Impact of second histopathological review of melanocytic skin lesions at a melanoma reference center in Brazil.

BACKGROUND: After the biopsy of a suspicious melanocytic lesion, patients depend on the pathologist's precision of specimen evaluation. METHODS: We assessed the agreement between histopathological reports made by general pathologists and reviewed by a dermatopathologist to evaluate the impact on the patient's management. RESULTS: In 79 cases analyzed, underdiagnosis was observed in 21.6% and overdiagnosis in 17.7%, resulting in changes in the patients' conduct. The assessment of the Clark level, ulceration and histological type showed mild agreement (P<0.001); the Breslow thickness, surgical margin, and staging showed moderate agreement (P<0.001). CONCLUSIONS: A dermatopathologist's review should be incorporated into the routine of reference services for pigmented lesions.

Complications of Extended Pelvic Lymph Node Dissection in Patients Undergoing Minimally Invasive Radical Prostatectomy: Analysis and Risk Factors.

Background: The knowledge of risk factors and complications related to extended pelvic lymph node dissection (ePLND) during radical prostatectomy can help selecting patients who will benefit the most with lymph node dissection concomitant to radical prostatectomy. Materials and Methods: Retrospective cohort evaluating 135 patients with PC, with a high risk for lymph node metastasis, submitted to ePLND by a single surgeon between 2013 and 2019, performed either by the laparoscopic or laparoscopic robot-assisted approach. Data related to complications were properly recorded using the Martin's criteria and were classified by the Satava and Clavien-Dindo-Strasberg methods. Logistic regression was used to determine predictors of complications related to ePLND. Results: The mean number of lymph nodes removed was 10.2 ± 4.9, and in 28.2%, they were positive for metastasis. There were five intraoperative complications (4%), all in patients operated by laparoscopic approach. There were nine severe postoperative complications (7.3%), four of which occurred after postoperative day 30. Three patients (2.4%) had thromboembolic complications and five patients (4.0%) had lymphocele that required treatment. There was a correlation between the American Society of Anesthesiologists (ASA) physical status classification and postoperative complications (p=0.06), but it was not possible to identify statistically significant predictors. Conclusion: ePLND during radical prostatectomy has a low rate of intraoperative complications and may change prostate cancer staging. Postoperative complications, especially venous thromboembolism and lymphocele, need to be monitored even in the late postoperative period.

Toxicity profile of treatment with PD-1 inhibitors for lung cancer, melanoma and renal cell carcinoma: A real-world Brazilian study.

INTRODUCTION: Immunotherapy revolutionized cancer care in the last decade and, notably among its tools, the programmed cell death protein-1 (PD-1) inhibitors. These drugs are related to increased life expectancy rates. However, they can cause several adverse events that have not been fully characterized, thus challenging clinical practice. OBJECTIVE: To evaluate the toxicity profile, determining its frequency, causality, and severity associated with treatment with PD-1 inhibitors in patients treated at an oncology service in the private health sector in Belo Horizonte. METHODS: Observational, retrospective, and cross-sectional study, based on the review of electronic medical records. The eligibility criteria included patients over 18 years old with a diagnosis of any cancer and staging, receiving a PD-1 inhibitor from January 2017 to January 2020. RESULTS: The sample consisted of 134 patients with lung cancer (46,3%), melanoma (34,3%), and kidney cancer (19,4%). The most common adverse event (AE) related to treatment were fatigue (51.5%), anorexia (23.1%), hypothyroidism (15.7%), and skin rash (14.9%), being grades 1 and 2 more prevalent. Between 3 and 12 months, there were more cutaneous, nutritional, and metabolic toxicities, and fatigue was present throughout the entire treatment period. Gastrointestinal and pulmonary toxicities were more frequent up to the 9th month. CONCLUSION: Based on real-world evidence, it was possible to reveal important findings to support the safe practice of PD-1 inhibitors treatment. Fatigue was the most prevalent AE among patients. In addition, the kinetics of AE allowed the identification of major occurrences according to the period o treatment, allowing more precise monitoring and surveillance.

Decreased expression of neuronal nitric oxide synthase contributes to the endothelial dysfunction associated with cigarette smoking in human.

Endothelial nitric oxide synthase (eNOS) malfunctioning has been proposed to contribute to the endothelial damage produced by cigarette. Besides eNOS, neuronal NOS (nNOS) is also expressed in most vascular tissues and plays an important role in the endothelium-dependent vascular relaxation. We hypothesize that nNOS may contribute to the endothelium dysfunction produced by cigarette in smokers. Vascular function was assessed in human resistance mesenteric arteries using a wire myograph, the level of protein expression by Western blot, eNOS and nNOS localization by immunofluorescence. Measurement of NO was assessed by fluorescence microscopy. Arteries of smokers showed impaired endothelium-dependent vascular relaxation in response to acetylcholine. Pharmacological nonselective blockade of NOS with l-NAME and selective nNOS blockade with inhibitor 1 reduced the relaxation of the mesenteric artery of both smokers and nonsmokers. Interestingly, the inhibitory effect of NOS inhibitors was greater in nonsmokers than in smokers. The expression of total nNOS and eNOS and the level of phosphorylation at eNOS-pSer1177 were reduced in arteries of smokers as compared with nonsmokers. No differences between groups were observed in the expression of total COX-1, COX-2, catalase and SOD-1. Immunofluorescence analysis showed the presence of nNOS in the vascular endothelium in both groups. Acetylcholine-induced NO production was impaired in arteries from smokers as compared to nonsmokers. Selective inhibition of nNOS caused a decreased in NO production, which was greater in nonsmokers than in smokers. Our data show that a decrease in nNOS expression contributes to the endothelial dysfunction caused by cigarette smoking in human.

Impact of multisection and immunohistochemistry in lymph node staging of Gastric Carcinoma - Case series.

Gastric carcinoma (GC) locoregional recurrence may occur even in cases where the tumor has been completely resected, possibly due to lymph node (LN) micrometastases. It is estimated that in 10% to 30% of cases, LN micrometastases are not detected by a conventional method for histological assessment of LN metastases with hematoxylin-eosin (HE). A cross-sectional study assessed 51 patients with GC by histological evaluation of the LN micrometastases through LN multi sectioning associated with immunohistochemistry analysis with monoclonal antibodies AE1 and AE3. Total gastrectomy was performed in 51% of patients. The total number of resected LN nodes was 1698, with a mean number of resected LN of 33.3 ± 13.2 per surgical specimen, of which 187 had metastasis. After the application of LN multisection and immunohistochemistry, LN micrometastases were found in 45.1% of the cases. LN staging changed in 29.4%, and tumor staging changed in 23.5% of the cases. In patients initially staged as pN0, LN staging and tumor staging changed, both in 19.2% of the cases. In patients initially staged as pN1 or more, LN staging changed in 40.0% of them, and tumor staging changed in 28.0% of the cases. The accuracy of HE for the histological staging of LN tumoral involvement was 76%, which was considered insufficient for CG patients staging. Investigation of LN micrometastasis through LN multisection and immunohistochemistry should be performed, particularly in cases where the presence of blood and lymphatic vessel invasion has been identified after conventional histological analysis, as well as in patients with advanced GC.

Hypodermoclysis as a Strategy for Patients With End-of-Life Cancer in Home Care Settings.

BACKGROUND: The increase in the elderly population associated with a higher incidence of cancer strongly endorses palliative care (PC). Hypodermoclysis (HDC) is a feasible technique for drugs and fluids delivery at the home care setting. OBJECTIVES: To assess the use and benefits of HDC in patients with end-of-life cancer assisted by a single home-based palliative care program (HPCP) in Belo Horizonte, Brazil. METHODS: This was a retrospective study that analyzed medical charts from patients with end-of-life cancer who were assisted by an HPCP in a 1-year period of time. RESULTS: A total of 333 patients, 81.7% with advanced cancer, were included. The most frequent symptoms were fatigue (44.4%) and pain (43.2%). Hypodermoclysis was used in 77.5% of the patients for the administration of fluids or medicines. Continuous palliative sedation was applied to 70.5% of patients. The place of death was home for 90.2% of the patients. CONCLUSION: Receiving home care assistance with palliative intention may decrease the need for dying patients with cancer to visit emergency units, as their symptoms were well controlled. Hypodermoclysis was a safe and effective alternative for hydration and drug delivery when provided and supervised by an experienced team. The place of death is a reliable indicator of the quality of death, and, in this study, the HPCP allowed patients to die at home with their families. It is essential for PC professionals to understand the impact of HDC use at home care setting for patients with end-of-life cancer allowing the increase of quality of death indicators.

Melanoma signature in Brazil: epidemiology, incidence, mortality, and trend lessons from a continental mixed population country in the past 15 years.

The current research aimed to understand melanoma epidemiology in Brazil and to evaluate temporal trends in incidence and mortality. The data came from Brazilian Hospital Cancer Registries, Population Based Cancer Registries, and the National Mortality Information System from 2000 to 2014. Descriptive statistics were used for epidemiological and clinical characteristics. To describe trends in change in incidence and mortality rates, the Average Annual Percentage Change (AAPC) was calculated. Between 2000 and 2013, in men, the median incidence rate rose from 2.52 to 4.84, with an AAPC of +21.5% [95% confidence interval (CI): 15.4-28] and in women from 1.93 to 3.22 per 100 000, with an AAPC of +13.9% (95% CI: 8.1-20). Regarding mortality, between 2000 and 2014, the rates went from 0.85 to 0.9 per 100 000 for men (AAPC=+0.8, 95% CI: 0.4-1.1) and from 0.56 for 0.53 per 100 000 for women (AAPC=-0.1, 95% CI: -0.2 to 0). From the database, a total of 28 624 patients with melanoma were included. Most of the patients were females (51.9%), White (75%) and with stage I or II (53.2%). Sex, ethnicity, education level, geographical area of the cancer center, topography, histology, time between diagnosis and treatment, and early death were significantly associated with distant metastases. Brazil is a large country with a very young population and a low rate of melanoma incidence and prevalence that should increase over the years. Understanding the trends attributed to melanoma is important for behavioral counseling interventions that focus on promoting skin cancer prevention.

Neuronal nitric oxide synthase contributes to the normalization of blood pressure in medicated hypertensive patients.

Neuronal nitric oxide synthase (nNOS) is expressed in the cardiovascular system and besides NO, generates H2O2. nNOS has been proposed to contribute to the control of blood pressure in healthy humans. The aim of this study was to verify the hypothesis that nNOS can contribute to the control of vascular relaxation and blood pressure in hypertensive patients undergoing drug treatment. The study was conducted in resistance mesenteric arteries from 63 individuals, as follows: 1) normotensive patients; 2) controlled hypertensive patients (patients on antihypertensive treatment with blood pressure normalized); 3) uncontrolled hypertensive patients (patients on antihypertensive treatment that remained hypertensive). Only mesenteric arteries from uncontrolled hypertensive patients showed impaired endothelium-dependent vasorelaxation in response to acetylcholine (ACh). Selective nNOS blockade with inhibitor 1 and catalase, which decomposes H2O2, decreased vasorelaxation in the three groups. However, the inhibitory effect was greater in controlled hypertensive patients. Decreased eNOS expression was detected in both uncontrolled and controlled hypertensive groups. Interestingly nNOS expression and ACh-stimulated H2O2 production were greater in controlled hypertensive patients, than in the other groups. ACh-stimulated NO production was lower in controlled hypertensive when compared to normotensive patients, while uncontrolled hypertensive patients showed the lowest levels. Catalase and nNOS blockade inhibited ACh-induced H2O2 production. In conclusion, nNOS-derived H2O2 contributes to the endothelium-dependent vascular relaxation in human resistance mesenteric arteries. The endothelial dysfunction observed in uncontrolled hypertensive patients involves decreased eNOS expression and NO production. The normalization of vascular relaxation and blood pressure in controlled hypertensive patients involves increased nNOS-derived H2O2 and NO production.

Follistatin Expression in Human Invasive Breast Tumors: Pathologic and Clinical Associations.

Follistatin is a potent native activin antagonist that is expressed in the normal mammary gland and in different breast proliferative diseases. Despite experimental evidence that follistatin can modulate the breast cancer cell cycle, the clinical significance of follistatin expression in these tumors is unknown. The aim of this study was to correlate the intensity of follistatin expression in invasive breast cancer with some of its clinical and pathologic features, such as the disease stage and the hormonal receptor status. Paraffin blocks of tumor samples that had been fixed in buffered formalin were obtained from 154 women subjected to surgery for breast cancer between 2008 and 2012. Sections from all paraffin blocks were cut and processed together by immunohistochemistry using a commercial monoclonal antibody to human follistatin. The intensity of follistatin staining was unrelated to the menopausal status, the disease stage, the grade, progesterone receptor expression, and local or systemic recurrence. However, follistatin immunoreactivity was significantly stronger in estrogen receptor (ER)-negative tumors than in ER-positive tumors. These findings suggest that follistatin expression in invasive breast cancer is unrelated to the disease severity and the risk of recurrence, but is more intense in ER-negative tumors.

Prognostic value of follistatin-like 3 in human invasive breast cancer.

Follistatin-like 3 (FSTL3) binds and inactivates activin, a growth factor involved with cell growth and differentiation. We have previously shown FSTL3 overexpression in invasive breast cancers, but its clinical relevance remained unexplored. Here we evaluate FSTL3 as a prognostic tool and its relation with clinical and pathological features of breast cancer. A cohort of 154 women diagnosed with invasive breast cancer between 2008 and 2012 was followed up for 5 years. Tumor samples were processed by immunohistochemistry to detect FSTL3 expression in tumor epithelium. FSTL3 expression was classified semiquantitatively and tested for possible correlation with age, menopause status, stage, tumor histological type and grade, estrogen receptor, progesterone receptor, and HER2 expression. Survival plots with Kaplan-Mayer statistics were used to assess whether FSTL3 expression predicted disease-free survival. Our findings show that FSTL3 staining was unrelated to menopausal status, histological type, disease stage, or receptor profile. However, the intensity of FSTL3 immunostaining correlated inversely with tumor size (r = -0.366, p<0.001) and with nuclear grade (p<0.01). The intensity of FSTL3 expression in the tumoral epithelium was not predictive of the disease-free survival (p = 0.991, log-rank test), even though the follow-up length and the study size were sufficient to detect a significant reduction in disease-free survival among women with stage III-IV compared to stage I-II disease (p<0.001). FSTL3 expression in invasive breast cancer is inversely associated with tumor size and nuclear grade but it does not predict disease relapse in the short term.

Adjuvant Weekly Girentuximab Following Nephrectomy for High-Risk Renal Cell Carcinoma: The ARISER Randomized Clinical Trial.

IMPORTANCE: Girentuximab is a chimeric monoclonal antibody that binds carbonic anhydrase IX, a cell surface glycoprotein ubiquitously expressed in clear cell renal cell carcinoma (ccRCC). Its safety and activity in phase 2 studies prompted investigation into its use as adjuvant monotherapy in participants with high-risk ccRCC. OBJECTIVE: To evaluate the safety and efficacy of adjuvant girentuximab on disease-free survival (DFS) and overall survival (OS) in patients with localized completely resected high-risk ccRCC. DESIGN, SETTING, AND PARTICIPANTS: The ARISER trial (Adjuvant Rencarex Immunotherapy Phase 3 Trial to Study Efficacy in Nonmetastatic RCC) was a randomized, double-blind, placebo-controlled phase 3 clinical trial that took place between June 10, 2004, and April 2, 2013, at 142 academic medical centers in 15 countries in North and South America and Europe. Eligible adult patients had undergone partial or radical nephrectomy for histologically confirmed ccRCC and fell into 1 of the following high-risk groups: pT3/pT4Nx/N0M0 or pTanyN+M0 or pT1b/pT2Nx/N0M0 with nuclear grade 3 or greater. Patients were assigned via central computerized double-blind 1:1 randomization to receive either a single loading dose of girentuximab, 50 mg (week 1), followed by weekly intravenous infusions of girentuximab, 20 mg (weeks 2-24), or placebo, stratified by risk group and region. The data were analyzed from March 31, 2012, to April 2, 2013. MAIN OUTCOMES AND MEASURES: Co-primary end points were DFS and OS, based on imaging studies assessed by independent radiological review committee. Secondary end points included safety, assessed as the rate and grade of adverse events. RESULTS: A total of 864 patients (66% male; median [interquartile range] age, 58 [51-65] years) were randomized to girentuximab (n = 433) or placebo (n = 431). Compared with placebo, participants treated with girentuximab had no statistically significant DFS (hazard ratio, 0.97; 95% CI, 0.79-1.18) or OS advantage (hazard ratio, 0.99; 95% CI, 0.74-1.32). Median DFS was 71.4 months (interquartile range, 3 months to not reached) for girentuximab and never reached for placebo group. Median OS was never reached regardless of treatment. Drug-related adverse events occurred in 185 patients (21.6%), reported comparably between arms. Serious adverse events occurred in 72 patients (8.4%), reported comparably between arms. One drug-related serious adverse event occurred in a patient receiving placebo. CONCLUSIONS AND RELEVANCE: Girentuximab had no clinical benefit as adjuvant treatment for patients with high-risk ccRCC. The surprisingly long DFS and OS in these patients represent a challenge to adjuvant ccRCC drug development. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00087022.

Delay in cutaneous melanoma diagnosis: Sequence analyses from suspicion to diagnosis in 211 patients.

Advanced melanoma is an incurable disease with complex and expensive treatments. The best approach to prevent melanoma at advanced stages is an early diagnosis. A knowledge of factors associated with the process of detecting cutaneous melanomas and the reasons for delays in diagnosis is essential for the improvement of the secondary prevention of the disease.Identify sociodemographic, individual, and medical aspects related to cutaneous melanoma diagnosis delay.Interviews evaluated the knowledge of melanoma, signals, symptoms, persons who were suspected, delays in seeking medical attention, physician's deferrals, and related factors of 211 patients.Melanomas were self-discovered in 41.7% of the patients; healthcare providers detected 29.9% of patients and others detected 27%. The main component in delay was patient-related. Only 31.3% of the patients knew that melanoma was a serious skin cancer, and most thought that the pigmented lesion was not important, causing a delay in seeking medical assistance. Patients (36.4%) reported a wait interval of more than 6 months from the onset of an observed change in a pigmented lesion to the first visit to a physician. The delay interval from the first physician visit to a histopathological diagnosis was shorter (<1 month) in 55.5% of patients. Improper treatments without a histopathological confirmation occurred in 14.7% of patients. A professional delay was related to both inappropriate treatments performed without histopathological confirmation (P = 0.003) and long requirements for medical referrals (P < 0.001).A deficient knowledge in the population regarding melanoma and physicians' misdiagnoses regarding suspicious lesions contributed to delays in diagnosis.

A phase II trial with anti-Lewis-Y monoclonal antibody (hu3S193) for the treatment of platinum resistant/refractory ovarian, fallopian tube and primary peritoneal carcinoma.

OBJECTIVES: The primary objective was to evaluate the clinical efficacy of hu3S193, a humanized monoclonal antibody against the Lewis-Y antigen, in patients with platinum resistant/refractory ovarian, fallopian tube and primary peritoneal carcinoma. Secondary objectives were safety and pharmacokinetics. In addition, we sought to determine the potential interaction of clinical benefit and patient characteristics. METHODS: This two-stage, multicenter, single arm, phase II trial enrolled eligible patients to receive hu3S193 weekly at a dose of 20mg/m(2) intravenously for 8 weeks (1 cycle) to a maximum of 3 cycles. Efficacy was measured as clinical benefit rate (objective response or stable disease for at least 24 weeks). RESULTS: 26 of 31 patients were eligible for efficacy analysis. No complete/partial responses were observed. Six patients had stable disease for 24+weeks [clinical benefit rate 23% (95% CI=9.77%-46.71%)]. Median PFS was 8.4 weeks (95% CI=6.0 to 16.1). Median PFS differed between patients with no ascites and no visceral disease and patients with ascites and/or visceral disease [16.1 vs. 8.1 weeks (p=0.0058)]. The most commonly reported treatment-related adverse events were fatigue (19.3%) and nausea (16.2%). Allergic reactions occurred in 6 patients (5 with Grade 1/2; 1 with Grade 3). CONCLUSIONS: Hu3S193 lacked sufficient activity in the first stage of the study to open enrollment to the second stage. However, based on the longer PFS in patients with no ascites and no visceral disease, consolidation strategies in platinum sensitive disease are currently being tested.

Acute toxicity of long-circulating and pH-sensitive liposomes containing cisplatin in mice after intraperitoneal administration.

AIMS: The objective of this work was to evaluate the acute toxicity of long-circulating and pH-sensitive liposomes containing cisplatin (SpHL-CDDP), after their intraperitoneal administration in male and female mice. MAIN METHODS: After single administration of free CDDP (5,10,and 20 mg/kg) or SpHL-CDDP (7,12,30,45 and 80 mg/kg), the body weight was recorded and the LD(50) was calculated. Blood samples were collected for biochemical and hematological analysis. Kidneys, liver, spleen and bone marrow were removed to histopathological examination. KEY FINDINGS: Mice treated with high doses of free CDDP showed a greater loss of body weight and more delayed recovery time than those treated with SpHL-CDDP. The LD(50) values for SpHL-CDDP treatment for male and female mice groups were 2.7 and 3.2 fold higher, respectively, than that obtained for free CDDP. The red and white blood cells counts and quantification of hemoglobin and hematocrit presented no change upon administration of SpHL-CDDP treatment. Free CDDP treatment, however, did lead to an appearance of mild anemia and a reduction in total white blood cell counts. As regards nephrotoxicity, it was observed that free CDDP treatment caused pronounced alterations in the blood urea and creatinine levels of mice. In contrast, these parameters were slightly altered only after SpHL-CDDP treatment at a dose of 30 mg/kg. Microscopic analysis of kidneys from mice treated with SpHL-CDDP showed no morphological alteration. Concerning hepatotoxicity, no histopathological alteration was observed after both treatments. SIGNIFICANCE: These findings reveal that SpHL-CDDP can eliminate CDDP-induced toxicity and is thus a promising candidate for intraperitoneal chemotherapy.

Tissue distribution evaluation of stealth pH-sensitive liposomal cisplatin versus free cisplatin in Ehrlich tumor-bearing mice.

Multidrug resistance and drug toxicity represent major obstacles to cancer chemotherapy. Drug delivery systems, such as liposomes, offer improved chemical stability of encapsulated drugs, enhanced accumulation in tumors and decreased toxicity. The aim of this study was to evaluate the tissue distribution of stealth pH-sensitive liposomes containing cisplatin (SpHL-CDDP), compared with free cisplatin (CDDP), in solid Ehrlich tumor-bearing mice. After administering a 6 mg/kg single intravenous bolus injection of either free radiolabeled cisplatin or SpHL containing radiolabeled cisplatin, blood and tissues were analyzed for cisplatin content by determining radioactivity using an automatic scintillation apparatus. The area under the CDDP concentration-time curve (AUC) obtained for blood after SpHL-CDDP administration was 2.1 fold larger when compared with free CDDP treatment. The longer circulation of SpHL-CDDP led to a higher tumor AUC, and the determination of the ratio between AUC in each tissue and that in blood (Kp) showed a higher accumulation of CDDP in SpHL-CDDP administrated tumors. The SpHL-CDDP was also significantly uptaken by the liver and spleen. The distribution of SpHL-CDDP in these organs was extensive, revealing a high extravasation of CDDP to the tissues. The SpHL-CDDP kidney uptake was also greater than that of free CDDP; however, the Kp value found was lower. This indicates that the SpHL-CDDP led to a reduction of CDDP retention by renal tissue. Thus, these results indicate that the SpHL-CDDP may indeed be useful in alleviating renal damage induced by CDDP and thus represents a promising delivery system for cancer treatment through CDDP.