Marc Barry

Phase 2 study of neoadjuvant docetaxel plus bevacizumab in patients with high-risk localized prostate cancer: a Prostate Cancer Clinical Trials Consortium trial.

Treatment of high‐risk localized prostate cancer remains inadequate. The authors performed a phase 2 multicenter trial of neoadjuvant docetaxel plus bevacizumab before radical prostatectomy.

Characterization and outcomes of renal leukocyte chemotactic factor 2-associated amyloidosis

Amyloidosis derived from leukocyte chemotactic factor 2 (ALECT2) is a recently described disease. Here, we report the characteristics and outcome of 72 patients with renal ALECT2, which included 19 who had another kidney disease on biopsy. Ninety-two percent of patients were Hispanics and over half were elderly. Three had other organ, but not cardiac, amyloidosis involvement. All patients without concurrent disease, except three, presented with chronic renal insufficiency. Proteinuria was variable and absent in a third, whereas nephrotic syndrome and hematuria were rare. After a median follow-up of 26 months, one-third developed end-stage renal disease (ESRD). The median renal survival was 62 months. Independent predictors of renal survival were serum creatinine at diagnosis, with a value of 2.0 mg/dl being the best cutoff for predicting ESRD, percentage global glomerulosclerosis, and presence of diabetes. Only four patients died and four had received chemotherapy for an erroneous diagnosis of immunoglobulin light chain-derived amyloidosis. Five patients underwent kidney transplantation; none had graft loss but one had disease recurrence. Patient survival is superior to renal immunoglobulin light chain-derived amyloidosis and reactive amyloidosis largely due to the absence of cardiac involvement. Thus, renal ALECT2 mainly affects elderly Hispanics who typically present with chronic renal insufficiency and bland urine sediment, with or without proteinuria.

Phase 2 study of neoadjuvant docetaxel plus bevacizumab in patients with high‐risk localized prostate cancer

Treatment of high‐risk localized prostate cancer remains inadequate. The authors performed a phase 2 multicenter trial of neoadjuvant docetaxel plus bevacizumab before radical prostatectomy.

Nephropathy in dietary hyperoxaluria: A potentially preventable acute or chronic kidney disease

Hyperoxaluria can cause not only nephrolithiasis and nephrocalcinosis, but also renal parenchymal disease histologically characterized by deposition of calcium oxalate crystals throughout the renal parenchyma, profound tubular damage and interstitial inflammation and fibrosis. Hyperoxaluric nephropathy presents clinically as acute or chronic renal failure that may progress to end-stage renal disease (ESRD). This sequence of events, well recognized in the past in primary and enteric hyperoxalurias, has also been documented in a few cases of dietary hyperoxaluria. Estimates of oxalate intake in patients with chronic dietary hyperoxaluria who developed chronic kidney disease or ESRD were comparable to the reported average oxalate content of the diets of certain populations worldwide, thus raising the question whether dietary hyperoxaluria is a primary cause of ESRD in these regions. Studies addressing this question have the potential of improving population health and should be undertaken, alongside ongoing studies which are yielding fresh insights into the mechanisms of intestinal absorption and renal excretion of oxalate, and into the mechanisms of development of oxalate-induced renal parenchymal disease. Novel preventive and therapeutic strategies for treating all types of hyperoxaluria are expected to develop from these studies.

Trends in United States Prostate Cancer Incidence Rates by Age and Stage, 1995–2012

Background: The advent of PSA testing in the late 1980s substantially increased prostate cancer incidence rates. Concerns about overscreening and overdiagnosis subsequently led professional guidelines (circa 2000 and later) to recommend against routine PSA testing. We evaluated trends in prostate cancer incidence, including late-stage diagnoses, from 1995 through 2012. Methods: We used joinpoint regression analyses to evaluate all-, localized/regional-, and distant-stage prostate cancer incidence trends based on Surveillance, Epidemiology, and End Results (SEER) data. We stratified analyses by age (50–69, 70+). We reported incidence trends as annual percent change (APC). Results: Overall age-adjusted incidence rates for localized/regional stage prostate cancer have been declining since 2001, sharply from 2010 to 2012 [APC, −13.1; 95% confidence intervals (CI), −23.5 to −1.3]. Distant-stage incidence rates have declined since 1995, with greater declines from 1995 to 1997 (APC, −8.4; 95% CI, −2.3 to −14.1) than from 2003 to 2012 (APC, −1.0; 95% CI, −1.7 to −0.4). Distant-stage incidence rates declined for men ages 70+ from 1995 to 2012, but increased in men ages 50 to 69 years from 2004 to 2012 (APC, 1.7; 95% CI, 0.2 to 3.2). Conclusions: Guidelines discouraging routine prostate cancer screening were temporally associated with declining localized/regional prostate cancer incidence rates; however, incidence rates of distant-stage disease are now increasing in younger men. Impact: This trend may adversely affect prostate cancer mortality rates. Cancer Epidemiol Biomarkers Prev; 25(2); 259–63. ©2015 AACR.

Targeted molecular-genetic imaging and ligand-directed therapy in aggressive variant prostate cancer

Significance Aggressive variant prostate cancer (AVPC) is a clinically defined tumor with neuroendocrine or small-cell differentiation, visceral metastases, low prostate-specific antigen, androgen receptor insensitivity, and poor/brief responses to androgen-deprivation or platinum-based chemotherapy. AVPC incidence has markedly increased, yielding an unmet diagnostic/therapeutic need. Here we adapted a patient-derived xenograft model and tumor samples to demonstrate ligand-directed theranostics of AVPC in vivo. We engineered human Herpes simplex virus thymidine kinase type-1 as a noninvasive imaging reporter/suicide transgene into adeno-associated virus/phage (AAVP) particles displaying motif ligands to cell surface-associated glucose-regulated protein 78kD (GRP78), toward a clinic-ready system. Although individual components of the AAVP system have been extensively investigated, this study is evidence of successful application in relevant preclinical models of untreatable and hard to diagnose aggressive tumor variants. Aggressive variant prostate cancers (AVPC) are a clinically defined group of tumors of heterogeneous morphologies, characterized by poor patient survival and for which limited diagnostic and treatment options are currently available. We show that the cell surface 78-kDa glucose-regulated protein (GRP78), a receptor that binds to phage-display-selected ligands, such as the SNTRVAP motif, is a candidate target in AVPC. We report the presence and accessibility of this receptor in clinical specimens from index patients. We also demonstrate that human AVPC cells displaying GRP78 on their surface could be effectively targeted both in vitro and in vivo by SNTRVAP, which also enabled specific delivery of siRNA species to tumor xenografts in mice. Finally, we evaluated ligand-directed strategies based on SNTRVAP-displaying adeno-associated virus/phage (AAVP) particles in mice bearing MDA-PCa-118b, a patient-derived xenograft (PDX) of castration-resistant prostate cancer bone metastasis that we exploited as a model of AVPC. For theranostic (a merging of the terms therapeutic and diagnostic) studies, GRP78-targeting AAVP particles served to deliver the human Herpes simplex virus thymidine kinase type-1 (HSVtk) gene, which has a dual function as a molecular-genetic sensor/reporter and a cell suicide-inducing transgene. We observed specific and simultaneous PET imaging and treatment of tumors in this preclinical model of AVPC. Our findings demonstrate the feasibility of GPR78-targeting, ligand-directed theranostics for translational applications in AVPC.

Towards a transcriptome-based theranostic platform for unfavorable breast cancer phenotypes

Significance Inflammatory breast cancer (IBC) is defined clinically and pathologically. Dermal lymphatic invasion is typical but is neither necessary nor sufficient for diagnosis; sentinel lymph node biopsy is contraindicated, challenging multidisciplinary management with upfront chemotherapy, surgery, and postoperative radiotherapy. Here we applied a ligand-directed “theranostic” (a combination of therapeutic and diagnostic) enabling platform to target IBC based on adeno-associated virus/phage (AAVP)-Herpes simplex virus thymidine kinase type-1 (HSVtk) particles displaying ligands to cell surface-associated 78-kD glucose-regulated protein (GRP78). In a suite of preclinical models and human tumor samples, we show simultaneous noninvasive molecular serial PET/CT imaging and targeted suicide transgene therapy. This study shows that a tumor-specific promoter, human GRP78 (hGRP78), can drive the expression of an imaging/suicide transgene in IBC and aggressive breast cancer in vivo. Inflammatory breast carcinoma (IBC) is one of the most lethal forms of human breast cancer, and effective treatment for IBC is an unmet clinical need in contemporary oncology. Tumor-targeted theranostic approaches are emerging in precision medicine, but only a few specific biomarkers are available. Here we report up-regulation of the 78-kDa glucose-regulated protein (GRP78) in two independent discovery and validation sets of specimens derived from IBC patients, suggesting translational promise for clinical applications. We show that a GRP78-binding motif displayed on either bacteriophage or adeno-associated virus/phage (AAVP) particles or loop-grafted onto a human antibody fragment specifically targets orthotopic IBC and other aggressive breast cancer models in vivo. To evaluate the theranostic value, we used GRP78-targeting AAVP particles to deliver the human Herpes simplex virus thymidine kinase type-1 (HSVtk) transgene, obtaining simultaneous in vivo diagnosis through PET imaging and tumor treatment by selective activation of the prodrug ganciclovir at tumor sites. Translation of this AAVP system is expected simultaneously to image, monitor, and treat the IBC phenotype and possibly other aggressive (e.g., invasive and/or metastatic) subtypes of breast cancer, based on the inducible cell-surface expression of the stress-response chaperone GRP78, and possibily other cell-surface receptors in human tumors.

α-Methylacyl-CoA racemase expression and lethal prostate cancer in the Physicians' Health Study and Health Professionals Follow-up Study†

α‐Methylacyl‐CoA racemase (AMACR) is an enzyme that serves as a diagnostic biomarker of prostate cancer in clinical practice. Recent studies suggest that low AMACR expression is associated with biochemical recurrence and the development of fatal disease.

BK nephropathy in the native kidneys of patients with organ transplants: Clinical spectrum of BK infection

Nephropathy secondary to BK virus, a member of the Papoviridae family of viruses, has been recognized for some time as an important cause of allograft dysfunction in renal transplant recipients. In recent times, BK nephropathy (BKN) of the native kidneys has being increasingly recognized as a cause of chronic kidney disease in patients with solid organ transplants, bone marrow transplants and in patients with other clinical entities associated with immunosuppression. In such patients renal dysfunction is often attributed to other factors including nephrotoxicity of medications used to prevent rejection of the transplanted organs. Renal biopsy is required for the diagnosis of BKN. Quantitation of the BK viral load in blood and urine are surrogate diagnostic methods. The treatment of BKN is based on reduction of the immunosuppressive medications. Several compounds have shown antiviral activity, but have not consistently shown to have beneficial effects in BKN. In addition to BKN, BK viral infection can cause severe urinary bladder cystitis, ureteritis and urinary tract obstruction as well as manifestations in other organ systems including the central nervous system, the respiratory system, the gastrointestinal system and the hematopoietic system. BK viral infection has also been implicated in tumorigenesis. The spectrum of clinical manifestations from BK infection and infection from other members of the Papoviridae family is widening. Prevention and treatment of BK infection and infections from other Papovaviruses are subjects of intense research.

Sustained Remission of Antineutrophil Cytoplasmic Antibody-Mediated Glomerulonephritis and Nephrotic Syndrome in Mixed Connective Tissue Disease

A woman diagnosed with mixed connective tissue disease (MCTD) developed an anti-myeloperoxidase (MPO) antineutrophil cytoplasmic antibody (ANCA) and nephrotic syndrome with normal serum creatinine. Percutaneous kidney biopsy showed pauci-immune glomerulonephritis with superimposed immune complex deposition. After treatment with cyclophophamide and prednisone, proteinuria decreased progressively to a level of 0.4 g/g creatinine, ANCA became undetectable, while serum creatinine remained normal seven years after the beginning of treatment. Sustained remission of nephrotic proteinuria with preserved renal function may follow treatment of ANCA-mediated disease developing in patients with MCTD.