Biochemical progression free and overall survival among Black men with stage IV prostate cancer in South Africa: Results from a prospective cohort study.

BACKGROUND: Men of African descent are disproportionately affected by prostate cancer (PCa), and many have metastatic disease at presentation. In South Africa (SA), androgen deprivation therapy (ADT) is the first-line treatment for stage IV PCa. OBJECTIVE: To identify predictors of overall survival (OS) in Black South African men with stage IV PCa treated with ADT. DESIGN, SETTING, AND PARTICIPANTS: Men diagnosed with prostate cancer (3/22/2016-10/30/2020) at Chris Hani Baragwanath Academic Hospital in Soweto, Johannesburg, were recruited for the Men of African Descent with Cancer of the Prostate study. We included men with newly diagnosed stage IV PCa treated with ADT who had a prostate-specific antigen (PSA) level drawn prior to initiation of ADT and had ≥1 PSA drawn ≥12 weeks after ADT start. OUTCOMES MEASURES AND STATISTICAL ANALYSIS: We used Kaplan-Meier statistics to estimate OS and Cox regression models to identify predictors of OS. RESULTS AND LIMITATIONS: Of the 1097 men diagnosed with prostate cancer, we included 153 men with stage IV PCa who received ADT and met PSA requirements. The median age was 68.0 years (interquartile range 64-73 years). Median OS from time of ADT initiation was 3.39 years (95% confidence interval (CI): 3.14%-noncalculable), while biochemical progression-free survival was 2.36 years (95% CI: 2.03%-3.73%). Biochemical progression (HR 3.52, 95% CI: 1.85%-6.70%), PSA nadir level >4 ng/mL (HR 3.77, 95% CI: 1.86%-7.62%), alkaline phosphatase level at diagnosis >150 IU/dL (HR 3.09, 95% CI: 1.64%-5.83%), and hemoglobin at diagnosis <13.5 g/dL (HR 2.90, 95% CI: 1.28%-6.56%) were associated with worse OS. CONCLUSIONS: In this study, we identified factors associated with poor OS among Black South African men with stage IV PCa treated with ADT. These factors may be useful in identifying patients for upfront treatment escalation, including the use of docetaxel chemotherapy or escalation of therapy at the time of biochemical progression. PATIENT SUMMARY: In this study, we found that high alkaline phosphatase level, anemia at diagnosis, and high PSA nadir after initiation of androgen deprivation therapy are associated with worse overall survival among Black South African men treated with androgen deprivation therapy for metastatic prostate cancer.

Heterogeneous genetic architectures and evolutionary genomics of prostate cancer in Sub-Saharan Africa.

Men of African descent have the highest prostate cancer (CaP) incidence and mortality rates, yet the genetic basis of CaP in African men has been understudied. We used genomic data from 3,963 CaP cases and 3,509 controls recruited in Ghana, Nigeria, Senegal, South Africa, and Uganda, to infer ancestry-specific genetic architectures and fine-mapped disease associations. Fifteen independent associations at 8q24.21, 6q22.1, and 11q13.3 reached genome-wide significance, including four novel associations. Intriguingly, multiple lead SNPs are private alleles, a pattern arising from recent mutations and the out-of-Africa bottleneck. These African-specific alleles contribute to haplotypes with odds ratios above 2.4. We found that the genetic architecture of CaP differs across Africa, with effect size differences contributing more to this heterogeneity than allele frequency differences. Population genetic analyses reveal that African CaP associations are largely governed by neutral evolution. Collectively, our findings emphasize the utility of conducting genetic studies that use diverse populations.

Prevalence of multimorbidity in men of African descent with and without prostate cancer in Soweto, South Africa.

OBJECTIVE: With increases in chronic disease, men with prostate cancer are likely to have at least one other chronic health condition. The burden and complexity of each additional chronic disease may complicate prostate cancer treatment and reduce survival. In this paper, we describe the frequency of multimorbid chronic diseases, HIV and depression among men in Soweto, South Africa (SA) with and without prostate cancer and determine whether the presence of multimorbid diseases is associated with metastatic and high-risk, non-metastatic prostate cancer. METHODS: A population-based case-control study on prostate cancer was conducted among black men in Soweto. All participants completed a baseline survey on sociodemographics, lifestyle, and comorbid medical conditions. All participants completed a depression screening survey and HIV testing at enrolment. Blood pressure measurements and blood testing for fasting glucose, total cholesterol, and high-density lipoprotein were performed on a subset of randomly selected cases and controls. For men with prostate cancer, clinical T staging was assessed with the digital rectal examination, the diagnosis was confirmed with a biopsy and PSA levels were assessed at presentation. The metastatic staging was assessed by bone scans, and this was confirmed with PSMA PET scans, CT scans and X-rays, standard for our resource-constrained setting. Normal PSA scores were used as an inclusion criterion for controls. RESULTS: Of the 2136 men (1095 with prostate cancer and 1041 controls) included in the analysis, 43.0% reported at least one chronic metabolic disease; 24.1% reported two metabolic diseases; 5.3% reported three metabolic diseases; and 0.3% reported four metabolic diseases. Men with prostate cancer were more likely to report a multimorbid chronic metabolic disease compared to controls (p<0.001) and more likely to test positive for HIV (p = 0.05). The majority of men (66.2%) reported at least one metabolic disease, tested negative for HIV and had a negative depression screen. The clinical characteristics of men with prostate cancer, were as follows: 396 (36.2%) had a Gleason score of 8 and above; 552 (51.3%) had a PSA score of >20ng/ml; 233 (21.7%) had confirmed metastatic prostate cancer at diagnosis. Older age was associated with metastatic prostate cancer (OR = 1.043 95% CI:1.02-1.07) and NCCN defined high-risk non-metastatic prostate cancer (OR = 1.03 95% CI:1.01-1.05), whilst being hypertensive was protective (OR = 0.63 95% CI:0.47-0.84 and OR = 0.55 95% CI:0.37-0.83) respectively for metastatic and high-risk, non-metastatic prostate cancer. CONCLUSION: The high prevalence of multimorbid metabolic diseases and HIV among men with prostate cancer represents a public health concern in South Africa. There is a need to effectively address multiple chronic diseases among men with prostate cancer by incorporating coordinated care models.

Ocular Drug Delivery: Advancements and Innovations.

Ocular drug delivery has been significantly advanced for not only pharmaceutical compounds, such as steroids, nonsteroidal anti-inflammatory drugs, immune modulators, antibiotics, and so forth, but also for the rapidly progressed gene therapy products. For conventional non-gene therapy drugs, appropriate surgical approaches and releasing systems are the main deliberation to achieve adequate treatment outcomes, whereas the scope of "drug delivery" for gene therapy drugs further expands to transgene construct optimization, vector selection, and vector engineering. The eye is the particularly well-suited organ as the gene therapy target, owing to multiple advantages. In this review, we will delve into three main aspects of ocular drug delivery for both conventional drugs and adeno-associated virus (AAV)-based gene therapy products: (1) the development of AAV vector systems for ocular gene therapy, (2) the innovative carriers of medication, and (3) administration routes progression.

In vivo base editing rescues Hutchinson-Gilford progeria syndrome in mice.

Hutchinson-Gilford progeria syndrome (HGPS or progeria) is typically caused by a dominant-negative C•G-to-T•A mutation (c.1824 C>T; p.G608G) in LMNA, the gene that encodes nuclear lamin A. This mutation causes RNA mis-splicing that produces progerin, a toxic protein that induces rapid ageing and shortens the lifespan of children with progeria to approximately 14 years1-4. Adenine base editors (ABEs) convert targeted A•T base pairs to G•C base pairs with minimal by-products and without requiring double-strand DNA breaks or donor DNA templates5,6. Here we describe the use of an ABE to directly correct the pathogenic HGPS mutation in cultured fibroblasts derived from children with progeria and in a mouse model of HGPS. Lentiviral delivery of the ABE to fibroblasts from children with HGPS resulted in 87-91% correction of the pathogenic allele, mitigation of RNA mis-splicing, reduced levels of progerin and correction of nuclear abnormalities. Unbiased off-target DNA and RNA editing analysis did not detect off-target editing in treated patient-derived fibroblasts. In transgenic mice that are homozygous for the human LMNA c.1824 C>T allele, a single retro-orbital injection of adeno-associated virus 9 (AAV9) encoding the ABE resulted in substantial, durable correction of the pathogenic mutation (around 20-60% across various organs six months after injection), restoration of normal RNA splicing and reduction of progerin protein levels. In vivo base editing rescued the vascular pathology of the mice, preserving vascular smooth muscle cell counts and preventing adventitial fibrosis. A single injection of ABE-expressing AAV9 at postnatal day 14 improved vitality and greatly extended the median lifespan of the mice from 215 to 510 days. These findings demonstrate the potential of in vivo base editing as a possible treatment for HGPS and other genetic diseases by directly correcting their root cause.

The Clinical Spectrum of Primary Cutaneous CD4+ Small/Medium-Sized Pleomorphic T-Cell Lymphoproliferative Disorder: An Updated Systematic Literature Review and Case Series.

BACKGROUND: Primary cutaneous CD4+ small/medium pleomorphic T-cell lymphoproliferative disorder (SMPLPD) is a provisional entity within the 2016 World Health Organization classification of primary cutaneous lymphomas. The condition is currently classified as a lymphoproliferative disorder to emphasize its benign course and discourage aggressive, systemic treatment modalities. OBJECTIVE: To provide a relevant synthesis for the dermatological practitioner on the prevalence, presentation, and treatment of SMPLPD. METHODS: We conducted an updated systematic literature review and a retrospective chart review of diagnosed cases of SMPLPD from 2 Canadian academic cutaneous lymphoma centers. RESULTS: A total of 23 studies with 136 cases were extracted from the systematic review and 24 patients from our retrospective chart review. SMPLPD proved relatively common accounting for 12.5% of all cutaneous T-cell lymphomas encountered in our cutaneous lymphoma clinics, second in frequency only to mycosis fungoides. The typical clinical presentation was that of an older individual (median age 59 years) with an asymptomatic solitary lesion on their upper extremity. The most common clinical differentials were cutaneous lymphoid hyperplasia, basal cell carcinoma, and lymphoma unspecified. T follicular helper markers were reliably detected. The main treatment modalities were surgical excision, local radiation therapy, and topical or intralesional steroids. Cure was achieved in the vast majority of cases. CONCLUSIONS: SMPLPD is an underdiagnosed T-cell lymphoma with an overtly benign clinical course. The condition has an excellent prognosis and responds well to skin-directed therapies. Practitioners should be aware of this condition to avoid aggressive systemic treatments.

Xanthogranulomatous prostatitis: A rare mimicker of prostate adenocarcinoma.

Xanthogranulomatous prostatitis as mimicker of prostate adenocarcinoma can cause a diagnostic dilemma, as presented in this case. Therefore, alongside histopathology analysis, multiparametric magnetic resonance imaging (mpMRI) would be useful in this situation by identifying and characterizing suspicious prostatic lesions before biopsy thereby supporting current recommendations on the use of mpMRI.

A Urodynamic Comparison of Neural Targets for Transcutaneous Electrical Stimulation to Acutely Suppress Detrusor Contractions Following Spinal Cord Injury.

OBJECTIVES: To assess and compare the effect of transcutaneous Dorsal Genital Nerve Stimulation (DGNS), Tibial Nerve Stimulation (TNS), Sacral Nerve Stimulation (SNS), and Spinal Stimulation (SS) on Neurogenic Detrusor Overactivity (NDO) and bladder capacity in people with Spinal Cord Injuries (SCI). MATERIALS AND METHODS: Seven male participants with supra-sacral SCI were tested. Standard cystometry (CMG) was performed to assess bladder activity at baseline and with stimulation applied at each site. This was conducted over four separate sessions. All stimulation was monophasic, 15 Hz, 200 µS pulses and applied at maximum tolerable amplitude. Results were analysed against individual control results from within the same session. RESULTS: Dorsal Genital Nerve Stimulation increased bladder capacity by 153 ± 146 ml (p = 0.016) or 117 ± 201%. DGNS, TNS and SNS all increased the volume held following the first reflex contraction, by 161 ± 175, 46 ± 62, and 34 ± 33 ml (p = 0.016, p = 0.031, p = 0.016), respectively. SS results showed small reduction of 33 ± 26 ml (p = 0.063) from baseline bladder capacity in five participants. Maximum Detrusor Pressure before leakage was increased during TNS, by 10 ± 13 cmH2O (p = 0.031) but was unchanged during stimulation of other sites. DGNS only was able to suppress at least one detrusor contraction in five participants and reduced first peak detrusor pressure below 40 cmH2O in these 5. Continuous TNS, SNS, and SS produced non-significant changes in bladder capacity from baseline, comparable to conditional stimulation. Increase in bladder capacity correlated with stimulation amplitude for DGNS but not TNS, SNS or SS. CONCLUSION: In this pilot study DGNS acutely suppressed detrusor contractions and increased bladder capacity whereas TNS, SNS, and SS did not. This is the first within individual comparison of surface stimulation sites for management of NDO in SCI individuals.

Safety and Efficacy of a Noninvasive 1,060-nm Diode Laser for Fat Reduction of the Flanks.

BACKGROUND: Preliminary reports indicate a hyperthermic diode laser treatment could be a safe and effective method for noninvasive fat reduction using the 1,060-nm wavelength. This wavelength penetrates the skin to heat subcutaneous adipocytes causing cellular disruption, leaving extracellular lipids, and cellular debris to be evacuated naturally by the body. OBJECTIVE: To evaluate the safety and effectiveness of this modality for noninvasive fat reduction of the flanks. MATERIALS AND METHODS: Forty-nine subjects received single laser treatment to 1 flank. Ultrasound images were taken at baseline, follow-up at 6 and 12 weeks after treatment. High-resolution photographs were taken at baseline and 12 weeks after treatment and then evaluated by independent reviewers. Adverse events recorded at all visits. Subjects completed a satisfaction questionnaire at the conclusion of the trial. RESULTS: Ultrasound images showed statistically significant (p < .001) average fat reduction of 2.6 ± 1.1 mm. Reviewers correctly ordered photographs 90.3% of the time. Ninety-six percentage of subjects rated that they were satisfied. Noted side effects were transient mild to moderate tenderness which subsided within 1 to 3 weeks; no serious adverse events were reported. CONCLUSION: The hyperthermic 1,060-nm diode laser treatment used in this study was safe and effective for noninvasive fat reduction of the flank.

Polarization enhanced wide-field imaging for evaluating dermal changes caused by non-ablative fractional laser treatment.

BACKGROUND AND OBJECTIVE: Laser non-ablative fractional treatment (NAFT) is an important part of armamentarium of modern dermatology. Recently, such treatments have become available in at-home setting due to advent of self-application NAFT devices. Safety and clinical efficacy of NAFT are well established in multiple studies. Less information is available on morphological and functional changes in tissue occurring as a result of NAFT. Polarization-enhanced multispectral wide-field imaging device allows for in vivo real time visualization of dermal structures. The objective of this study is to use this imaging modality to monitor early effects of the home-use NAFT on collagen networks. MATERIALS AND METHODS: Eight subjects (skin types I-III) used a commercially available NAFT device (wavelength 1410 nm, energy per pulse up to 15 mJ) to treat peri-orbital wrinkles in standard recommended mode, that is daily, for a period of two weeks. In each session, subjects applied a pre-treatment gel to the peri-orbital areas and then used the device, delivering 8-10 applications to each side of the face without overlap. Subjects were asked to use the highest device setting. Cross-polarized 440 nm wide-field images were acquired from peri-orbital areas before and two weeks after the onset of the treatment regimen. Wide-field images were normalized and thresholded to a level of 40% brightness to emphasize collagen structure. Collagen content was quantitatively determined from thresholded collagen images. Improvement in collagen content at two weeks of daily treatments was assessed. RESULTS: Eight subjects (age 24-53 years) completed the study. Cross-polarized 440 nm wide-field images clearly delineated collagen networks. Quantitative assessment of collagen images revealed statistically significant (P < 0.05) improvement of collagen content at a time point of two weeks. Seven out of eight subjects showed varying degree of improvement. The increase of collagen content in responders ranged from 1-26%, with the mean improvement of 11%. Subjects in their early 40s showed the best improvement in comparison to younger and older age groups. CONCLUSIONS: Polarization-enhanced multispectral wide-field reflectance imaging method is a suitable technique for noninvasive in vivo assessment of dermal structures. Post-treatment images, taken three days after the last treatment session, demonstrate that non-ablative fractional treatment resulted in increased dermal collagen content as measured by the polarization-enhanced technique as early as two weeks post onset of the treatments. However, further studies with a larger number of subjects and longer treatment period are required to determine the optimal regimen and how long the results will last.

Combined hepatocellular and cholangiocarcinoma (biphenotypic) tumors: imaging features and diagnostic accuracy of contrast-enhanced CT and MRI.

OBJECTIVE: The purpose of this study was to evaluate the diagnostic accuracy of preoperative imaging for diagnosis of combined hepatocellular cholangiocarcinoma tumors and to evaluate the clinical and imaging features and demographics of patients presenting to our institution with such tumors. MATERIALS AND METHODS: From January 2001 to January 2011, 29 patients presented with pathologically proven combined hepatocellular cholangiocarcinoma tumors to our institution. A retrospective review of the imaging studies, clinical data, and demographic information in these patients was conducted. Two radiologists with 6 and 18 years of experience reviewed the imaging studies of patients with combined hepatocellular cholangiocarcinoma tumors and matched control cases of hepatocellular carcinoma (HCC) (n = 15) and cholangiocarcinoma (n = 18). The reviewers were blinded to the pathologic diagnosis. Imaging features on contrast-enhanced MRI and CT with the suggested final diagnosis were recorded. RESULTS: The demographics of our patient population were similar to other reported U.S. populations, with cirrhosis and hepatitis present in a minority of patients. The imaging features of combined hepatocellular cholangiocarcinoma tumors overlapped with those of HCC and cholangiocarcinoma. The correct diagnosis of combined hepatocellular cholangiocarcinoma tumors was made in a minority of cases by either radiologist, with misdiagnosis more often leading to suggestion of cholangiocarcinoma than HCC. Sensitivities and specificities for diagnosis of combined hepatocellular cholangiocarcinoma tumors ranged from 33% to 34% and 81% to 100%, respectively. CONCLUSION: Preoperative diagnosis of combined hepatocellular cholangiocarcinoma tumors on the basis of imaging features is accurate in the minority of cases. Tumor markers and risk factors may help improve accuracy; however, in the absence of classic imaging features and supportive information for HCC or cholangiocarcinoma, biopsy should be considered for confirmation of diagnosis.

Isolated splenic metastasis from carcinoma of the breast: a case report.

Breast carcinoma with visceral metastasis to the lungs, liver, and bone is common. However, isolated splenic metastases from breast carcinoma are rare. This has been rarely described in the medical literature. This case report presents a 48-year-old woman with newly diagnosed breast cancer and an isolated splenic metastasis diagnosed by ultrasound-guided fine-needle aspiration (FNA). Radiologic staging revealed no involvement of other organs, such as lungs, liver, or bone. The pathogenesis of rare single splenic metastasis and the diagnostic role of FNA on the spleen lesion are discussed. This case is being reported due to its rare metastatic initial presentation and the role of FNA in achieving the diagnosis.

Exploring blood glucose variation over geographical space.

BACKGROUND: Type 2 diabetes mellitus is known to be associated with environmental, behavioral, and lifestyle factors such as a sedentary lifestyle, overly rich nutrition, and obesity. However, the day-to-day human-environment interactions and real-life activities that cause an individual's blood glucose to fluctuate remain relatively unexplored, owing in part to data collection challenges. This article presents a novel data collection system that overcomes these challenges and allows exploration of the spatial correlates of blood glucose fluctuation. METHODS: An automated monitoring system was developed combining a Global Positioning System (GPS) receiver with a continuous blood glucose monitor. The GPS was used to elicit a second-by-second accounting of an individual's daily activities alongside blood glucose measurement every 5 min. A pilot study of 40 diabetes patients was conducted over a 72-h period. Geographic Information System software was used to generate blood glucose maps, incorporating methods to deal with scale issues, overlapping data, and to protect subject identity. RESULTS: Individual blood glucose variation maps revealed a variety of distinct patterns. Most subjects had at least two major anchor points in their life combined with a variety of other activity locations at varying distances from home, many associated with quite distinct low or high blood glucose values. Further statistical analysis revealed location and distance from home were significantly correlated with blood glucose variation-although the strength and direction of the effect was quite mixed. CONCLUSIONS: Results suggests that blood glucose and space/location are highly correlated and should be considered further as a lifestyle-related risk factor for diabetes patients. In the future, patients and caregivers may benefit from individualized visualization tools that help identify problematic locations that require special attention.

Actinic cheilitis: a treatment review.

All other factors being equal, the presence of actinic cheilitis, a pre-invasive malignant lesion of the lips, doubles the risk of squamous cell carcinoma developing in this anatomic area. Various forms of local ablation,immunomodulation and surgical extirpation have been proposed as therapeutic interventions. This paper critically evaluates the available medical literature to highlight the evidence-based strength of each recommended therapy for actinic cheilitis. Vermilionectomy remains the gold standard for efficacy; trichloroacetic acid application is easy and convenient, but the least efficacious overall.

Innovative uses of thalidomide.

Thalidomide is approved for treating erythema nodosum leprosum and multiple myeloma, but it has also emerged as a useful treatment option for many refractory dermatologic disorders. Some of the innovative but off-label uses of thalidomide include aphthous stomatitis, Behçet's disease, lupus erythematosus, prurigo nodularis, sarcoidosis, actinic prurigo, graft-versus-host disease, Langerhans cell histiocytosis, erythema multiforme, lichen planus, Kaposi sarcoma, Jessner lymphocytic infiltrate, uremic pruritus, pyoderma gangrenosum, scleroderma, scleromyxedema, and necrobiosis lipoidica. This article reviews the background, pharmacology, and innovative uses of thalidomide in dermatology.

Disseminated porokeratosis of Mibelli: A case report.

Porokeratosis is a disorder of clonal hyperproliferation of keratinocytes with several different clinical manifestations. Cutaneous lesions vary in their appearance and distribution. All variants share the distinguishing cornoid lamella on histopathological examination. We present an unusual case of disseminated porokeratosis of Mibelli in an immunocompetent patient.

Acquired dermal melanocytosis of the hand at the site of treated psoriasis.

Dermal melanocytosis is a benign phenomenon most commonly noted in people with darkly pigmented skin. Multiple entities with dermal melanocytosis are described, including Mongolian spot, nevus of Ota, nevus of Ito, nevus of Hori, and acquired dermal melanocytosis. We report a case of acquired dermal melanocytosis occurring in a 42-year-old Hispanic man with psoriasis treated with infliximab for 9 months. The patient presented with an isolated pigmented patch on his left dorsal hand. Histopathologic examination of the skin revealed numerous dendritic, heavily pigmented melanocytes in the papillary and upper reticular dermis. We review the literature and discuss the pathogenesis of acquired dermal melanocytosis.

Granuloma faciale: Case report and review.

Granuloma faciale (GF) is a rare benign chronic inflammatory dermatosis usually appearing only on the face. The lesions of GF typically present as single, asymptomatic, erythematous, non-changing nodules or plaques. We present an illustrative case of GF and briefly review available treatment options.