomic(20 differential DNA methylation sites) was capable of identifying patients with CRPC-NE. Conclusions: WES and whole genome methylation of ctDNA is feasible, concordant with biopsy tissues, and identifies the spectrum and frequency of CRPC-NE genomic and epigenomic changes. A targeted panel extended and validated in larger cohorts could potentially improve the detection of CRPC-NE using non-invasive ctDNA profiling.
Phase II trial of monoamine oxidase inhibitor phenelzine in biochemical recurrent prostate cancer.
Authors: Gross Mitchell E. , Agus David B. , Dorff Tanya B. , Pinski Jacek K. , Quinn David I. , Castellanos Olga O. , Gilmore Patrick O. , Shih Jean 
Published: February 2020

94 Background: Monoamine oxidase A (MAOA) influences prostate cancer growth and metastasis in pre-clinical models. We examined effects of phenelzine (a monoamine oxidase inhibitor) in patients with biochemical recurrent castrate-sensitive prostate cancer. Methods: An open-label single arm clinical trial enrolled subjects with biochemical recurrent prostate cancer defined by: PSA ≥ 0.4 ng/ml (post-prostatectomy) or PSA ≥ 2 ng/ml above nadir (post-radiation therapy); no evidence of metastasis on imaging; and normal androgen levels. Subjects received phenelzine 30 mg orally twice daily. Mood symptoms were assessed with the hospital anxiety depression score (HADS) questionnaire. The primary endpoint was the proportion of patients who achieved a PSA decline of ≥50% from baseline. Results: Characteristics of the 20 eligible patients enrolled included: mean ± SD age 66.9 ± 4.8 years and PSA 4.7 ± 5.8 ng/dl. Maximal PSA declines ≥ 30% and ≥ 50% were observed in 25% (n=5/20) and 10% (n=2/20) of subjects, respectively. At 12 weeks, 17 subjects remained on treatment with PSA declines ≥ 30% and ≥ 50% of 24% (n=4/17) and 6% (n=1/17), respectively. Common toxicities observed included dizziness (grade 1 = 45%, grade 2= 35%), hypertension (grade ≥ 2 =30%), and edema (grade 1=25%, grade 2=10%). There was 1 episode of grade 4 hypertension (cycle 4) and 2 episodes of grade 3 syncope (cycle 12 and cycle 14) requiring treatment discontinuation. HADS questionnaires demonstrated a significant decrease in anxiety with no change in depressive symptoms on treatment. Conclusions: Phenelzine demonstrated efficacy in patients with biochemical recurrent castrate sensitive prostate cancer. Most treatment related toxicities were mild, but rare significant and reversible cardiovascular toxicities were observed. Therapies directed at MAOA may represent a new avenue for treatment in patients with recurrent prostate cancer. Clinical trial information: NCT02217709.
A phase III randomized, placebo-controlled, double-blind study of niraparib plus abiraterone acetate and prednisone versus abiraterone acetate and prednisone in patients with metastatic prostate cancer (NCT03748641).
Authors: Chi Kim N. , Rathkopf Dana E. , Attard Gerhardt , Smith Matthew Raymond , Efstathiou Eleni , Olmos David , Small Eric Jay , Lee Ji Youl , Sieber Paul R. , Dunshee Curtis , Ricci Deborah S. , Simon Jason S. , Zhao Xin , Kothari Nishi , Cheng Shinta , Sandhu Shahneen Kaur 
Published: February 2020

TPS257 Background: Preclinical data suggest synergistic antitumor activity when the PARP inhibitor (PARPi) niraparib is combined with the androgen pathway inhibitor abiraterone acetate. (1) The addition of a PARPi to abiraterone acetate plus prednisone (AAP) showed improved radiographic progression-free survival (rPFS) vs AAP alone in patients with mCRPC regardless of DNA repair gene defect (DRD) status. (2) Interim results from a phase 1 study support safety and tolerability of niraparib 200 mg combined with AAP in patients with mCRPC. (3) The objective of this Phase 3 study is to compare the efficacy and safety of niraparib plus AAP versus AAP with placebo as first-line therapy for mCRPC. Methods: This ongoing multicenter MAGNITUDE study will open in 300 sites across 28 countries and will enroll patients with mCRPC who have not received treatment in the metastatic castrate resistant setting other than ongoing androgen deprivation therapy [ADT] and ≤4 months of AAP. The DRD positive cohort (Cohort 1, n=400) will comprise patients whose tumors have DRD, as determined by a previously validated plasma or tissue assay. The cohort without DRD (Cohort 2, n=600) will enroll patients whose tumors are not found to have DRD. Enrollment began in February 2019. The primary objective of the study is to compare radiographic progression-free survival (rPFS) as assessed by blinded independent central radiology review for patients treated with niraparib and AAP versus placebo and AAP. To test superiority of the combination vs AAP, sample sizes were estimated to provide 92% power to detect HR≤0.65 rPFS in the DRD positive cohort and 94% power to detect HR≤0.67 in rPFS in the cohort without DRD, both at a 2-tailed level of significance of 0.05. The main secondary objectives are time to symptomatic progression, time to cytotoxic chemotherapy, and overall survival. Safety and pharmacokinetic profiles will be evaluated.1) Rajendra N, et al. Cancer Res 2019;79 (13 Suppl): Abstract nr 2134. 2) Clarke N, et al. Lancet Oncol. 2018;(7):975-986. 3) Saad, et al. Ann Oncol, 2018;29 (suppl 8), mdy284.043, https://doi.org/10.1093/annonc/mdy284.043 ). Clinical trial information: NCT03748641.
VISION: An international, prospective, open-label, multicenter, randomized phase III study of 177Lu-PSMA-617 in the treatment of patients with progressive PSMA-positive metastatic castration-resistant prostate cancer (mCRPC).
Authors: Sartor A. Oliver , Morris Michael J. , Messman Richard , Krause Bernd J. 
Published: February 2020

TPS259 Background: The novel therapeutic drug 177Lu-PSMA-617 is a prostate-specific membrane antigen (PSMA) targeting agent that is used to deliver radionuclide therapy for the treatment of patients with mCRPC. Based on preclinical data that demonstrated high PSMA binding affinity and internalization, prolonged tumor uptake, rapid kidney clearance, and high tumor-to-background ratio, 177Lu-PSMA-617 proceeded into clinical development. Preliminary clinical data indicates that 177Lu-PSMA-617 may demonstrate clinical benefit in patients with mCRPC in a setting where patients had no clear standard of care. VISION (NCT03511664) is a phase 3 study designed to assess the efficacy of 177Lu-PSMA-617 in patients with PSMA-positive mCRPC. Methods: Patients were randomized 2:1 to receive best standard of care with or without 177Lu-PSMA-617. Eligibility criteria were: PSMA expressing tumor assessed by PSMA positron emission tomography imaging; prior exposure to a taxane and a novel androgen axis inhibitor (NAAI). The primary objective of this study is to compare the two alternative endpoints of progression-free survival (rPFS) and overall survival (OS). Stratification factors include lactate dehydrogenase, liver metastasis, ECOG PS, and use of an NAAI at time of randomization. On active treatment, median OS is assumed to be 13.7 months with a hazard ratio (HR) of 0.7306, and rPFS is assumed to be 6 months with an HR of 0.67. Enrollment began in June 2018 and the target of 814 patients has been reached. Clinical trial information: NCT03511664.
A phase II study of onvansertib in combination with abiraterone and prednisone in patients with metastatic castration-resistant prostate cancer (mCRPC).
Authors: Einstein David Johnson , Choudhury Atish Dipankar , Saylor Philip James , Werner Lillian , Erlander Mark G. , Ridinger Maya , Bubley Glenn 
Published: February 2020

TPS266 Background: Metastatic CRPC remains a leading cause of cancer-related deaths worldwide. Although abiraterone (abi) in either the castration-sensitive or castration-resistant setting increases survival, resistance is universal and generally occurs within 9-16 months of initiating treatment. Polo-like kinase 1 (PLK1) is a serine/threonine protein kinase that regulates mitotic functions and progression, and it is highly upregulated in prostate cancer following castration. PLK1 inhibition enhances the efficacy of abi in cell line models and patient-derived tumor xenografts via several mechanisms. Onvansertib (PCM-075; Trovagene, Inc.) is the first orally available PLK1-specific inhibitor. In phase 1 testing, onvansertib demonstrated a manageable safety profile, with transient and reversible hematologic effects. Methods: The goal of this phase 2 study (NCT03414034) is to observe the effects of onvansertib in combination with abi + prednisone on disease control, as assessed by prostate-specific antigen (PSA) decline or stabilization after 12 weeks of study treatment, in subjects with mCRPC and early resistance to abi. Patients will be enrolled at time of PSA progression while on standard abi. A safety lead-in phase has been completed at one dosing schedule (24 mg/m2 on days 1-5 of a 21-day cycle) and is ongoing at a second dosing schedule (18 mg/m2 on days 1-5 of a 14-day cycle). Expansion phases are ongoing on both arms. In addition, a more continuous dosing schedule has been proposed (12 mg/m2 on days 1-14 of a 21-day cycle). With 32 patients in each arm, there will be 90% power to detect a change in disease-control rate from 10% (null) to 30% (alternative). Based on a Simon’s two-stage optimal design, the study will terminate early if <2 of the first 13 patients achieve disease control. Exploratory analyses include evaluation of the presence of the androgen receptor variant 7 (AR-V7) and other genomic alterations in circulating tumor cells and circulating tumor DNA that may be associated with response to treatment. Clinical trial information: NCT03414034.
Phase II trial of a DNA vaccine encoding prostatic acid phosphatase (pTVG-HP) and nivolumab (Nivo) in patients (pts) with nonmetastatic, PSA-recurrent prostate cancer (PCa).
Authors: Emamekhoo Hamid , Kyriakopoulos Christos , Liu Glenn , McNeel Douglas G. 
Published: February 2020

TPS273 Background: Radical prostatectomy (RP) and radiation therapy (RT) are the gold standard, curative intent treatment for pts with presumed organ-confined PCa. However, about one third of these pts will have progressive or metastatic disease at 10 years (yr). Pts with PSA recurrence without radiographic evidence of metastatic (m) PCa (stage M0) will ultimately develop radiographically apparent mPCa within a median of 8 yr. Pts with rapid PSA doubling time (DT) have a markedly shorter time to mPCa and death. Utilizing an immunotherapeutic approach could utilize the sensitivity and specificity of the immune system to treat microscopic disease and potentially avoid or postpone androgen deprivation therapy (ADT) and its unwanted side effects. Methods: In this single arm, two-stage phase II trial, a total of 21-41 PCa pts with PSA only progression (4 rising PSA with final PSA ≥ 2 ng/mL) after initial RP for presumed organ-confined disease who have no radiographic evidence of mPCa in conventional imaging (CT and bone scan) will be enrolled. Pts with small cell or other variant PCa, or history of ADT other than concurrent with RT are excluded. All pts will be treated with pTVG-HP 100 μg intradermally (id) and Nivo 240 mg IV every (Q) 2 weeks (w) x6, and then pTVG-HP 100 μg id and Nivo 480 mg IV Q4w x9 beginning w12 on study. Pts with PSA on w4 > PSA on day 1 will additionally receive rhGM-CSF 208 μg id, as a vaccine adjuvant, Q2w x4 beginning w4 on study. Pts will be treated until progression or up to a total of 1 yr. Response will be monitored by CT and bone scan Q6 months or as clinically indicated. Primary endpoints are safety and tolerability of this combination and PSA complete response rate (PSA < 0.2 ng/mL). Key secondary endpoints are 2-yr metastasis-free survival, median radiographic progression-free survival, PSA response rate (≤50% of baseline), and changes in PSA DT. Elicited antigen-specific T-cell and/or IgG response and its correlation with PSA response will be explored. Bone mets not detected by conventional imaging and their association with response will be evaluated by Quantitative Total Bone Imaging (QTBI) by NaF PET/CT. Updated enrollment will be presented. Clinical trial information: NCT03600350.
Phase II trial of cytoreductive stereotactic hypofractionated radiotherapy with combination ipilimumab/nivolumab for metastatic kidney cancer (CYTOSHRINK).
Authors: Lalani Aly-Khan A. , Swaminath Anand , Pond Gregory Russell , Kapoor Anil , Chu William , Bramson Jonathan L. , Surette Michael G. , Levine Mark Norman , Hotte Sebastien J. 
Published: February 2020

TPS761 Background: Randomized data from the interferon era demonstrated modest survival benefits of cytoreductive nephrectomy (CN) in patients with advanced renal cell carcinoma (aRCC). Results from SURTIME and CARMENA, conducted in the VEGF-targeted therapy era, have challenged the routine use of upfront CN especially in IMDC intermediate and poor risk patients. Furthermore, the treatment landscape in aRCC now includes first-line combination immunotherapy. Data from the Checkmate-214 trial showed that intermediate/poor risk patients have improved overall survival and objective response rate with ipilimumab and nivolumab (I/N) compared to sunitinib. Stereotactic body radiation therapy (SBRT) provides a convenient method for cytoreduction of the primary kidney lesion and may induce an ‘abscopal effect’, leading to enhanced systemic anti-tumour immune response. We hypothesize that SBRT to the primary kidney mass in aRCC patients will enhance the efficacy of I/N compared to standard of care I/N alone. Methods: This phase II trial randomizes untreated aRCC patients in a 2:1 fashion to I/N plus SBRT (30-40 Gy in 5 fractions) to the primary kidney mass between cycles 1 and 2 (experimental arm, E), versus standard of care I/N alone (standard arm, S). Eligible patients have biopsy-proven aRCC (any histology), IMDC intermediate/poor risk disease, and who decline or are unsuitable for CN. Patients with a primary kidney lesion ≥ 20cm, previous abdominal radiation precluding SBRT, or who have a contraindication to I/N are excluded. The primary objective is to compare the efficacy of I/N plus SBRT versus I/N alone, as determined by the hazard ratio for progression free survival (PFS). Secondary objectives include evaluation of safety, overall survival, objective response rate, and health-related quality of life. Exploratory analyses include blood immune signatures and stool microbiome. Up to 78 patients will be enrolled under the assumption of an improved 12-month PFS from 50% (S) to 75% (E), using a two-sided α=0.1, power=80%, and accounting for loss-to-follow-up and stratification using IMDC criteria 1-2 vs 3-6. Clinical trial information: NCT04090710.
Twice as High Diet-Induced Thermogenesis After Breakfast vs Dinner On High-Calorie as Well as Low-Calorie Meals
Authors: Richter Juliane , Herzog Nina , Janka Simon , Baumann Thalke , Kistenmacher Alina , Oltmanns Kerstin M 
Published: February 2020

AbstractBackgroundThe question of whether there is daytime time variation in diet-induced thermogenesis (DIT) has not been clearly answered. Moreover, it is unclear whether a potential diurnal variation in DIT is preserved during hypocaloric nutrition.ObjectiveWe hypothesized that DIT varies depending on the time of day and explored whether this physiological regulation is preserved after low-calorie compared with high-calorie intake.DesignUnder blinded conditions, 16 normal-weight men twice underwent a 3-day in-laboratory, randomized, crossover study. Volunteers consumed a predetermined low-calorie breakfast (11% of individual daily kilocalorie requirement) and high-calorie dinner (69%) in one condition and vice versa in the other. DIT was measured by indirect calorimetry, parameters of glucose metabolism were determined, and hunger and appetite for sweets were rated on a scale.ResultsIdentical calorie consumption led to a 2.5-times higher DIT increase in the morning than in the evening after high-calorie and low-calorie meals (P &lt; .001). The food-induced increase of blood glucose and insulin concentrations was diminished after breakfast compared with dinner (P &lt; .001). Low-calorie breakfast increased feelings of hunger (P &lt; .001), specifically appetite for sweets (P = .007), in the course of the day.ConclusionsDIT is clearly higher in the morning than in the evening, irrespective of the consumed calorie amount; that is, this physiological rhythmicity is preserved during hypocaloric nutrition. Extensive breakfasting should therefore be preferred over large dinner meals to prevent obesity and high blood glucose peaks even under conditions of a hypocaloric diet.
Health-related Quality of Life of Nurses Working in Tertiary Care Hospital of Karachi
Authors: Ali Amjad , Rasheed Abdur , Naz Subia 
Published: February 2020

Objective: The aim of this study was to assess nurses’ health-related quality of life.
Methods: This cross-sectional analytical study was accomplished among 154 nurses. Data were collected from two tertiary care hospitals of Karachi. Consent was taken prior to data collection from every participant. Questionnaire Short Form Health Survey-26 (SF-26) and Patients Health Questionnaire-9(PHQ-9) were used as a study tool. Data were analyzed through SPSS version 21.
Results: ANOVA and T-test confirmed that energy/fatigue domain differed significantly with level of education, duty shift and monthly income with p-values 0.025, 0.001 and 0.006 respectively. It was observed that mean scores of physical functioning, role limitation due to physical health and pain domains differ significantly between depressive and non-depressive participants, with p-values 0.045, 0.01 and 0.005 respectively.
Conclusions: Health related quality of life differs in comparison of physical health domain with depressive and non-depressive nurses. Only energy/fatigue domain was significantly associated with level of education, duty shift and monthly income of nurses.
doi: https://doi.org/10.12669/pjms.36.3.1267
How to cite this:Ali A, Rasheed A, Naz S. Health-related Quality of Life of Nurses Working in Tertiary Care Hospital of Karachi. Pak J Med Sci. 2020;36(3):490-495. doi: https://doi.org/10.12669/pjms.36.3.1267
This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
The early outcome of primary anterior sagittal approach for low anorectal malformations in female patients
Authors: Zamir Naima , Rasool Naima 
Published: February 2020

Objective: To document our experience of the primary anterior sagittal anorectoplasty (ASARP) in female patients with lower and wide fistula in term of the early post operative outcome.
Methods: A retrospective descriptive study was conducted in one surgical unit of the National Institute of Child Health Karachi, from January 2010 to April 2018. The study included female patients with diagnosis of imperforate anus with wide Vestibular or Perineal fistula with minimal or no straining during defecation and no excoriation of perineum. All patients underwent primary ASARP. Data regarding the age of the patients, site of fistula, the difficulties in dissection, post operative complications, stoma and re-do ASARP needed, were documented. Wound assessment was done during hospital stay, at two weeks and then at three months after surgery. Outcome was documented in terms of complications of surgery and cosmetic appearance of perineum. Data was analyzed on SPSS version 20.
Results: A total of 70 patients underwent primary surgery, 48(68.57%) females had perineal fistula while 22(31.42%) had vestibular fistula. Age ranges between three months to 276 months with median of 6±39.73 months. No major injury to the rectal or vaginal wall occurred during surgical procedure. In early post-operative period, 12(17.14%) patients had wound infection with or without various extent of disruption. A total of seven (10.11%) patients underwent stoma formation, six (8.57%) patients because of wound disruption with in a week of primary surgery and in one patient due to severe anal stenosis and retraction of anal segment within three month follow up. Median hospital stay was 5±1.52 days. In 38(54.28%) paients complete wound healing occurred with no per or post operative complications. In 25(35.71%) patients, minor complications were noted and treated accordingly and results were labelled satisfactory with acceptable perineal appearance.
Conclusion: The single stage procedure can be a good choice for both vestibular and perineal fisula. In majority of cases wound heals completely with minimal or no scaring and give good cosmetic results.
doi: https://doi.org/10.12669/pjms.36.3.1503
How to cite this:Zamir N, Rasool N. The early outcome of primary anterior sagittal approach for low anorectal malformations in female patients. Pak J Med Sci. 2020;36(3):456-460. doi: https://doi.org/10.12669/pjms.36.3.1503
This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.