El impacto de la pandemia del COVID-19 en la educación médica: adaptabilidad y experiencia con enseñanza a distancia de la Sociedad Médica Peruano Americana

La pandemia del COVID-19 tuvo un impacto significativo en el cuidado y la educación médicos en el Perú. En respuesta, la Sociedad Médica Peruano Americana (PAMS), una organización médica benéfica con sede en los EE.UU., adoptó sus misiones médicas y educativas en Perú usando estrategias virtuales. Desarrollamos colaboración con varias facultades de medicina y la Asociación Peruana de Facultades de Medicina (ASPEFAM) y ofrecimos un panel de veinte y cuatro miembros para brindar conferencias y seminarios multidisciplinarios en español. Hicimos 19 seminarios, incluyendo temas relacionados y no relacionados al COVID-19, que en los últimos dos años atrajo a 14 489 participantes de 23 países. Ellas fueron la base de 20 publicaciones en revistas médicas peruanas. Nuestro concurso de investigaciones clínicas y nuestro proyecto piloto de mentoría de investigación fueron recibidos positivamente. La pandemia del COVID-19 tuvo un efecto positivo en la misión educativa de PAMS en Perú.

The COVID-19 pandemic had a significant impact on medical care and medical education in Peru. In response, the Peruvian American Medical Society (PAMS), a charitable medical organization based in the USA, pursued its medical and educational missions in Peru by adopting virtual learning technology. We developed closer collaborative relationships with several medical schools and the Peruvian Association of Medical Schools (ASPEFAM) while offering a faculty panel of twenty-four members to provide lectures and multidisciplinary webinars in Spanish. We conducted 19 webinars including COVID -19 and non-COVID-19 related topics that over the last two years attracted 14,489 participants from 23 countries. They were the foundation for twenty publications in Peruvian medical journals. Our clinical investigations competition was positively received as was our pilot project on research mentorship. The COVID -19 pandemic had a positive effect on the educational mission of PAMS in Peru.

Metastatic Mature Teratoma and Growing Teratoma Syndrome in Patients with Testicular Non-Seminomatous Germ Cell Tumors.

Metastatic mature teratoma is a common radiologic and histopathologic finding after chemotherapy for metastatic non-seminomatous germ cell tumors. The leading theory for these residual tumors is the selective chemotherapy resistance of teratomas versus the high chemotherapy sensitivity of the embryonal components. Growing teratoma syndrome is a relatively rare phenomenon defined as an enlarging residual mass histologically proven to be a mature teratoma in the setting of normal serum tumor markers. Metastatic mature teratomas should be resected because of their malignant potential and occasional progression to growing teratoma syndrome with the invasion of the surrounding structures. CT is the preferred imaging modality for post-chemotherapy surveillance and should cover all sites of potential metastatic disease. This article reviews the clinical, pathologic, and multimodality imaging features of metastatic mature teratomas in patients with primary testicular non-seminomatous germ cell tumors.

A Potential New Mouse Model of Axial Spondyloarthritis Involving the Complement System.

Many mouse models of rheumatoid arthritis have been identified, but only a limited number are present for axial spondyloarthritis (AxSpA). Collagen Ab-induced arthritis (CAIA) is one of the most widely used mouse models of arthritis, and it is complement-dependent. We found that mice developing CAIA also developed spinal lesions similar to those found in AxSpA. To induce CAIA, mice were injected intraperitoneally at day 0 with anti-collagen Abs, followed by LPS injection at day 3. CAIA mice demonstrated a significant kyphosis through the spine, as well as hypertrophic cartilage and osseous damage of the intravertebral joints. Immunohistochemical staining of the kyphotic area revealed increased complement C3 deposition and macrophage infiltration, with localization to the intravertebral joint margins. Near Infrared (NIR) in vivo imaging showed that anti-collagen Abs conjugated with IRDye® 800CW not only localized to cartilage surface in the joints but also to the spine in arthritic mice. We report here a novel preclinical mouse model in which, associated with the induction of CAIA, mice also exhibited salient features of AxSpA; this new experimental model of AxSpA may allow investigators to shed light on the local causal mechanisms of AxSpA bone and soft tissue changes as well as treatment.

Assessment of high-grade prostate cancer risk using prostate cancer biomarkers.

INTRODUCTION: To identify patients at risk of high-grade prostate cancer using prostate cancer biomarkers. MATERIALS AND METHODS: A total of 601 men were screened for prostate cancer in 2012, 2015, and 2016 using prostate cancer biomarkers: prostate health index (phi), 4KScore, and SelectMDx. The first two are blood tests that incorporate several PSA isoforms; SelectMDx measures mRNA levels of homeobox C6 and distal-less homeobox 1 in post-digital rectal examination urine samples. The performance of each biomarker was evaluated using cut off values based on published literature. Gleason Grade Group (GG) ≥ 2 is considered as high-grade prostate cancer. RESULTS: For patients with PSA < 1.5 ng/mL, none were at risk for GG ≥ 2 cancer based on SelectMDx > 0%, whereas 17.1% were at intermediate to high risk of finding GG ≥ 2 cancer with 4KScore ≥ 7.5%, and 3.5% were at risk of finding any prostate cancer with phi ≥ 36 at biopsy. For cut offs revised for finding men at high risk for GG ≥ 2 cancer at biopsy, only one patient with PSA < 1.5 ng/mL would be at risk with 4KScore ≥ 20% and none with phi ≥ 52.7. For patients with PSA 1.5 to 3.99 ng/mL, 2%, 8%, and 1% were at high risk for finding GG ≥ 2 cancer at biopsy based on phi, 4KScore, and SelectMDx, respectively. CONCLUSIONS: Men with PSA < 1.5 ng/mL are at very low risk of finding high-grade prostate cancer at biopsy. However, some men with PSA between 1.5 to 3.99 ng/mL may be at intermediate to high risk for high-grade prostate cancer. Thus, primary care physicians could run biomarkers test and refer those with positive biomarker results to a specialist for further evaluation.

Genetic Risk of Arrhythmic Phenotypes in Patients With Dilated Cardiomyopathy.

BACKGROUND: Genotype-phenotype correlations in dilated cardiomyopathy (DCM) and, in particular, the effects of gene variants on clinical outcomes remain poorly understood. OBJECTIVES: The purpose of this study was to investigate the prognostic role of genetic variant carrier status in a large cohort of DCM patients. METHODS: A total of 487 DCM patients were analyzed by next-generation sequencing and categorized the disease genes into functional gene groups. The following composite outcome measures were assessed: 1) all-cause mortality; 2) heart failure-related death, heart transplantation, or destination left ventricular assist device implantation (DHF/HTx/VAD); and 3) sudden cardiac death/sustained ventricular tachycardia/ventricular fibrillation (SCD/VT/VF). RESULTS: A total of 183 pathogenic/likely pathogenic variants were found in 178 patients (37%): 54 (11%) Titin; 19 (4%) Lamin A/C (LMNA); 24 (5%) structural cytoskeleton-Z disk genes; 16 (3.5%) desmosomal genes; 46 (9.5%) sarcomeric genes; 8 (1.6%) ion channel genes; and 11 (2.5%) other genes. All-cause mortality was no different between variant carriers and noncarriers (p = 0.99). A trend toward worse SCD/VT/VF (p = 0.062) and DHF/HTx/VAD (p = 0.061) was found in carriers. Carriers of desmosomal and LMNA variants experienced the highest rate of SCD/VT/VF, which was independent of the left ventricular ejection fraction. CONCLUSIONS: Desmosomal and LMNA gene variants identify the subset of DCM patients who are at greatest risk for SCD and life-threatening ventricular arrhythmias, regardless of the left ventricular ejection fraction.

The Ratio of the Number of Biopsy Specimens to Prostate Volume (Biopsy Density) Greater Than 1.5 Improves the Prostate Cancer Detection Rate in Men Undergoing Transperineal Biopsy of the Prostate.

PURPOSE: We sought to determine the minimum number of transperineal prostate mapping biopsies needed to optimize the prostate cancer detection rate. MATERIALS AND METHODS: A total of 436 men underwent transperineal prostate mapping biopsy at 2 institutions. Biopsy density was calculated as the ratio of the total number of specimens retrieved (mean 59.4) to prostate volume (mean 44.9 cc). Associations of biopsy density with prostate specific antigen, prostate specific antigen density, cancer diagnosis and the Gleason score were tested by ANOVA and the chi-square test. Regression analysis was done to determine factors associated with a positive transperineal prostate mapping biopsy and Gleason score 7 or higher cancer. RESULTS: Transperineal prostate mapping biopsy was positive in 299 of 436 men (68.6%). The mean number of positive cores was 7.1 (range 1 to 41) and mean biopsy density was 1.46 (range 0.39 to 3.67). The mean number of cores in positive vs negative transperineal prostate mapping biopsies was 1.61 vs 1.14 (p <0.001). Biopsy density cut points of 0.5 or less, greater than 0.5 to 1.0, greater than 1.0 to 1.5 and greater than 1.5 were associated with positive biopsy in 25%, 37.4%, 70.7% and 84.9% of patients (p <0.001). Dichotomizing biopsy density to 1.5 or less vs greater than 1.5 resulted in a positive biopsy rate of 56.4% vs 84.9% (OR 1.5, 95% CI 1.3-1.7, p <0.001). More Gleason score 6 cancers were diagnosed with higher biopsy density (94 of 158 or 59.5% vs 62 of 141 or 44.9%, p = 0.007). However, the number of positive cores with Gleason score 6 was greater in men with higher biopsy density at 4.9 vs 3.6 (p = 0.036). Prostate specific antigen (p = 0.053) and biopsy density (p = 0.012) were significant on regression analysis for positive transperineal prostate mapping biopsy and Gleason score 7+ disease. CONCLUSIONS: Biopsy density greater than 1.5 increases the diagnosis of prostate cancer by 1.5 times, detects higher volume Gleason score 6 disease and should be considered the optimal sampling approach when performing transperineal prostate mapping biopsy.

Perilipin-2 promotes obesity and progressive fatty liver disease in mice through mechanistically distinct hepatocyte and extra-hepatocyte actions.

KEY POINTS: Wild-type mice and mice with hepatocyte-specific or whole-body deletions of perilipin-2 (Plin2) were used to define hepatocyte and extra-hepatocyte effects of altered cellular lipid storage on obesity and non-alcoholic fatty liver disease (NAFLD) pathophysiology in a Western-diet (WD) model of these disorders. Extra-hepatocyte actions of Plin2 are responsible for obesity, adipose inflammation and glucose clearance abnormalities in WD-fed mice. Hepatocyte and extra-hepatic actions of Plin2 mediate fatty liver formation in WD-fed mice through distinct mechanisms. Hepatocyte-specific actions of Plin2 are primary mediators of immune cell infiltration and fibrotic injury in livers of obese mice. ABSTRACT: Non-alcoholic fatty liver disease (NAFLD) is an obesity- and insulin resistance-related metabolic disorder with progressive pathology. Perilipin-2 (Plin2), a ubiquitously expressed cytoplasmic lipid droplet scaffolding protein, is hypothesized to contribute to NAFLD in humans and rodent models through effects on cellular lipid metabolism. In this study, we delineate hepatocyte-specific and extra-hepatocyte Plin2 mechanisms regulating the effects of obesity and insulin resistance on NAFLD pathophysiology in mice fed an obesogenic Western-style diet (WD). Total Plin2 deletion (Plin2-Null) fully protected WD-fed mice from obesity, insulin resistance, adipose inflammation, steatohepatitis (NASH) and liver fibrosis found in WT animals. Hepatocyte-specific Plin2 deletion (Plin2-HepKO) largely protected against NASH and fibrosis and partially protected against steatosis in WD-fed animals, but it did not protect against obesity, insulin resistance, or adipose inflammation. Significantly, total or hepatocyte-specific Plin2 deletion impaired WD-induced monocyte recruitment and pro-inflammatory macrophage polarization found in livers of WT mice. Analyses of the molecular and cellular processes mediating steatosis, inflammation and fibrosis identified differences in total and hepatocyte-specific actions of Plin2 on the mechanisms promoting NAFLD pathophysiology. Our results demonstrate that hepatocyte-specific actions of Plin2 are central to the initiation and pathological progression of NAFLD in obese and insulin-resistant mice through effects on immune cell recruitment and fibrogenesis. Conversely, extra-hepatocyte Plin2 actions promote NAFLD pathophysiology through effects on obesity, inflammation and insulin resistance. Our findings provide new insight into hepatocyte and extra-hepatocyte mechanisms underlying NAFLD development and progression.

Lipid catabolism inhibition sensitizes prostate cancer cells to antiandrogen blockade.

Prostate cancer (PCa) is the most common malignancy among Western men and the second leading-cause of cancer related deaths. For men who develop metastatic castration resistant PCa (mCRPC), survival is limited, making the identification of novel therapies for mCRPC critical. We have found that deficient lipid oxidation via carnitine palmitoyltransferase (CPT1) results in decreased growth and invasion, underscoring the role of lipid oxidation to fuel PCa growth. Using immunohistochemistry we have found that the CPT1A isoform is abundant in PCa compared to benign tissue (n=39, p<0.001) especially in those with high-grade tumors. Since lipid oxidation is stimulated by androgens, we have evaluated the synergistic effects of combining CPT1A inhibition and anti-androgen therapy. Mechanistically, we have found that decreased CPT1A expression is associated with decreased AKT content and activation, likely driven by a breakdown of membrane phospholipids and activation of the INPP5K phosphatase. This results in increased androgen receptor (AR) action and increased sensitivity to the anti-androgen enzalutamide. To better understand the clinical implications of these findings, we have evaluated fat oxidation inhibitors (etomoxir, ranolazine and perhexiline) in combination with enzalutamide in PCa cell models. We have observed a robust growth inhibitory effect of the combinations, including in enzalutamide-resistant cells and mouse TRAMPC1 cells, a more neuroendocrine PCa model. Lastly, using a xenograft mouse model, we have observed decreased tumor growth with a systemic combination treatment of enzalutamide and ranolazine. In conclusion, our results show that improved anti-cancer efficacy can be achieved by co-targeting the AR axis and fat oxidation via CPT1A, which may have clinical implications, especially in the mCRPC setting.

The Antineoplastic Activity of Photothermal Ablative Therapy with Targeted Gold Nanorods in an Orthotopic Urinary Bladder Cancer Model.

BACKGROUND: Gold nanoparticles treated with near infrared (NIR) light can be heated preferentially, allowing for thermal ablation of targeted cells. The use of novel intravesical nanoparticle-directed therapy in conjunction with laser irradiation via a fiber optic cystoscope, represents a potential ablative treatment approach in patients with superficial bladder cancer. OBJECTIVE: To examine the thermal ablative effect of epidermal growth factor receptor (EGFR)-directed gold nanorods irradiated with NIR light in an orthotopic urinary bladder cancer model. METHODS: Gold nanorods linked to an anti-EGFR antibody (Conjugated gold NanoRods - CNR) were instilled into the bladder cavity of an orthotopic murine xenograft model with T24 bladder cancer cells expressing luciferase. NIR light was externally administered via an 808 nm diode laser. This treatment was repeated weekly for 4 weeks. The anti-cancer effect was monitored by an in vivo imaging system in a non-invasive manner, which was the primary outcome of our study. RESULTS: The optimal approach for an individual treatment was 2.1 W/cm2 laser power for 30 seconds. Using this in vivo model, NIR light combined with CNR demonstrated a statistically significant reduction in tumor-associated bioluminescent activity (n = 16) compared to mice treated with laser alone (n = 14) at the end of the study (p = 0.035). Furthermore, the CNR+NIR light treatment significantly abrogated bioluminescence signals over a 6-week observation period, compared to pre-treatment levels (p = 0.045). CONCLUSIONS: Photothermal tumor ablation with EGFR-directed gold nanorods and NIR light proved effective and well tolerated in a murine in vivo model of urinary bladder cancer.

Granular cell tumor presenting in the scrotum of a pediatric patient: a case report and review of the literature.

BACKGROUND: Granular cell tumors are neoplasms of Schwann cell origin. They typically arise in the head and neck of adults, with the tongue being the most common location; granular cell tumors of male genitalia are exceedingly rare. We identified only eight prior cases of scrotal granular cell tumor in the literature, and only one was in a child. Herein, we report a second case of childhood scrotal granular cell tumor and provide a review of the most relevant literature. CASE PRESENTATION: A fifteen-year-old hispanic boy was referred to our hospital's pediatric surgery service for a painless and firm scrotal mass. Clinical impression was that of an epidermal inclusion cyst. There was no evidence of associated medical problems from the clinical history and physical examination. Surgical enucleation of the lesion demonstrated a solid nodule with morphological and immunohistochemical features consistent with a benign granular cell tumor. CONCLUSIONS: This is the second case reported of a scrotal granular cell tumor in a child. Although genital granular cell tumors are rare, and most are benign, careful clinical examination, complete surgical excision, expert histologic evaluation, and a close follow-up are recommended for accurate diagnosis and to rule out eventual malignancy.

Diffuse reflectance spectroscopy can differentiate high grade and low grade prostatic carcinoma.

Prostate tumors are graded by the revised Gleason Score (GS) which is the sum of the two predominant Gleason grades present ranging from 6-10. GS 6 cancer exclusively with Gleason grade 3 is designated as low grade (LG) and correlates with better clinical prognosis for patients. GS >7 cancer with at least one of the Gleason grades 4 and 5 is designated as HG indicate worse prognosis for patients. Current transrectal ultrasound guided prostate biopsies often fail to correctly diagnose HG prostate cancer due to sampling errors. Diffuse reflectance spectra (DRS) of biological tissue depend on tissue morphology and architecture. Thus, DRS could potentially differentiate between HG and LG prostatic carcinoma. A 15-gauge optical biopsy needle was prototyped to take prostate biopsies after measuring DRS with a laboratory fluorometer. This needle has an optical sensor that utilizes 8×100 µm optical fibers for tissue excitation and a single 200 µm central optical fiber to measure DRS. Tissue biopsy cores were obtained from 20 surgically excised prostates using this needle after measuring DRS at 5 nm intervals between 500-700 nm wavelengths. Tissue within a measurement window was histopathologically classified as either benign, LG, or HG and correlated with DRS. Partial least square analysis of DRS identified principal components (PC) as potential classifiers. Statistically significant PCs (p<;0.05) were tested for their ability to classify biopsy tissue using support vector machine and leave-one-out cross validation method. There were 29 HG and 49 LG cancers among 187 biopsy cores included in the study. Study results show 76% sensitivity, 80% specificity, 93% negative predictive value, and 50% positive predictive value for HG versus benign, and 76%, 73%, 84%, and 63%, for HG versus LG prostate tissue classification. DRS failed to diagnose 7/29 (24%) HG cancers. This study demonstrated that an optical biopsy needle guided by DRS has sufficient accuracy to differentiate HG from LG carcinoma and benign tissue. It may allow precise targeting of HG prostate cancer providing more accurate assessment of the disease and improvement in patient care.

Anaplastic lymphoma kinase (ALK) gene alteration in signet ring cell carcinoma of the gastrointestinal tract.

OBJECTIVES: ALK-EML4 translocation is an established driver aberration in non-small cell lung cancer (NSCLC), with reported predilection for cases with signet ring histology. We assessed the presence of anaplastic lymphoma kinase (ALK) gene rearrangements in signet ring cancers arising in the stomach and colon. METHODS: Histologically confirmed cases of signet ring adenocarcinoma of the stomach or the colon were identified. The presence of the classic ALK and EML4 fusion gene was initially determined by fluorescence in-situ hybridization (FISH) technique. Immunohistochemistry (IHC) was performed using two previously validated antibodies, ALK1 clone (1:100; DAKO) and 5A4 (Novocastra, Leica Biosystems) along with positive controls of ALK-translocated lung cancer. RESULTS: We employed 42 cases of signet ring carcinoma diagnosed between 2001 and 2011; 25 gastric and 17 colon cancer. Median age 63.3 years; male/female 17/25; race, black 47.5%, white 47.5%, others, 5%; stage I, 21.4%; stage II, 31%; stage III, 26.2%; stage IV, 21.4%. One of 42 cases (2.3%) was positive for ALK translocation by FISH using the standard criteria of at least 15% positive cells for the break-apart signal (50-70 cells enumerated per case). Using a less restrictive cut-off of 10% positive cells, 7 cases (16%) were considered possibly positive. None of the 'possibly positive' cases was found to harbor ALK translocation by another molecular testing approach (IHC). IHC with two previously validated monoclonal antibodies showed 0 of 42 (0%) cases positive. CONCLUSIONS: ALK gene rearrangement is very rare in gastrointestinal cancers and enrichment strategy focusing on signet ring cell histology did not significantly improve the detection rate.

Reduced expression of GDF-15 is associated with atrophic inflammatory lesions of the prostate.

BACKGROUND: Accumulating evidence suggests that chronic prostatic inflammation may lead to prostate cancer development. Growth differentiation factor-15 (GDF-15) is highly expressed in the prostate and has been associated with inflammation and tumorigenesis. METHODS: To examine the relationship between GDF-15 and prostatic inflammation, GDF-15 expression was measured by immunohistochemical (IHC) staining in human prostatectomy specimens containing inflammation. The relationship between GDF-15 and specific inflammatory cells was determined using non-biased computer image analysis. To provide insight into a potential suppressive role for GDF-15 in inflammation, activation of inflammatory mediator nuclear factor of kappa B (NFκB) was measured in PC3 cells. RESULTS: GDF-15 expression in luminal epithelial cells was decreased with increasing inflammation severity, suggesting an inverse association between GDF-15 and inflammation. Quantification of IHC staining by image analysis for GDF-15 and inflammatory cell markers revealed an inverse correlation between GDF-15 and CD3+, CD4+, CD8+, CD68+, and inos+ leukocytes. GDF-15 suppressed NFκB activity in luciferase reporter assays. Expression of the NFκB target, interleukin 8 (IL-8), was downregulated by GDF-15. CONCLUSIONS: The inverse relationship between GDF-15 and inflammation demonstrates a novel expression pattern for GDF-15 in the human prostate and suppression of NFκB activity may shed light on a potential mechanism for this inverse correlation.

Multi-parametric MRI findings of transitional zone prostate cancers: correlation with 3-dimensional transperineal mapping biopsy.

PURPOSE: A preliminary project to correlate MR findings with mapping prostate biopsy to help differentiate malignant transitional zone lesions form benign prostatic hyperplasia (BPH) nodules. MATERIALS AND METHODS: Institutional IRB approved retrospective study with 14 patients suspected of having prostate cancer who underwent both prostate 3T MRI using endorectal coil and 3D transperineal mapping prostate biopsy. MR exams were independently reviewed by two abdominal radiologists blinded to pathology with disagreement resolved by consensus. An MRI lesion was defined as having hypointense T2 signal subjectively without corresponding T1 high signal intensity and low signal on ADC maps in the central gland. Mapping biopsy consisted of systematic transperineal US guided biopsy with 55-108 cores per patient. RESULTS: Twenty-nine lesions were detected on MRI. Of these, 13 correlated with Gleason 6 or higher biopsy samples. 16 were biopsy negative. Among the various MRI characteristics assessed, lack of T2 hypointense rim demonstrated the highest specificity (93%) and positive predictive value (89%). Highest sensitivity (85%) and negative predictive value (78%) were seen with ill-defined nodules. When suspicious MR characteristics were combined, the specificity and PPV rose to 100% while sensitivity decreased to 45% and NPV decreased to 73%. CONCLUSIONS: Preliminary study indicates MR findings which can help differentiate a BPH nodule from transitional zone prostate cancers which could help direct biopsy in the large and growing number of people suspected of having prostate cancer. Further work will be needed for validation.