Publications by authors named "Priti Lal"

81 Publications

External validation of genomic classifier-based risk-stratification tool to identify candidates for adjuvant radiation therapy in patients with prostate cancer.

World J Urol 2021 Jan 3. Epub 2021 Jan 3.

VUI Center for Outcomes Research Analytics and Evaluation, Senior staff, Vattikuti Urology Institute (VUI), Henry Ford Hospital, 2799 W Grand Blvd, Detroit, MI, 48202-2689, USA.

Objective: To externally validate a Genomic Classifier (GC) based risk-stratification nomogram identifying candidates who would benefit from adjuvant radiation (aRT) therapy after radical prostatectomy (RP).

Methods: We identified 350 patients who underwent RP, between 2013 and 2018, and had adverse pathological features (positive margin, and/or pT3a or higher) on final pathology. Genomic profile was available for all these men. The clinical recurrence-free survival was estimated using the Kaplan-Meier method. The external validity of the nomogram was tested using the concordance index (c-index), calibration plot, and decision curve analysis.

Results: The median follow-up of the cohort was 26.5 months. Overall, 14% of the patients received aRT. During the follow-up period, 3.4% of the patients developed metastasis. Overall 3-year metastasis-free survival was 95% (95% CI 0.92-0.98). The c-index of the nomogram was 0.84. The calibration of the model was favorable. Decision-curve analysis showed a positive net benefit for probabilities ranging between 0.01 and 0.09, with the highest difference at threshold probability around 0.05. At that threshold, the net benefit is 0.06 for the model and 0 for treating all the patients.

Conclusion: Our report is the first to confirm the validity of this genomic-based risk-stratification tool in identifying men who might benefit from aRT after RP. As such, it can be a useful instrument to be incorporated in shared decision making on whether administration of aRT will lead to a clinically meaningful benefit. Such a model can also be useful for patients' classification in future clinical trials.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00345-020-03540-1DOI Listing
January 2021

A novel imaging based Nomogram for predicting post-surgical biochemical recurrence and adverse pathology of prostate cancer from pre-operative bi-parametric MRI.

EBioMedicine 2021 Jan 13;63:103163. Epub 2020 Dec 13.

Center for Computational Imaging and Personalized Diagnostics, Case Western Reserve University, Cleveland, OH, USA; Louis Stokes Cleveland Veterans Administration Medical Center, USA. Electronic address:

Background: We developed and validated an integrated radiomic-clinicopathologic nomogram (RadClip) for post-surgical biochemical recurrence free survival (bRFS) and adverse pathology (AP) prediction in men with prostate cancer (PCa). RadClip was further compared against extant prognostics tools like CAPRA and Decipher.

Methods: A retrospective study of 198 patients with PCa from four institutions who underwent pre-operative 3 Tesla MRI followed by radical prostatectomy, between 2009 and 2017 with a median 35-month follow-up was performed. Radiomic features were extracted from prostate cancer regions on bi-parametric magnetic resonance imaging (bpMRI). Cox Proportional-Hazards (CPH) model warped with minimum redundancy maximum relevance (MRMR) feature selection was employed to select bpMRI radiomic features for bRFS prediction in the training set (D, N = 71). In addition, a bpMRI radiomic risk score (RadS) and associated nomogram, RadClip, were constructed in D and then compared against the Decipher, pre-operative (CAPRA), and post-operative (CAPRA-S) nomograms for bRFS and AP prediction in the testing set (D, N = 127).

Findings: "RadClip yielded a higher C-index (0.77, 95% CI 0.65-0.88) compared to CAPRA (0.68, 95% CI 0.57-0.8) and Decipher (0.51, 95% CI 0.33-0.69) and was found to be comparable to CAPRA-S (0.75, 95% CI 0.65-0.85). RadClip resulted in a higher AUC (0.71, 95% CI 0.62-0.81) for predicting AP compared to Decipher (0.66, 95% CI 0.56-0.77) and CAPRA (0.69, 95% CI 0.59-0.79)."

Interpretation: RadClip was more prognostic of bRFS and AP compared to Decipher and CAPRA. It could help pre-operatively identify PCa patients at low risk of biochemical recurrence and AP and who therefore might defer additional therapy.

Funding: The National Institutes of Health, the U.S. Department of Veterans Affairs, and the Department of Defense.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ebiom.2020.103163DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7744939PMC
January 2021

TMPRSS2-ERG fusion impacts anterior tumor location in men with prostate cancer.

Prostate 2021 Feb 3;81(2):109-117. Epub 2020 Nov 3.

Dana Farber Cancer Institute and Harvard TH Chan School of Public Health, Boston, Massachusetts, USA.

Background: In prostate cancer (PCa), lack of androgen receptor (AR) regulated TMPRSS2-ETS-related gene (ERG) gene fusion (ERG ) status has been associated with African American race; however, the implications of ERG status for the location of dominant tumors within the prostate remains understudied.

Methods: An African American-enriched multiinstitutional cohort of 726 PCa patients consisting of both African American men (AAM; n = 254) and European American men (EAM; n = 472) was used in the analyses. Methods of categorical analysis were used. Messenger RNA (mRNA) expression differences between anterior and posterior tumor lesions were analyzed using Wilcoxon rank-sum tests with multiple comparison corrections.

Results: Anti-ERG immunohistochemistry staining showed that the association between ERG status and anterior tumors is independent of race and is consistently robust for both AAM (ERG 81.4% vs. ERG 18.6%; p = .005) and EAM (ERG 60.4% vs. ERG 39.6%; p < .001). In a multivariable model, anterior tumors were more likely to be IHC-ERG (odds ratio [OR]: 3.20; 95% confidence interval [CI]: 2.14-4.78; p < .001). IHC-ERG were also more likely to have high-grade tumors (OR: 1.73; 95% CI: 1.06-2.82; p = .02). In the exploratory genomic analysis, mRNA expression of location-dependent genes is highly influenced by ERG status and African American race. However, tumor location did not impact the expression of AR or the major canonical AR-target genes (KLK3, AMACR, and MYC).

Conclusions: ERG tumor status is the strongest predictor of anterior prostate tumors, regardless of race. Furthermore, AR expression and canonical AR signaling do not impact tumor location.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/pros.24086DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7810127PMC
February 2021

Circulating Donor Heart Exosome Profiling Enables Noninvasive Detection of Antibody-mediated Rejection.

Transplant Direct 2020 Nov 19;6(11):e615. Epub 2020 Oct 19.

Division of Cardiac Surgery, Department of Surgery, Yale University School of Medicine, New Haven, CT.

Background: Endomyocardial biopsy remains the gold standard for distinguishing types of immunologic injury-acute versus antibody-mediated rejection (AMR). Exosomes are tissue-specific extracellular microvesicles released by many cell types, including transplanted heart. Circulating transplant heart exosomes express donor-specific human leukocyte antigen (HLA) I molecules. As AMR is mediated by antibodies to donor HLAs, we proposed that complement deposition that occurs with AMR at tissue level would also occur on circulating donor heart exosomes.

Methods: Plasma exosomes in 4 patients were isolated by column chromatography and ultracentrifugation. Donor heart exosomes were purified using anti-donor HLA I antibody beads and complement C4d protein expression was assessed in this subset as marker for AMR.

Results: Three patients had no rejection episodes. Circulating donor heart exosomes showed troponin protein and mRNA expression at all follow-up time points. One patient developed AMR on day 14 endomyocardial biopsy that was treated with rituximab, IVIG/plasmapheresis. Time-specific detection of C4d protein was seen in donor heart exosome subset in this patient, which resolved with treatment. C4d was not seen in other 3 patients' donor exosomes.

Conclusions: Anti-donor HLA I specificity enables characterization of circulating donor heart exosomes in the clinical setting. Further characterization may open the window to noninvasively diagnose rejection type, such as AMR.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/TXD.0000000000001057DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7575166PMC
November 2020

Comparative Genomics Reveals Distinct Immune-oncologic Pathways in African American Men with Prostate Cancer.

Clin Cancer Res 2021 Jan 9;27(1):320-329. Epub 2020 Oct 9.

Department of Cancer Epidemiology, H Lee Moffitt Cancer Center & Research Institutes, Tampa, Florida.

Purpose: The role of immune-oncologic mechanisms of racial disparities in prostate cancer remains understudied. Limited research exists to evaluate the molecular underpinnings of immune differences in African American men (AAM) and European American men (EAM) prostate tumor microenvironment (TME).

Experimental Design: A total of 1,173 radiation-naïve radical prostatectomy samples with whole transcriptome data from the Decipher GRID registry were used. Transcriptomic expressions of 1,260 immune-specific genes were selected to assess immune-oncologic differences between AAM and EAM prostate tumors. Race-specific differential expression of genes was assessed using a rank test, and intergene correlational matrix and gene set enrichment was used for pathway analysis.

Results: AAM prostate tumors have significant enrichment of major immune-oncologic pathways, including proinflammatory cytokines, IFNα, IFNγ, TNFα signaling, ILs, and epithelial-mesenchymal transition. AAM TME has higher total immune content score (ICS) compared with 0 (37.8% vs. 21.9%, = 0.003). AAM tumors also have lower DNA damage repair and are genomically radiosensitive as compared with EAM. (IFN-inducible transmembrane protein 3) was one of the major proinflammatory genes overexpressed in AAM that predicted increased risk of biochemical recurrence selectively for AAM in both discovery [HR = 2.30; 95% confidence interval (CI), 1.21-4.34; = 0.01] and validation (HR = 2.42; 95% CI, 1.52-3.86; = 0.0001) but not in EAM.

Conclusions: Prostate tumors of AAM manifest a unique immune repertoire and have significant enrichment of proinflammatory immune pathways that are associated with poorer outcomes. Observed immune-oncologic differences can aid in a genomically adaptive approach to treating prostate cancer in AAM.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1158/1078-0432.CCR-20-2925DOI Listing
January 2021

Practice patterns related to prostate cancer grading: results of a 2019 Genitourinary Pathology Society clinician survey.

Urol Oncol 2020 Sep 15. Epub 2020 Sep 15.

Departments of Pathology, The Johns Hopkins Medical Institutions, Baltimore, MD; Departments of Urology and Oncology, The Johns Hopkins Medical Institutions, Baltimore, MD.

Purpose: To survey urologic clinicians regarding interpretation of and practice patterns in relation to emerging aspects of prostate cancer grading, including quantification of high-grade disease, cribriform/intraductal carcinoma, and impact of magnetic resonance imaging-targeted needle biopsy.

Materials And Methods: The Genitourinary Pathology Society distributed a survey to urology and urologic oncology-focused societies and hospital departments. Eight hundred and thirty four responses were collected and analyzed using descriptive statistics.

Results: Eighty percent of survey participants use quantity of Gleason pattern 4 on needle biopsy for clinical decisions, less frequently with higher Grade Groups. Fifty percent interpret "tertiary" grade as a minor/<5% component. Seventy percent of respondents would prefer per core grading as well as a global/overall score per set of biopsies, but 70% would consider highest Gleason score in any single core as the grade for management. Seventy five percent utilize Grade Group terminology in patient discussions. For 45%, cribriform pattern would affect management, while for 70% the presence of intraductal carcinoma would preclude active surveillance.

Conclusion: This survey of practice patterns in relationship to prostate cancer grading highlights similarities and differences between contemporary pathology reporting and its clinical application. As utilization of Gleason pattern 4 quantification, minor tertiary pattern, cribriform/intraductal carcinoma, and the incorporation of magnetic resonance imaging-based strategies evolve, these findings may serve as a basis for more nuanced communication and guide research efforts involving pathologists and clinicians.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.urolonc.2020.08.027DOI Listing
September 2020

PD-L1 Positivity Associated With Presence of Tertiary Lymphoid Structures and High-Stage Disease in Upper Tract Urothelial Carcinoma.

Am J Clin Pathol 2020 11;154(6):802-810

Department of Pathology and Laboratory Medicine, Hospital of the University of Pennsylvania, Philadelphia.

Objectives: Persistent antigen exposure leads to the accumulation of lymphocytes and subsequent tertiary lymphoid structures (TLS). We investigated the relationship of tumor microenvironment (TME) with respect to programmed death ligand 1 (PD-L1), its receptor programmed death 1 (PD-1), and TLS in upper tract urothelial carcinoma (UTUC) cases and compared them with UTUC associated with urothelial bladder carcinoma (UTUC-BCa).

Methods: We retrospectively identified 72 patients with UTUC. Representative slides were reviewed, and TLS were counted. Immunohistochemical stains for PD-1 and PD-L1 were performed. PD-1-positive lymphocytes were counted and H-score for PD-L1-positive membranous staining was determined.

Results: PD-L1 expression in the tumor was present in 55.1% of the UTUC cases. Higher stage was associated with increased PD-L1 expression (P = .035). TLS were present in 33.3% and their presence was significantly associated with PD-L1 positivity (P = .024). This association remained significant after adjustment for UTUC-BCa. TLS were also associated with a greater number of infiltrating PD-1-positive lymphocytes (P = .013).

Conclusions: This study is one of the first comparative studies of the TME in UTUC and UTUC-BCa. PD-L1 is expressed in a subset of UTUC and is associated with TLS. The presence of TLS is an inherent characteristic of UTUC and not secondary to the presence of BCa.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/ajcp/aqaa105DOI Listing
November 2020

Urethral involvement is associated with higher mortality and local recurrence in vulvar melanoma: a single institutional experience.

Hum Pathol 2020 Oct 20;104:1-8. Epub 2020 Jul 20.

Department of Pathology and Laboratory Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, 19104, USA. Electronic address:

Vulvar malignant melanoma (VMM), although uncommon, comprises 5-10% of all vulvar malignancies. Local control is notoriously poor in VMM with recurrence rates of 30-50% compared with approximately 3% in cutaneous melanomas. We studied clinicopathologic features of 37 women with VMM, after reviewing three decades of clinical follow-up data in our institutional databases. Most patients were Caucasian (n = 35) with an average age at diagnosis of 60.6 years (range 23-83). The most common subtype was mucosal lentiginous melanoma (n = 25). We compared Kaplan-Meier survival curves of 31 patients defined by clinical and microscopic attributes using exact log-rank tests. Younger patients at diagnosis (23-64 years), those with thin melanomas (≤1 mm), and those with Clark's level II or III tumors had better 5-year survival rates than older patients (65-83 years) and those with thick melanomas (>1 mm) and those with Clark's level IV or V (P ≤ 0.05), respectively, by exact log-rank test. Local recurrence of melanoma occurred in 15 patients. Nine patients (24%) had eventual urethral involvement by malignant melanoma, and this feature was associated with significantly shorter survival (P = 0.036). Patients with urethral involvement had shorter median time to death and worse 5-year survival rates. Given that spread to the urethra is common in VMM and urethral recurrence is also associated with mortality, pathology excision specimens should be carefully reviewed with attention to urethral involvement as a potentially important prognostic factor.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.humpath.2020.07.017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7669565PMC
October 2020

Acquired Cystic Kidney Disease-associated Renal Cell Carcinoma (ACKD-RCC) Harbor Recurrent Mutations in KMT2C and TSC2 Genes.

Am J Surg Pathol 2020 11;44(11):1479-1486

Department of Pathology and Laboratory Medicine, Hospital of the University of Pennsylvania.

Individuals with acquired cystic kidney disease (ACKD) in the setting of end-stage renal disease (ESRD) have a high risk of developing renal cell carcinoma (RCC). ACKD-RCC is considered a distinct renal neoplasm in the International Society of Urologic Pathologists (ISUP)-World Health Organization (WHO) classification of kidney tumors which may behave aggressively. Since its original description, there have been multiple case reports and series published; however, the pathogenesis of this neoplasm is uncertain and there is limited data on the genetic aberrations of this tumor. Herein, we present our experience with ESRD kidneys, with emphasis on ACKD-RCC, associated cysts, and the somatic mutation analysis of a subset of ACKD-RCCs using next-generation sequencing. Our data on 59 cases with ESRD that underwent nephrectomy, shows that ACKD-RCC represents more than half of the tumors (25/46; 54%) developing in ESRD, followed by papillary RCC (13; 28%). History of dialysis, male sex, and African American race were potential risk factors for developing ACKD-RCCs. Further, ACKD-RCC-like cysts are possible precursors of RCCs in the ACKD setting noted in 40 of 46 (87%) cases with tumors. Next-generation sequencing analysis revealed recurrent mutations in the KMT2C gene in 4 of 5 ACKD-RCCs (80%), exclusively exhibiting cribriform "sieve-like" morphology; whereas the case negative for KMT2C mutations exhibited "type 2" papillary RCC morphology and lacked "sieve-like" growth pattern. Pathogenic mutations in TSC2 were the second common abnormality (3/5; 60%), often coexisting with KMT2C mutations. Deleterious mutations in additional genes such as CBL, PDGFRA, and SYNE1, etc. were noted but were nonrecurrent and always coexisted with mutations in KMT2C or TSC2. To conclude, our study highlights that mutations in a chromatin-modifying gene KMT2C may potentially be oncogenic drivers for the development of ACKD-RCC with classic sieve-like morphology. In addition, pathogenic mutations in TSC2 possibly play a role in the development of cysts/tumors in a subset of ACKD patients. If corroborated in larger cohorts, these findings would be useful in planning surveillance and early intervention in ESRD patients developing ACKD.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/PAS.0000000000001530DOI Listing
November 2020

The 2019 Genitourinary Pathology Society (GUPS) White Paper on Contemporary Grading of Prostate Cancer.

Arch Pathol Lab Med 2020 Jun 26. Epub 2020 Jun 26.

From the Departments of Pathology (Drs Epstein, DeMarzo, and Lotan), Urology (Dr Epstein), and Oncology (Dr Epstein), The Johns Hopkins Medical Institutions, Baltimore, Maryland; Department of Pathology and Laboratory Medicine and Urology, University of Tennessee Health Science, Memphis (Dr Amin); Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York (Dr Fine); Department of Pathology, Fundacio Puigvert, Barcelona, Spain (Dr Algaba); Department of Pathology, University of Southern California, Los Angeles (Dr Aron); Department of Pathology, Faculty of Medicine, Koç University, İstanbul, Turkey (Dr Baydar); Department of Pathology, Champalimaud Centre for the Unknown, Lisbon, Portugal (Dr Beltran); Department of Pathology, McGill University Health Center, Montréal, QC, Canada (Dr Brimo); Department of Pathology, Mayo Clinic, Rochester, Minnesota (Drs Cheville and Jimenez); Department of Pathology and Laboratory Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy (Dr Colecchia); Department of Pathology, Hôpital Tenon, Sorbonne University, Paris, France (Dr Comperat); Pathology Department, Rede D'OR-Sao Luiz, Sao Paulo, SP, Brazil (Dr da Cunha); Douglass Hanly Moir Pathology, Sydney, Australia (Dr Delprado); Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, Tennessee (Drs Giannico and Gordetsky); Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston (Dr Guo); Department of Pathology, Oregon Health and Science University, Portland (Dr Hansel); Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts (Dr Hirsch); Department of Pathology and Laboratory Medicine, David Geffen School of Medicine at UCLA, Los Angeles, California (Dr Huang); Department of Pathology, Yale School of Medicine, New Haven, Connecticut (Dr Humphrey); Department of Pathology and Laboratory Medicine and Urology, Weill Cornell Medicine, New York, New York (Drs Khani and Robinson); Department of Pathology, Qingdao Municipal Hospital, Qingdao, Shandong, China (Dr Kong); Departments of Pathology and Laboratory Medicine and Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, Florida (Dr Kryvenko); Department of Pathology, University of Michigan Medical School, Ann Arbor, Michigan (Drs Kunju and Mehra); Perelman School of Medicine, University of Pennsylvania, Philadelphia (Dr Lal); Department of Pathology, CHUM, Université de Montréal, Montréal, QC, Canada (Dr Latour); Douglass Hanly Moir Pathology, Faculty of Medicine and Health Sciences Macquarie University, North Ryde, Australia (Dr Maclean); Department of Pathology, The University of Alabama at Birmingham, Birmingham (Drs Magi-Galluzzi and Netto); Department of Surgical Pathology, Tata Memorial Hospital, Parel, Mumbai, India (Dr Menon); Departments of Pathology and Laboratory Medicine and Urology, University of Rochester Medical Center, Rochester, New York (Dr Miyamoto); Section of Pathological Anatomy, School of Medicine, Polytechnic University of the Marche Region, United Hospitals, Ancona, Italy (Dr Montironi); Robert J. Tomsich Pathology and Laboratory Medicine Institute, Cleveland Clinic, Cleveland, Ohio (Dr Nguyen); Department of Pathology, Emory University School of Medicine, Atlanta, Georgia (Dr Osunkoya); Department of Pathology, Ohio State University, Columbus (Drs Parwani and Zynger); Department for BioMedical Research, University of Bern, Bern, Switzerland (Dr Rubin); Department of Pathology, The University of Texas Southwestern Medical Center, Dallas (Dr Shah); Institute of Pathology, St Luke's Medical Center, Quezon City and Global City, Philippines (Dr So); Department of Pathology, The Jikei University School of Medicine, Tokyo, Japan (Dr Takahashi); Argos Laboratory, Federal University of Ceara, Fortaleza, Brazil (Dr Tavora); Department of Pathology, University of Washington School of Medicine, Seattle (Drs Tretiakova and True); Departments of Pathology and Laboratory Medicine and Urology, University of North Carolina, Chapel Hill (Dr Wobker); Department of Pathology, Northwestern University, Chicago, Illinois (Dr Yang); Department of Pathology, Tufts Medical Center, Boston, Massachusetts (Dr Zhou); and Department of Pathology and Laboratory Medicine, University of Calgary, Calgary, AB, Canada (Dr Trpkov). Dr Kong is currently located at Kaiser Permanente Sacramento Medical Center, Sacramento, California.

Context.—: Controversies and uncertainty persist in prostate cancer grading.

Objective.—: To update grading recommendations.

Data Sources.—: Critical review of the literature along with pathology and clinician surveys.

Conclusions.—: Percent Gleason pattern 4 (%GP4) is as follows: (1) report %GP4 in needle biopsy with Grade Groups (GrGp) 2 and 3, and in needle biopsy on other parts (jars) of lower grade in cases with at least 1 part showing Gleason score (GS) 4 + 4 = 8; and (2) report %GP4: less than 5% or less than 10% and 10% increments thereafter. Tertiary grade patterns are as follows: (1) replace "tertiary grade pattern" in radical prostatectomy (RP) with "minor tertiary pattern 5 (TP5)," and only use in RP with GrGp 2 or 3 with less than 5% Gleason pattern 5; and (2) minor TP5 is noted along with the GS, with the GrGp based on the GS. Global score and magnetic resonance imaging (MRI)-targeted biopsies are as follows: (1) when multiple undesignated cores are taken from a single MRI-targeted lesion, an overall grade for that lesion is given as if all the involved cores were one long core; and (2) if providing a global score, when different scores are found in the standard and the MRI-targeted biopsy, give a single global score (factoring both the systematic standard and the MRI-targeted positive cores). Grade Groups are as follows: (1) Grade Groups (GrGp) is the terminology adopted by major world organizations; and (2) retain GS 3 + 5 = 8 in GrGp 4. Cribriform carcinoma is as follows: (1) report the presence or absence of cribriform glands in biopsy and RP with Gleason pattern 4 carcinoma. Intraductal carcinoma (IDC-P) is as follows: (1) report IDC-P in biopsy and RP; (2) use criteria based on dense cribriform glands (>50% of the gland is composed of epithelium relative to luminal spaces) and/or solid nests and/or marked pleomorphism/necrosis; (3) it is not necessary to perform basal cell immunostains on biopsy and RP to identify IDC-P if the results would not change the overall (highest) GS/GrGp part per case; (4) do not include IDC-P in determining the final GS/GrGp on biopsy and/or RP; and (5) "atypical intraductal proliferation (AIP)" is preferred for an intraductal proliferation of prostatic secretory cells which shows a greater degree of architectural complexity and/or cytological atypia than typical high-grade prostatic intraepithelial neoplasia, yet falling short of the strict diagnostic threshold for IDC-P. Molecular testing is as follows: (1) Ki67 is not ready for routine clinical use; (2) additional studies of active surveillance cohorts are needed to establish the utility of PTEN in this setting; and (3) dedicated studies of RNA-based assays in active surveillance populations are needed to substantiate the utility of these expensive tests in this setting. Artificial intelligence and novel grading schema are as follows: (1) incorporating reactive stromal grade, percent GP4, minor tertiary GP5, and cribriform/intraductal carcinoma are not ready for adoption in current practice.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.5858/arpa.2020-0015-RADOI Listing
June 2020

Computationally Derived Image Signature of Stromal Morphology Is Prognostic of Prostate Cancer Recurrence Following Prostatectomy in African American Patients.

Clin Cancer Res 2020 04 5;26(8):1915-1923. Epub 2020 Mar 5.

Department of Biomedical Engineering, Case Western Reserve University, Cleveland, Ohio.

Purpose: Between 30%-40% of patients with prostate cancer experience disease recurrence following radical prostatectomy. Existing clinical models for recurrence risk prediction do not account for population-based variation in the tumor phenotype, despite recent evidence suggesting the presence of a unique, more aggressive prostate cancer phenotype in African American (AA) patients. We investigated the capacity of digitally measured, population-specific phenotypes of the intratumoral stroma to create improved models for prediction of recurrence following radical prostatectomy.

Experimental Design: This study included 334 radical prostatectomy patients subdivided into training (V, = 127), validation 1 (V, = 62), and validation 2 (V, = 145). Hematoxylin and eosin-stained slides from resected prostates were digitized, and 242 quantitative descriptors of the intratumoral stroma were calculated using a computational algorithm. Machine learning and elastic net Cox regression models were constructed using V to predict biochemical recurrence-free survival based on these features. Performance of these models was assessed using V and V, both overall and in population-specific cohorts.

Results: An AA-specific, automated stromal signature, AAstro, was prognostic of recurrence risk in both independent validation datasets [V: AUC = 0.87, HR = 4.71 (95% confidence interval (CI), 1.65-13.4), = 0.003; V: AUC = 0.77, HR = 5.7 (95% CI, 1.48-21.90), = 0.01]. AAstro outperformed clinical standard Kattan and CAPRA-S nomograms, and the underlying stromal descriptors were strongly associated with IHC measurements of specific tumor biomarker expression levels.

Conclusions: Our results suggest that considering population-specific information and stromal morphology has the potential to substantially improve accuracy of prognosis and risk stratification in AA patients with prostate cancer.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1158/1078-0432.CCR-19-2659DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7165025PMC
April 2020

Differences in PD-L1-Expressing Macrophages and Immune Microenvironment in Testicular Germ Cell Tumors.

Am J Clin Pathol 2020 02;153(3):387-395

Department of Anatomic Pathology, Hospital of the University of Pennsylvania, Philadelphia.

Objectives: To characterize the tumor microenvironment of testicular germ cell tumors (GCTs) using immunohistochemical markers.

Methods: Seventy-seven orchiectomies, including 36 nonmetastatic (NM) seminomas, 15 metastatic (M) seminomas, 13 nonmetastatic nonseminomatous germ cell tumors (NSGCTs), and 13 metastatic NSGCTs, were studied with PD-1, PD-L1, FOXP3, CD68, CD163, and mismatch repair (MMR) immunohistochemistry. FOXP3+ and PD-1+ tumor-infiltrating lymphocytes (TILs) and tumor-associated macrophages (TAMs) expressing CD68 and CD163 were enumerated. PDL-1 expression was evaluated on tumor cells and macrophages.

Results: GCTs primarily express PD-L1 on TAMs, except choriocarcinoma, where true tumor cell positivity was noted. Seminomas reveal increased intratumoral PD-L1+ TAMs compared with NSGCTs (P < .05). Activated TILs are increased in NM-seminomas compared with M-seminomas (P < .05). All GCTs retained MMR expression.

Conclusions: Robust PD-L1+ TAMs are significantly expanded in seminomas compared with NSGCTs. Among all GCTs, only choriocarcinoma cells reveal true positivity for PD-L1. These findings expand the realm of potentially targeted treatments for GCTs.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/ajcp/aqz184DOI Listing
February 2020

Long Term Outcomes of Intratympanic Dexamethasone in Intractable Unilateral Meniere's Disease.

Indian J Otolaryngol Head Neck Surg 2019 Nov 24;71(Suppl 2):1369-1373. Epub 2018 Jun 24.

3Department of Otorhinolaryngology, Dr. RML Hospital, New Delhi, India.

To evaluate the long term effect of Intratympanic dexamethasone in intractable Meniere's disease. 30 patients with refractory Meniere's disease which did not respond to the standard medical management, were treated with Intratympanic dexamethasone injections. Post treatment hearing outcome and dizziness scores were compared with the pretreatment values respectively. The mean dizziness handicap inventory (DHI) score was reduced from 91.58 (range 80-100) to be 31.00 ( = 0.00) at 3 months of treatment. With the successive follow-up periods, the mean DHI scores were reduced to 51.50, 46.6, and 50.90 at the end of, 6, 12, and 24 months ( = 0.04, 0.35, and 0.49 respectively). Again at the end of 24 months, 23.80% of patients were free of vertigo (= 0.01). No patient had improvement in the hearing (> 10 dB) in any of the follow-up periods and 6.6% demonstrated deterioration in hearing. There were no major intraoperative or postoperative complications detected. Intratympanic injection of steroid is a safe and effective method for treating intractable Meniere's disease. Although short term improvement in the vertigo is well documented, still in 23% of the patients were found to be free of vertigo at even the end of 24 months. There was no significant improvement in hearing noticed, either in short term or in long term.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s12070-018-1431-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6841822PMC
November 2019

Palaeolithic Diet in Diabesity and Endocrinopathies - A Vegan's Perspective.

Eur Endocrinol 2019 Aug 16;15(2):77-82. Epub 2019 Aug 16.

Department of Endocrinology, CEDAR Super-specialty Clinics New Delhi, India.

Introduction: The Palaeolithic diet is designed to resemble that of human hunter-gatherer ancestors thousands to millions of years ago. This review summarises the evidence and clinical application of this diet in various disorders. An empiric vegan variant of it has been provided, keeping in mind vegan food habits.

Review Of The Literature: different types of Palaeolithic diets in vogue include the 80/20, the autoimmune, the lacto, the Palaeolithic vegan and the Palaeolithic ketogenic. We have developed an Indian variant of the Palaeolithic vegan diet, which excludes all animal-based foods. The Palaeolithic diet typically has low carbohydrate and lean protein of 30-35% daily caloric intake in addition to a fibre diet from non-cereal, plant-based sources, up to 45-100 g daily. In different observational studies, beneficial effects on metabolic syndrome, blood pressure, glucose tolerance, insulin secretion, lipid profiles and cardiovascular risk factors have been documented with the Palaeolithic diet. Short-term randomised controlled trials have documented weight loss, and improved glycaemia and adipo-cytokine profiles. Few concerns of micronutrient deficiency (e.g. calcium) have been raised.

Conclusion: Initial data are encouraging with regard to the use of the Palaeolithic diet in managing diabesity. There is an urgent need for large randomised controlled trials to evaluate the role of the Palaeolithic diet with different anti-diabetes medications for glycaemic control and the reversal of type 2 diabetes.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.17925/EE.2019.15.2.77DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6785956PMC
August 2019

CDK7 Inhibition Suppresses Castration-Resistant Prostate Cancer through MED1 Inactivation.

Cancer Discov 2019 11 29;9(11):1538-1555. Epub 2019 Aug 29.

Department of Cancer Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.

Metastatic castration-resistant prostate cancer (CRPC) is a fatal disease, primarily resulting from the transcriptional addiction driven by androgen receptor (AR). First-line CRPC treatments typically target AR signaling, but are rapidly bypassed, resulting in only a modest survival benefit with antiandrogens. Therapeutic approaches that more effectively block the AR-transcriptional axis are urgently needed. Here, we investigated the molecular mechanism underlying the association between the transcriptional coactivator MED1 and AR as a vulnerability in AR-driven CRPC. MED1 undergoes CDK7-dependent phosphorylation at T1457 and physically engages AR at superenhancer sites, and is essential for AR-mediated transcription. In addition, a CDK7-specific inhibitor, THZ1, blunts AR-dependent neoplastic growth by blocking AR/MED1 corecruitment genome-wide, as well as reverses the hyperphosphorylated MED1-associated enzalutamide-resistant phenotype. , THZ1 induces tumor regression of AR-amplified human CRPC in a xenograft mouse model. Together, we demonstrate that CDK7 inhibition selectively targets MED1-mediated, AR-dependent oncogenic transcriptional amplification, thus representing a potential new approach for the treatment of CRPC. SIGNIFICANCE: Potent inhibition of AR signaling is critical to treat CRPC. This study uncovers a driver role for CDK7 in regulating AR-mediated transcription through phosphorylation of MED1, thus revealing a therapeutically targetable potential vulnerability in AR-addicted CRPC...
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1158/2159-8290.CD-19-0189DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7202356PMC
November 2019

Factors Determining the Success of Therapeutic Lifestyle Interventions in Diabetes - Role of Partner and Family Support.

Eur Endocrinol 2019 Apr 12;15(1):18-24. Epub 2019 Apr 12.

Department of Endocrinology, Diabetes & Metabolic Disorders, Venkateshwar Hospitals, New Delhi, India.

: Knowledge of therapeutic lifestyle interventions is one of the most important pillars of diabetes care; however, its incorporation in real-world settings is poor. This review evaluates the role of partner and family support in diabetes management. : Literature searches were performed in PubMed, Medline and Embase for articles published before July 2018, using the terms "therapeutic lifestyle intervention" [MeSH Terms], OR "diet changes" [All Fields], OR "spousal participation" [All Fields], OR "lifestyle interventions" [All Fields], "lifestyle changes" [All Fields] AND "diabetes" [All Fields]. The search was not restricted to English-language literature; literature in Spanish, French and German were also evaluated. : A total of 66 of articles were reviewed, which included 33 original work, 21 review articles, and 12 systematic reviews and meta-analyses. Studies and meta-analyses have showed that if one partner has type-2 diabetes this increases the risk in other by 5-26%. Partner and family have similar diet, lifestyle, and micro- and macro-environments which could explain the similar increased risk of diabetes and non-communicable diseases. Studies have consistently shown that spousal and family support plays a key role in overcoming negative behaviours and optimising behaviours in diabetes control. Partner support has major role in prevention and control of diabetes distress, associated depression, and medication non-compliance which have an adverse impact in glycaemic outcomes. These data are predominantly available from observational studies. There is paucity of data from interventional trials evaluating effects of family and spousal participation on health, glycaemic control and quality of life. : The support of family and spouse/partner is beneficial to improve adherence to the lifestyle interventions and pharmacotherapy required to achieve optimum glycaemic control and avoid associated complications.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.17925/EE.2019.15.1.18DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6587903PMC
April 2019

Impact of Neoadjuvant Chemotherapy on Concordance of PD-L1 Staining Fidelity between the Primary Tumor and Lymph Node Metastases in Bladder Cancer.

Urology 2019 Sep 12;131:150-156. Epub 2019 Jun 12.

Division of Urology, Department of Surgery, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA. Electronic address:

Objective: To evaluate programmed death ligand 1 (PD-L1) staining fidelity between the primary tumor and associated lymph node metastases in bladder cancer. To secondarily evaluate whether neoadjuvant chemotherapy (NAC) affects this relationship.

Methods: Sixty-seven subjects with residual bladder cancer on cystectomy and associated positive lymph nodes were identified between 2008 and 2015. PD-L1 staining of tumor cells was evaluated using H score and 49 specimens were also evaluated using combined positive score (CPS). Univariable and multivariable logistic regression analysis were used to assess how various clinical variables affected odds of PD-L1 fidelity between primary and metastatic tumors.

Results: Tumor PD-L1 staining was concordant in 79.1% of cases and CPS was concordant in 79.6% of cases. NAC did not significantly impact odds of PD-L1 or CPS fidelity (OR 1.974, 95% CI 0.673-5.784, OR 0.500, 95% CI 0.093-2.700). Among clinical variables analyzed on univariable analysis of tumor PD-L1 fidelity, H-score, and PD-L1 staining intensity were associated with significantly increased odds of PD-L1 fidelity and the association with staining intensity was confirmed on multivariable analysis.

Conclusion: PD-L1 fidelity between primary bladder tumors and nodal metastases was observed in >75% of cases in this study. Additionally, NAC was not shown to diminish this propensity to maintain PD-L1 staining status. Further standardization of immunohistochemistry of tumor and infiltrating imsmune cells in metastatic bladder cancer is needed to improve application of therapeutics.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.urology.2019.05.039DOI Listing
September 2019

Thyroid-Like Follicular Carcinoma of the Kidney With Extensive Sarcomatoid Differentiation: A Case Report and Review of the Literature.

Int J Surg Pathol 2019 Sep 28;27(6):678-683. Epub 2019 Apr 28.

1 Hospital of the University of Pennsylvania, Philadelphia, PA, USA.

Thyroid-like follicular carcinoma of the kidney (TLFCK) is an extremely rare primary renal malignancy that typically has an indolent course and good prognosis. Histologically, this tumor mimics follicular carcinoma of the thyroid; however, typical thyroid markers are negative. There are fewer than 40 cases reported in the literature, and thus, the prognosis and course of disease is not well understood. Sarcomatoid differentiation has never been reported in a case of TLFCK. We present a case of a 48-year-old woman with an aggressive TLFCK with extensive sarcomatoid differentiation and metastatic disease at presentation. We performed targeted next-generation sequencing of both the thyroid-like component and the poorly differentiated sarcomatoid component using our solid tumor panel to evaluate for any disease-associated mutations and to better understand the molecular profile of these tumors.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1177/1066896919845490DOI Listing
September 2019

PD-L1 Expression Reveals Significant Association With Squamous Differentiation in Upper Tract Urothelial Carcinoma.

Am J Clin Pathol 2019 05;151(6):561-573

Department of Pathology and Laboratory Medicine, Hospital of the University of Pennsylvania, Philadelphia.

Objectives: Limited literature is available on the tumor microenvironment (TM) of upper tract urothelial carcinoma (UTUC). This study comprehensively reviews programmed death 1 receptor (PD-1)-positive and CD8+ tumor-infiltrating lymphocytes (TILs) and programmed death ligand 1 (PD-L1) expression on tumor epithelium (TE).

Methods: Seventy-two nephroureterectomy specimens were analyzed for PD-L1, PD-1, and CD8. One percent or more tumor and lymphohistiocyte PD-L1 expression was considered positive. TIL density by H&E was scored semiquantitatively from 0 to 3, and CD8+ and PD-1+ TILs were quantified in hotspots.

Results: Of the cases, 37.5% demonstrated PD-L1+ on TE. PD-L1+ TE showed an association with pathologic stage (P = .01), squamous differentiation (SqD) (P < .001), TILs by H&E (P = .02), PD-1+ peritumoral TILs (P = .01), and PD-L1+ peritumoral lymphohistiocytes (P = .002). Finally, there was a significant difference in PD-1+ peritumoral TILs in cases with SqD vs no SqD (P = .03).

Conclusions: Aggressive UTUC is associated with a distinct TM. Furthermore, TM of UTUC-SqD was distinctly different from those with no SqD, warranting study in a larger cohort.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/ajcp/aqz002DOI Listing
May 2019

Villous Adenoma Arising in the Native Bladder Mucosa and the Upper Urinary Tract With Coexisting Neuroendocrine Carcinoma Following Augmentation Cystoplasty.

Int J Surg Pathol 2019 Jun 31;27(4):450-456. Epub 2019 Jan 31.

1 University of Pennsylvania, Philadelphia, PA, USA.

Villous adenomas arising in the bladder following augmentation cystoplasty procedures are exceedingly rare. Even rarer is their occurrence in the native bladder mucosa and the upper urinary tract. In this article, we present a unique case of multifocal recurrent villous adenoma involving native bladder mucosa of an augmented bladder, bilateral ureters, and renal pelvis, with coexistent foci of adenocarcinoma and neuroendocrine carcinoma, in a patient with history of augmentation colocystoplasty. We additionally discuss the pathogenesis of development of carcinoma in the setting of augmentation cystoplasty.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1177/1066896919826708DOI Listing
June 2019

Diabetes Distress and Marriage in Type-1 Diabetes.

Indian J Community Med 2018 Oct-Dec;43(4):316-319

Department of Endocrinology, Diabetes and Metabolism, Venkateshwar Hospital, New Delhi, India.

Background: In spite of the large number of people with Type-1 diabetes mellitus (T1DM) in India, India is not a diabetes-friendly society. The society suffers from lots of myths regarding diabetes and insulin use. This review highlights challenges faced by young people living with T1DM with regards to marriage, associated diabetes distress, and suggests potential solutions.

Methods: PubMed, Medline, and Embase search for articles published up to October 2017, using the terms "marriage" (MeSH Terms) OR "diabetes distress" (All Fields) OR "depression" (All Fields) AND "diabetes" (All Fields). The reference lists of the articles thus identified were also searched. The search was not restricted to English-language literature.

Results: Misconception regarding social, occupational, marital abilities, fertility, genetics, quality of life, sexism in young people living with T1DM raises major barriers to marriage, resulting in significant diabetes distress, depression, and psychological issues in them. People with T1DM are wrongly assumed to be sick, disabled, dependent persons, unsuitable for marriages, and likely to have complicated pregnancies with the possibility of having children with diabetes. Counseling at the level of individual, spouse, family, and society can help in obviating such issues.

Conclusion: Diabetes distress and psychological issues are major problems related to marriage in young people with T1DM. Counseling of patients, family, relatives, prospective spouse, and increasing social awareness regarding diabetes through mass communication are the keys to their resolution.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.4103/ijcm.IJCM_74_18DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6319281PMC
January 2019

Combination Paclitaxel and Palbociclib: Results of a Phase I Trial in Advanced Breast Cancer.

Clin Cancer Res 2019 04 11;25(7):2072-2079. Epub 2019 Jan 11.

Department of Medicine, Division of Hematology/Oncology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania.

Purpose: The CDK 4/6 inhibitor palbociclib rapidly and reversibly inhibits the cell cycle. The goal of this study was to exploit the cell cycle through intermittent, alternating dosing with palbociclib/paclitaxel to enhance efficacy. We determined the combination dose-limiting toxicity (DLT) in patients with Rb protein-expressing, advanced breast cancer.

Patients And Methods: This open-label, phase I trial (NCT01320592) enrolled patients to sequential cohorts of palbociclib orally dosed intermittently between days 1 and 19 of a 28-day cycle alternating with weekly paclitaxel. Dose escalation proceeded in a standard 3 + 3 design. Ten additional patients received the combination at the recommended phase II dose (RP2D). Those who reached response plateau ≥6 cycles could continue on palbociclib alone on a 3 week on/1 week off schedule at one dose level above their combination dose.

Results: Twenty-seven patients enrolled. Although there was only 1 DLT (grade 3 alanine aminotransferase/aspartate aminotransferase at 125 mg), neutropenia (NTP) requiring dose modification in cycle 1 (C1) resulted in an RP2D of 75 mg palbociclib/80 mg/m paclitaxel. During C1, the most common adverse event was NTP, occurring in 15 patients (55.6%); grade 1 or 2 nausea and peripheral neuropathy were also observed in 8 patients each (29.6%). The clinical benefit rate was 55% at the RP2D; benefit was observed across all receptor subtypes.

Conclusions: Alternating sequential palbociclib/paclitaxel in patients with Rb advanced breast cancer is feasible and safe, without evidence of additive toxicity. This represents a new application for CDK 4/6 inhibitors in Rb breast cancer regardless of subtype; efficacy trials are warranted.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1158/1078-0432.CCR-18-0790DOI Listing
April 2019

Optimizing Time to Treatment to Achieve Durable Biochemical Disease Control after Surgery in Prostate Cancer: A Multi-Institutional Cohort Study.

Cancer Epidemiol Biomarkers Prev 2019 03 9;28(3):570-577. Epub 2018 Nov 9.

Department of Cancer Epidemiology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida.

Background: The impact of treatment delays on prostate cancer-specific outcomes remains ill-defined. This study investigates the effect of time to treatment on biochemical disease control after prostatectomy.

Methods: This retrospective study includes 1,807 patients who received a prostatectomy as a primary treatment at two large tertiary referral centers from 1987 to 2015. Multivariate cox model with restricted cubic spline was used to identify optimal time to receive treatment and estimate the risk of biochemical recurrence.

Results: Median follow-up time of the study was 46 (interquartile range, 18-86) months. Time to treatment was subcategorized based on multivariate cubic spline cox model. In multivariate spline model, adjusted for all the pertinent pretreatment variables, inflection point in the risk of biochemical recurrence was observed around 3 months, which further increased after 6 months. Based on spline model, time to treatment was then divided into 0 to 3 months (61.5%), >3 to 6 months (31.1%), and 6 months (7.4%). In the adjusted cox model, initial delays up to 6 months did not adversely affect the outcome; however, time to treatment >6 months had significantly higher risk of biochemical recurrence (HR, 1.84; 95% confidence interval, 1.30-2.60; < 0.01).

Conclusions: The initial delays up to 6 months in prostate cancer primary treatment may be sustainable without adversely affecting the outcome. However, significant delays beyond 6 months can unfavorably affect biochemical disease control.

Impact: Time to treatment can aid clinicians in the decision-making of prostate cancer treatment recommendation and educate patients against unintentional treatment delays.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1158/1055-9965.EPI-18-0812DOI Listing
March 2019

The Twin White Herrings: Salt and Sugar.

Indian J Endocrinol Metab 2018 Jul-Aug;22(4):542-551

Department of Endocrinology, All India Institute of Medical Sciences, New Delhi, India.

India has the dubious distinction of being a hotspot for both diabetes and hypertension. Increased salt and sugar consumption is believed to fuel these two epidemics. This review is an in-depth analysis of current medical literature on salt and sugar being the two white troublemakers of modern society. The PubMed, Medline, and Embase search for articles published in January 2018, using the terms "salt" [MeSH Terms] OR "sodium chloride" [All Fields] OR "sugar" [All Fields]. India is world's highest consumer of sugar with one of the highest salt consumption per day. Increased salt intake is associated with increased risk of hypertension, left ventricular hypertrophy and fibrosis, cardiovascular events, renal stones, proteinuria, and renal failure. Increased sugar intake is directly linked to increased risk of obesity, fatty liver disease, and metabolic syndrome. Also, increased sugar intake may be indirectly related to the increased risk of type 2 diabetes. Both salt and sugar intake is directly linked to increased systemic and hypothalamic inflammation, endothelial dysfunction, microangiopathy, cardiovascular remodelling, cancers, and death. High fructose corn is especially damaging. There is no safe limit of sugar consumption, as the human body can produce its own glucose. Being nature's gift to mankind, there is no harm in moderate consumption of salt and sugar, however, modest reduction in the consumption of both can substantially reduce the burden of non-communicable diseases. Public health interventions to facilitate this behavioural change must be instituted and encouraged.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.4103/ijem.IJEM_117_18DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6085961PMC
August 2018

Long-term Survival After Treating Cardiac Metastasis With Radiation and Immune Therapy: A Case Report.

Cureus 2018 May 10;10(5):e2607. Epub 2018 May 10.

Radiation Oncology, University of Pennsylvania.

Cardiac metastases are a rare clinical entity and they generally portend a poor prognosis. Management is generally directed toward symptom control and maintaining cardiac function; however, long-term survival is rare. Here, we report a case of isolated metastatic urothelial cell carcinoma to the right ventricle that was functionally limiting the patient. The metastasis was successfully palliated for 17 months following radiation and immune therapy; however, disease progression in and around his heart ultimately led to a cardiac arrest.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.7759/cureus.2607DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6039219PMC
May 2018

COX-2 mediates pro-tumorigenic effects of PKCε in prostate cancer.

Oncogene 2018 08 16;37(34):4735-4749. Epub 2018 May 16.

Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA.

The pro-oncogenic kinase PKCε is overexpressed in human prostate cancer and cooperates with loss of the tumor suppressor Pten for the development of prostatic adenocarcinoma. However, the effectors driving PKCε-mediated phenotypes remain poorly defined. Here, using cellular and mouse models, we showed that PKCε overexpression acts synergistically with Pten loss to promote NF-κB activation and induce cyclooxygenase-2 (COX-2) expression, phenotypic traits which are also observed in human prostate tumors. Targeted disruption of PKCε from prostate cancer cells impaired COX-2 induction and PGE production. Notably, COX-2 inhibitors selectively killed prostate epithelial cells overexpressing PKCε, and this ability was greatly enhanced by Pten loss. Long-term COX-2 inhibition markedly reduced adenocarcinoma formation, as well as angiogenesis in a mouse model of prostate-specific PKCε expression and Pten loss. Overall, our results provide strong evidence for the involvement of the canonical NF-κB pathway and its target gene COX2 as PKCε effectors, and highlight the potential of PKCε as a useful biomarker for the use of COX inhibition for chemopreventive and/or chemotherapeutic purposes in prostate cancer.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41388-018-0318-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6195867PMC
August 2018

Donor tissue-specific exosome profiling enables noninvasive monitoring of acute rejection in mouse allogeneic heart transplantation.

J Thorac Cardiovasc Surg 2018 06 1;155(6):2479-2489. Epub 2018 Feb 1.

Department of Surgery, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pa. Electronic address:

Objective: In heart transplantation, there is a critical need for development of biomarkers to noninvasively monitor cardiac allografts for immunologic rejection or injury. Exosomes are tissue-specific nanovesicles released into circulation by many cell types. Their profiles are dynamic, reflecting conditional changes imposed on their tissue counterparts. We proposed that a transplanted heart releases donor-specific exosomes into the recipient's circulation that are conditionally altered during immunologic rejection. We investigated this novel concept in a rodent heterotopic heart transplantation model.

Materials And Methods: Full major histocompatibility mismatch (BALB/c [H2-K] into C57BL/6 [H2-K]) heterotopic heart transplantation was performed in 2 study arms: Rejection (n = 64) and Maintenance (n = 28). In the Rejection arm, immunocompetent recipients fully rejected the donor heart, whereas in the Maintenance arm, immunodeficient recipients (C57BL/6 Prkdc) accepted the allograft. Recipient plasma exosomes were isolated and a donor heart-specific exosome signal was characterized on the nanoparticle detector for time-specific profile changes using anti-H2-K antibody quantum dot.

Results: In the Maintenance arm, allografts were viable throughout follow-up of 30 days, with histology confirming absence of rejection or injury. Time course analysis (days 1, 2, 3, 4, 5, 7, 9, 11, 15, and 30) showed that total plasma exosome concentration (P = .157) and donor heart exosome signal (P = .538) was similar between time points. In the Rejection arm, allografts were universally rejected (median, day 11). Total plasma exosome quantity and size distribution were similar between follow-up time points (P = .278). Donor heart exosome signals peaked on day 1, but significantly decreased by day 2 (P = 2 × 10) and day 3 (P = 3.3 × 10), when histology showed grade 0R rejection. The receiver operating characteristic curve for a binary separation of the 2 study arms (Maintenance vs Rejection) demonstrated that a donor heart exosome signal threshold < 0.3146 was 91.4% sensitive and 95.8% specific for diagnosis of early acute rejection.

Conclusions: Transplant heart exosome profiling enables noninvasive monitoring of early acute rejection with high accuracy. Translation of this concept to clinical settings might enable development of a novel biomarker platform for allograft monitoring in transplantation diagnostics.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jtcvs.2017.12.125DOI Listing
June 2018

A Novel Generalized Lipodystrophy-Associated Progeroid Syndrome Due to Recurrent Heterozygous LMNA p.T10I Mutation.

J Clin Endocrinol Metab 2018 03;103(3):1005-1014

Division of Nutrition and Metabolic Diseases, Department of Internal Medicine, Center for Human Nutrition, UT Southwestern Medical Center, Dallas, Texas.

Background: Lamin A/C (LMNA) gene mutations cause a heterogeneous group of progeroid disorders, including Hutchinson-Gilford progeria syndrome, mandibuloacral dysplasia, and atypical progeroid syndrome (APS). Five of the 31 previously reported patients with APS harbored a recurrent de novo heterozygous LMNA p.T10I mutation. All five had generalized lipodystrophy, as well as similar metabolic and clinical features, suggesting a distinct progeroid syndrome.

Methods: We report nine new patients and follow-up of two previously reported patients with the heterozygous LMNA p.T10I mutation and compare their clinical and metabolic features with other patients with APS.

Results: Compared with other patients with APS, those with the heterozygous LMNA p.T10I mutation were younger in age but had increased prevalence of generalized lipodystrophy, diabetes mellitus, acanthosis nigricans, hypertriglyceridemia, and hepatomegaly, together with higher fasting serum insulin and triglyceride levels and lower serum leptin and high-density lipoprotein cholesterol levels. Prominent clinical features included mottled skin pigmentation, joint contractures, and cardiomyopathy resulting in cardiac transplants in three patients at ages 13, 33, and 47 years. Seven patients received metreleptin therapy for 0.5 to 16 years with all, except one noncompliant patient, showing marked improvement in metabolic complications.

Conclusions: Patients with the heterozygous LMNA p.T10I mutation have distinct clinical features and significantly worse metabolic complications compared with other patients with APS as well as patients with Hutchinson-Gilford progeria syndrome. We propose that they be recognized as having generalized lipodystrophy-associated progeroid syndrome. Patients with generalized lipodystrophy-associated progeroid syndrome should undergo careful multisystem assessment at onset and yearly metabolic and cardiac evaluation, as hyperglycemia, hypertriglyceridemia, hepatic steatosis, and cardiomyopathy are the major contributors to morbidity and mortality.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1210/jc.2017-02078DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6283411PMC
March 2018

Fatal accelerated rejection with a prominent natural killer cell infiltrate in a heart transplant recipient with peripartum cardiomyopathy.

Transpl Immunol 2018 04 31;47:49-54. Epub 2017 Oct 31.

University of Pennsylvania, Department of Pathology and Laboratory Medicine, United States. Electronic address:

Accelerated rejection is uncommon after cardiac transplantation. The mechanism is hypothesized to be mediated by cytotoxic T cells and anti-HLA antibodies resulting from a memory response to the donor allograft in sensitized patients. A role for Natural Killer (NK) cell in cellular rejection has also been suggested. We report a case of fulminant accelerated rejection in a heart transplant recipient, with a history of peripartum cardiomyopathy (PPMC). The patient had no pre-transplant donor specific antibody and flow cytometric T and B cell crossmatches were negative. Autopsy revealed left ventricular subendocardial and intramyocardial hemorrhage with diffuse lymphocytic infiltrates and myocyte damage (Grade 3R rejection). Immunohistochemistry revealed a large proportion (50-70%) of mature CD16+ NK cells with cytotoxic potential in the interstitium and the intra capillary compartments. This case highlights the need for evaluating the potential role of NK cells in accelerated rejection in heart transplant recipients.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.trim.2017.10.002DOI Listing
April 2018

Malignant Mixed Epithelial and Stromal Tumor of the Kidney With 2 Simultaneous Renal Carcinomas in a Male Patient: Case Report and Review of the Literature.

Int J Surg Pathol 2018 Feb 11;26(1):56-63. Epub 2017 Jul 11.

1 Hospital of the University of Pennsylvania, Philadelphia, PA, USA.

The majority of mixed epithelial and stromal tumors (MEST) of the kidney are benign entities found in female patients. Malignant MEST of the kidney is an extremely rare entity that often behaves clinically similar to an undifferentiated sarcoma. We report a case of a malignant MEST with synchronous papillary and clear cell renal cell carcinomas (RCCs) in a 61-year-old Caucasian man who presented with an incidental finding of a left renal mass on workup for back pain. The patient underwent a left radical nephrectomy, with histopathology confirming a malignant MEST, intimately associated papillary RCC, and separate adjacent focus of clear cell RCC.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1177/1066896917720032DOI Listing
February 2018