Kanika Gupta

Neocortical neuron morphology in Afrotheria: comparing the rock hyrax with the African elephant

The mammalian neocortex contains a great variety of neuronal types. In particular, recent studies have shown substantial morphological diversity among spiny projecting neurons in species that diverged close to the base of the mammalian radiation (e.g., monotremes, afrotherians, and xenarthrans). Here, we used a Golgi technique to examine different neuronal morphologies in an afrotherian species, the rock hyrax (Procavia capensis), and provide a comparison with the related African elephant (Loxodonta africana). Results showed that spiny neurons in the rock hyrax neocortex exhibit less morphological variation than in elephants, displaying a higher frequency of relatively “typical” pyramidal neurons. A quantitative comparison of rock hyrax pyramidal neuron morphology between frontal and visual areas, moreover, revealed greater spine density of neurons in frontal cortex, but no differences in other morphological aspects. Regional variations in pyramidal structure have also been observed in the African elephant, as well as a number of primate species.

Neuron Types in the Presumptive Primary Somatosensory Cortex of the Florida Manatee (Trichechus manatus latirostris).

Within afrotherians, sirenians are unusual due to their aquatic lifestyle, large body size and relatively large lissencephalic brain. However, little is known about the neuron type distributions of the cerebral cortex in sirenians within the context of other afrotherians and aquatic mammals. The present study investigated two cortical regions, dorsolateral cortex area 1 (DL1) and cluster cortex area 2 (CL2), in the presumptive primary somatosensory cortex (S1) in Florida manatees (Trichechus manatus latirostris) to characterize cyto- and chemoarchitecture. The mean neuron density for both cortical regions was 35,617 neurons/mm3 and fell within the 95% prediction intervals relative to brain mass based on a reference group of afrotherians and xenarthrans. Densities of inhibitory interneuron subtypes labeled against calcium-binding proteins and neuropeptide Y were relatively low compared to afrotherians and xenarthrans and also formed a small percentage of the overall population of inhibitory interneurons as revealed by GAD67 immunoreactivity. Nonphosphorylated neurofilament protein-immunoreactive (NPNFP-ir) neurons comprised a mean of 60% of neurons in layer V across DL1 and CL2. DL1 contained a higher percentage of NPNFP-ir neurons than CL2, although CL2 had a higher variety of morphological types. The mean percentage of NPNFP-ir neurons in the two regions of the presumptive S1 were low compared to other afrotherians and xenarthrans but were within the 95% prediction intervals relative to brain mass, and their morphologies were comparable to those found in other afrotherians and xenarthrans. Although this specific pattern of neuron types and densities sets the manatee apart from other afrotherians and xenarthrans, the manatee isocortex does not appear to be explicitly adapted for an aquatic habitat. Many of the features that are shared between manatees and cetaceans are also shared with a diverse array of terrestrial mammals and likely represent highly conserved neural features. A comparative study across manatees and dugongs is necessary to determine whether these traits are specific to one or more of the manatee species, or can be generalized to all sirenians.

A synopsis of drugs currently in preclinical and early clinical development for the treatment of benign prostatic hyperplasia.

Introduction: Benign prostatic hyperplasia (BPH) is a common disease among men and significantly impacts quality of life by causing lower urinary tract symptoms (LUTS). Current medical therapies are not always adequate in controlling LUTS or slowing disease progression, and there is unmet need for new effective therapeutic options. Areas covered: The authors review the standard current medical therapies for BPH which include the use of α-1 blockers, 5-α reductase inhibitors, combination therapy and PDE inhibitors. Following this, the authors then discuss new therapies that are currently undergoing preclinical and clinical investigation. Expert opinion: Existing preclinical and clinical trials have highlighted many promising therapies to treat BPH. Further investigation with larger clinical trials is needed to establish these drugs as standard therapies. As the number of drugs in the arsenal against BPH continues to grow, providers and patients will have to engage in a discussion that weighs the risks and benefits of each therapy.

Characterization of Differences Between Prostate Cancer Patients Presenting With De Novo Versus Primary Progressive Metastatic Disease

Background Men who present with metastatic disease can have de novo or primary progressive disease. We characterized and compared the outcomes between these 2 groups. Patients and Methods A retrospective cross‐sectional analysis from a single institution of de novo versus primary progressive metastatic patients during a 2‐year consecutive period was undertaken. Patient characteristics such as demographics, Gleason score, duration of hormone sensitivity, and treatment were obtained. The t test, Mann‐Whitney U test, and Fisher exact test were used to test differences in patient and disease characteristics between the de novo and primary progressive metastatic groups. Differences in the Kaplan‐Meier survival curves were compared using the log‐rank test. Results A total of 90 patients (n = 38 with de novo and 52 with primary progressive disease) were included. Statistically significant median differences were found for the prostate‐specific antigen level at the development of metastases: de novo 63.1 ng/ml vs primary progressive 12.5 ng/ml, p= <.001; albumin and hemoglobin, P = .03 and P = .045, respectively). The median duration of hormone sensitivity was 372 days (range, 54‐3753 days) in the de novo group versus 1613 days (range, 7‐4314 days) in the primary progressive group (P = .00006). Overall survival was worse in the de novo arm, with a median survival of 6.2 years compared with a median survival in the primary progressive group of 11.6 years (P = .027). Conclusion Although the reported samples were small, our data revealed a potential difference in disease aggressiveness in those presenting with de novo metastatic cancer with higher risk disease and shorter time to castration resistance and worse survival. These data could have implications for earlier and more aggressive treatment for men presenting with de novo metastatic prostate cancer. Micro‐Abstract Men who present with metastatic prostate cancer can have distant metastases as their first presentation of cancer (de novo) or develop progression to metastases after a history of curative intent therapy (primary progressive). We found that men presenting with de novo metastatic disease have a shorter duration of hormone sensitivity and worse survival compared with those with primary progressive metastatic disease, suggesting a more aggressive disease course.

The promising role of nivolumab in renal cell cancers

ABSTRACT The therapeutic efficacy of checkpoint inhibitors across numerous tumor types has resulted in approval for neoplasms such as melanoma and lung cancer. Nivolumab is a fully humanized IgG4 antibody that inhibits immune checkpoint between programmed death 1 (PD-1) on T cells and PD-1 ligand 1 (PD-L1) and ligand 2 (PD-L2) on immune and cancer cells. Motzer and Colleagues published the findings of Nivolumab versus everolimus in advanced kidney cancer in the November issue of the New England Journal of Medicine. This trial showed that nivolumab resulted in better median overall survival of 25 months compared to everolimus at 19.6 months, with a hazard ratio for death at 0.73, meeting pre-specified criterion for superiority in favor of nivolumab. These findings mark the defining beneficial role of immune checkpoint inhibitor therapy in metastatic kidney cancer.

Incidence and characterization of pure non-urothelial bladder and upper tract cancers: A 10-year review.

414 Background: Bladder cancer is the sixth most common malignancy in the United States. Urothelial carcinoma makes up 90% of bladder cancer histology, which may be pure or mixed. It includes adenocarcinoma (Ad), squamous (SqC), glandular, sarcomatoid (St), micropapillary, small cell (SC) and plasmacytoid variants. Pure non-urothelial cancers have worse overall survival compared to urothelial cancer with mixed histologic features. However, little research has been done to characterize pure non-urothelial histologies, and there are no randomized clinical trials evaluating treatment modalities for non-urothelial cancers. This retrospective study characterizes pure non-urothelial cancers and their treatments. Methods: A retrospective chart review of the last 10 years was performed using data from the George Washington University Cancer Center Tumor Registry Data. Statistical analysis was done using the Fisher’s test and Kaplan-Meier survival curves. Results: Out of 449 consecutive patients with bladder cance...

The Utility of Chemotherapy in the Treatment of Metastatic Prostate Cancer

Prostate cancer is the most common cancer among American men and the second most common cause of cancer deaths among men. Treatment of prostate cancer remains a challenge. Despite decades of research, few cytotoxic chemotherapy agents have shown promise against prostate cancer. In this paper, we will discuss the history of chemotherapy in prostate cancer, the pivotal trials with docetaxel that advanced the field, the cytotoxic chemotherapy agents, including cabazitaxel, as well as combination therapy with docetaxel or cabazitaxel and the potential implications of biomarkers such as AR-V7 in chemotherapy use.

Characterization of differences between prostate cancer (PCa) patients presenting as de novo versus primary progressive metastatic disease.

285 Background: In 2014 alone, 29,480 men are projected to die of PCa (Cancer Statistics, 2014).Approximately 4% are metastatic on presentation (de novo, dn) while a subset of men progress on to metastatic disease during the course of their disease (primary progressive, pp). We sought to characterize and compare differences in disease characteristics and outcomes between those who present as dn vs pp metastatic disease in our institution. Methods: A retrospective chart review of dn vs pp metastatic patients for the past 2 years was undertaken. Characteristics such as demographics, Gleason score, duration of hormone sensitivity, and treatment, were obtained. T-test and Fisher’s exact test were used to test differences in patient and disease characteristics between dn and pp metastatic patients. Results: Preliminary results on 10 de novo and 13 primary progressive patients are presented herein. Statistically significant differences were noted for median age at diagnosis: de novo 66.5 years of age (range=48-...