Small biopsies for pancreatic lesions: Is there still room for fine needle aspiration?

Pancreatic carcinoma is an aggressive tumour with increasing incidence in both sexes worldwide. Early detection is, therefore, essential for patient management. A recent advancement involves the utilization of larger, thicker gauge needles, which enable the collection of core-type biopsies (FNB). Here, we investigated the role of fine needle aspiration and cytopathology in the diagnostic workflow of pancreatic lesions. A search query was designed to search for articles in the PubMed database comparing FNA and FNB for biopsy of pancreatic lesions, and detailed data were extracted from selected studies. Statistical analyses were performed using the R package meta version 6.2. Twenty-one studies made the final cut for data extraction. Overall, median age was 64.3 years (±6.1; 47.6-71.5), male: female proportion 53.9 (±11.3; 27.6-67.4), lesion size 3.1 cm (±0.5; 1.9-4.2 cm) and percentage of malignant cases 78.3% (±26.8; 2.1-100). FNA and FNB diagnostic yield was 85.8% (±10.3; 70.0-100.0) and 89.2% (±7.7; 70.0-98.6), respectively. Average accuracy was 89.5% (±11.7; 63.0-100.0) for FNA and 90.8% (±7.1; 77.0-100.0) for FNB. Adverse effects rate was 1.0% (±1.3; 0-4.3) for FNA and 2.2% (±4.4; 0-16.1) for FNB. None of the selected variables had a significant statistical difference between both methods. FNA and FNB perform similarly for diagnostic material acquisition in pancreatic lesions. The best outcome comes from the association of both techniques, emphasizing the value of combining cytological and histological morphology for the most accurate analysis.

Immunohistochemical Differentiation between Western and East Asian Types of CagA-Positive Helicobacter pylori in Gastric Biopsy Samples.

Background: Cag A-positive Helicobacter pylori isolated from human gastric mucosa is categorized as a Western or East Asian allele-type based on whether the cagA gene encodes an EPIYA-C or EPIYA-D motif. We aimed to differentiate between the 2 types of H. pylori by immunohistochemistry (IHC) using formalin-fixed paraffin-embedded (FFPE) gastric biopsy samples. Materials and Methods: We developed 2 monoclonal antibodies (mAbs) that detect either the EPIYA-C or EPIYA-D motif of the H. pylori CagA protein by IHC using FFPE tissues. FFPE tissue sections from 30 Japanese and 39 Brazilian gastric biopsy samples with H. pylori infection confirmed by Giemsa staining (moderate/severe in the Sydney classification system) were examined by IHC with the novel mAbs followed by polymerase chain reaction (PCR) for EPIYA-C or EPIYA-D using DNA extracted from adjacent tissue sections. Results: Differentiation among Western and East Asian types and CagA-negative H. pylori was successful in most (97%) samples by IHC with the novel mAbs and commercially available mAbs that react with a species-specific lipopolysaccharide or a common CagA motif of H. pylori. The detection status of EPIYA-C/D motifs by IHC with the novel mAbs was consistent with the PCR results in 61 (88%) of 69 samples: EPIYA-C(+)/D(-) in zero Japanese and 26 Brazilian samples, EPIYA-C(-)/D(+) in 26 Japanese and 1 Brazilian sample, and EPIYA-C(-)/D(-) in 1 Japanese and 7 Brazilian samples. The detection sensitivity and specificity of IHC with each novel mAb compared with the PCR results were, respectively, 84% and 97% for EPIYA-C, and 97% and 95% for EPIYA-D. Conclusions: The novel mAbs specific to each EPIYA-C or EPIYA-D motif differentiated between Western and East Asian types of CagA-positive H. pylori by IHC using FFPE tissues. Applying these novel mAbs to large numbers of archived pathology samples will contribute to elucidating the association of these allele types with gastric cancer.

Gestational age acceleration is associated with epigenetic biomarkers of prenatal physiologic stress exposure.

BACKGROUND: Physiological maternal stress response, such as imbalance in the glucocorticoid pathway and immune system seems to be mediated by DNA methylation (DNAm) and might translate intrauterine stress exposures into phenotypic changes in a sex-specific manner. DNAm in specific sites can also predict newborn gestational age and gestational age acceleration (GAA). GAA occurs when the predicted biological age is higher than the chronological age. In adults, poor health outcomes related to this deviance are well documented and raise questions for the interpretation and prediction in early stages of life. Boys seem to be more vulnerable to intrauterine stress exposure than girls; however, the mechanisms of adaptive sex-specific responses are still unclear. We hypothesize that intrauterine stress exposure is associated with GAA and could be different in boys and girls if inflammatory or glucocorticoid pathways exposure is considered. RESULTS: Using the Western Region Birth Cohort (ROC-São Paulo, Brazil) (n = 83), we calculated DNAm age and GAA from cord blood samples. Two epigenetic risk scores were calculated as an indirect proxy for low-grade inflammation (i-ePGS) and for glucocorticoid exposure (GES). Multivariate linear regression models were applied to investigate associations of GAA with prenatal exposures. The i-ePGS and GES were included in different models with the same co-variates considering sex interactions. The first multivariate model investigating inflammatory exposure (adj. R2 = 0.31, p = < 0.001) showed that GAA was positively associated with i-ePGS (CI, 0.26-113.87, p = 0.049) and negative pregnancy-related feelings (CI, 0.04-0.48 p = 0.019). No sex interaction was observed. The second model investigating glucocorticoid exposure (adj. R2 = 0.32, p = < 0.001) showed that the higher was the GAA was associated with a lower the lower was the GES in girls (CI, 0.04-2.55, p = 0.044). In both models, maternal self-reported mental disorder was negatively associated with GAA. CONCLUSION: Prenatal epigenetic score of exposure to low-grade inflammatory was a predictor of GAA for both sexes. Glucocorticoid epigenetic score seems to be more important to GAA in girls. This study supports the evidence of sex-specificity in stress response, suggesting the glucocorticoid as a possible pathway adopted by girls to accelerate the maturation in an adverse condition.

DNA methylation mediates a randomized controlled trial home-visiting intervention during pregnancy and the Bayley infant's cognitive scores at 12 months of age.

The crosstalk between maternal stress exposure and fetal development may be mediated by epigenetic mechanisms, including DNA methylation (DNAm). To address this matter, we collect 32 cord blood samples from low-income Brazilian pregnant adolescents participants of a pilot randomized clinical intervention study (ClinicalTrials.gov, Identifier: NCT02807818). We hypothesized that the association between the intervention and infant neurodevelopmental outcomes at 12 months of age would be mediated by DNAm. First, we searched genome methylation differences between cases and controls using different approaches, as well as differences in age acceleration (AA), represented by the difference of methylation age and birth age. According to an adjusted p-value ≤ 0.05 we identified 3090 differentially methylated positions- CpG sites (DMPs), 21 differentially methylated regions (DMRs) and one comethylated module weakly preserved between groups. The intervention group presented a smaller AA compared to the control group (p = 0.025). A logistic regression controlled by sex and with gestational age indicated a coefficient of -0.35 towards intervention group (p = 0.016) considering AA. A higher cognitive domain score from Bayley III scale was observed in the intervention group at 12 months of age. Then, we performed a potential causal mediation analysis selecting only DMPs highly associated with the cognitive domain (adj. R2 > 0.4), DMRs and CpGs of hub genes from the weakly preserved comethylated module and epigenetic clock as raw values. DMPs in STXBP6, and PF4 DMR, mediated the association between the maternal intervention and the cognitive domain at 12 months of age. In conclusion, DNAm in different sites and regions mediated the association between intervention and cognitive outcome.

Indoleamine 2,3-dioxygenase in melanoma progression and BRAF inhibitor resistance.

Indoleamine 2,3-dioxygenase (IDO) is associated with the progression of many types of tumors, including melanoma. However, there is limited information about IDO modulation on tumor cell itself and the effect of BRAF inhibitor (BRAFi) treatment and resistance. Herein, IDO expression was analyzed in different stages of melanoma development and progression linked to BRAFi resistance. IDO expression was increased in primary and metastatic melanomas from patients' biopsies, especially in the immune cells infiltrate. Using a bioinformatics approach, we also identified an increase in the IDO mRNA in the vertical growth and metastatic phases of melanoma. Using in silico analyses, we found that IDO mRNA was increased in BRAFi resistance. In an in vitro model, IDO expression and activity induced by interferon-gamma (IFNγ) in sensitive melanoma cells was decreased by BRAFi treatment. However, cells that became resistant to BRAFi presented random IDO expression levels. Also, we identified that treatment with the IDO inhibitor, 1-methyltryptophan (1-MT), was able to reduce clonogenicity for parental and BRAFi-resistant cells. In conclusion, our results support the hypothesis that the decreased IDO expression in tumor cells is one of the many additional outcomes contributing to the therapeutic effects of BRAFi. Still, the IDO production changeability by the BRAFi-resistant cells reiterates the complexity of the response arising from resistance, making it not possible, at this stage, to associate IDO expression in tumor cells with resistance. On the other hand, the maintenance of 1-MT off-target effect endorses its use as an adjuvant treatment of melanoma that has become BRAFi-resistant.

In vivo antitumoral effect of 4-nerolidylcatechol (4-NC) in NRAS-mutant human melanoma.

NRAS-mutations arise in 15-20% of all melanomas and are associated with aggressive disease and poor prognosis. Besides, the treatment for NRAS-mutant melanoma are not very efficient and is currently limited to immune checkpoints inhibitors or aggressive chemotherapy. 4-nerolidylcathecol (4-NC), a natural product extracted from Pothomorphe umbellata, induces apoptosis in melanoma cells by ROS production, DNA damage and increased p53 expression, in addition to inhibiting invasion in reconstructed skin. Moreover, 4-NC showed cytotoxicity in BRAF/MEKi-resistant and naive melanoma cells by Endoplasmic Reticulum (ER) stress induction in vitro. We evaluated the in vivo efficacy and the systemic toxicity of 4-NC in a NRAS-mutant melanoma model. 4-NC was able to significantly suppress tumor growth 4-fold compared to controls. Cleaved PARP and p53 expression were increased indicating cell death. As a proof of concept, MMP-2 and MMP-14 gene expression were decreased, demonstrating a possible role of 4-NC in melanoma invasion inhibition. Toxicological analysis indicated minor changes in the liver and bone marrow, but this toxicity was very mild when compared to other proteasome inhibitors and ER stress inductors already described. Our data indicate that 4-NC can counteract melanoma growth in vivo with minor adverse effects, suggesting further investigation as a potential NRAS-mutant melanoma treatment.

Tumour-derived transforming growth factor-ß signalling contributes to fibrosis in patients with cancer cachexia.

BACKGROUND: Cachexia is a paraneoplastic syndrome related with poor prognosis. The tumour micro-environment contributes to systemic inflammation and increased oxidative stress as well as to fibrosis. The aim of the present study was to characterise the inflammatory circulating factors and tumour micro-environment profile, as potentially contributing to tumour fibrosis in cachectic cancer patients. METHODS: 74 patients (weight stable cancer n = 31; cachectic cancer n = 43) diagnosed with colorectal cancer were recruited, and tumour biopsies were collected during surgery. Multiplex assay was performed to study inflammatory cytokines and growth factors. Immunohistochemistry analysis was carried out to study extracellular matrix components. RESULTS: Higher protein expression of inflammatory cytokines and growth factors such as epidermal growth factor, granulocyte-macrophage colony-stimulating factor, interferon-α, and interleukin (IL)-8 was observed in the tumour and serum of cachectic cancer patients in comparison with weight-stable counterparts. Also, IL-8 was positively correlated with weight loss in cachectic patients (P = 0.04; r = 0.627). Immunohistochemistry staining showed intense collagen deposition (P = 0.0006) and increased presence of α-smooth muscle actin (P < 0.0001) in tumours of cachectic cancer patients, characterizing fibrosis. In addition, higher transforming growth factor (TGF)-ß1, TGF-ß2, and TGF-ß3 expression (P = 0.003, P = 0.05, and P = 0.047, respectively) was found in the tumour of cachectic patients, parallel to p38 mitogen-activated protein kinase alteration. Hypoxia-inducible factor-1α mRNA content was significantly increased in the tumour of cachectic patients, when compared with weight-stable group (P = 0.005). CONCLUSIONS: Our results demonstrate TGF-ß pathway activation in the tumour in cachexia, through the (non-canonical) mitogen-activated protein kinase pathway. The results show that during cachexia, intratumoural inflammatory response contributes to the onset of fibrosis. Tumour remodelling, probably by TGF-ß-induced transdifferentiation of fibroblasts to myofibroblasts, induces unbalanced inflammatory cytokine profile, angiogenesis, and elevation of extracellular matrix components (EMC). We speculate that these changes may affect tumour aggressiveness and present consequences in peripheral organs.

Fatal necrotizing Candida esophagitis in a patient with leukocytoclastic cutaneous vasculitis and ankylosing spondylitis.

Esophageal infection by Candida spp. is a common opportunistic entity in immunocompromised hosts; however, systemic fungal dissemination due to perforation or transmural necrosis, also known as necrotizing Candida esophagitis (NCE), is rare. We report the case of a 61-year-old male patient with diagnosed ankylosing spondylitis, severe arteriosclerosis, and vasculitis under immunosuppressive therapy who presented NCE with fungal and bacterial septicemia diagnosed at autopsy. Necrotizing esophagitis is a rare manifestation of Candida infection, which may be a final complication in severely ill patients. Unfortunately, it may be underdiagnosed, and we call attention to this devastating complication in patients with leukocytoclastic cutaneous vasculitis and ankylosing spondylitis.

Immunohistochemical Assessment of the Expression of Biliary Transportation Proteins MRP2 and MRP3 in Hepatocellular Carcinoma and in Cholangiocarcinoma.

Multidrug resistance-associated protein 2 (MRP2) is a multi-specific organic anion transporter predominantly expressed in the canalicular membrane of hepatocytes, epithelial cells from gallbladder and apical membranes of proximal tubular kidney epithelium whereas multidrug resistance-associated protein 3 (MRP3) is present in the basolateral membrane of hepatocytes and cholangiocytes. This study aims to detect the expression of these transporters in hepatocellular carcinoma (HCC) and in cholangiocarcinoma (CC), searching for evidences for future studies on differential diagnosis and on clinical essays. The immunohistochemical reactivity (IHC) of these transporters was assessed in tissue microarrays of 80 HCC and 56 CC cases using monoclonal antibodies and compared with anatomopathological (AP) variables. The positivity of MRP2 was observed in 92.3% of HCC and in 96.3% of CC. The detection of high MRP2 expression in HCC was not significantly different (p > 0.05) according to the size, number of nodules architectural pattern and growth pattern of HCC and CC. Regarding histological grades, 22/22 well moderately differentiated HCC versus 50/56 poorly differentiated HCC were positive for MRP2. A trend for lower expression in poor differentiation HCC was found. And 50/50 well/moderately differentiated CC versus 2/4 poorly/undifferentiated CC were positive for MRP2. This result showed a reduced expression (p = 0,0004) in poorly differentiated CC. MRP3 positivity was observed in 18.8% of HCC and was not significantly different according to AP parameters. MRP3 was expressed in 44.5% CC, with a trend for lower expression in less differentiated CC and significantly lower rates in the ductular histological subtype (p = 0.023). The high expression of MRP2 in HCC and in CC is conserved regardless most of the anatomopathological parameters, except for a trend of lower expression in less differentiated HCC and CC. The observation of lower MRP3 expression in less differentiated CC and, especially, in the histological subtype with expression of hepatic progenitor cell phenotypes leads to future opportunities to evaluate the expression of this marker in cholangiocarcinomas.

Risk assessment of lymph node metastases in early gastric adenocarcinoma fulfilling expanded endoscopic resection criteria.

BACKGROUND AND AIMS: Early gastric cancer (EGC) is known to present a low rate of lymph node metastases (LNMs). Gastrectomy with D2 lymphadenectomy is usually curative for EGC. Endoscopic submucosal dissection (ESD) is a well-accepted treatment modality for lesions that meet the classic criteria: those mucosal differentiated adenocarcinoma measuring 20 mm or less, without ulceration. Expanded criteria for ESD have been proposed based on a null LNM rate from large gastrectomy series from Japan. Patients with LNM have been reported in Western centers, heightening the need for validation of expanded criteria. Our aim was to assess the risk of LNM in gastrectomy specimens of patients with EGC who met the expanded criteria for ESD. METHODS: We conducted an evaluation of gastrectomy specimens including LNM staging of patients submitted to gastrectomy for EGC in a 39-year retrospective cohort. RESULTS: A total of 389 surgical specimens were included. From them, 135 fulfilled criteria for endoscopic resection. None of the 31 patients with classic criteria had LNM. From the 104 patients with expanded criteria, 3 had LNM (n = 104 [2.9%], 95% confidence interval, .7%-8.6%), all of them with undifferentiated tumors without ulceration, measuring less than 20 mm. CONCLUSIONS: There is a small risk of LNM in EGC when expanded criteria for ESD are met. Refinement of the expanded criteria for the risk of LNM may be desirable in a Brazilian cohort. Meanwhile, the decision to complement the endoscopic treatment with gastrectomy will have to take into consideration the individual risk of perioperative morbidity and mortality.

Pulmonary histoplasmoma: a disguised malady.

Histoplasmosis is a mycosis caused by the dimorphic fungus, Histoplasma capsulatum, which is transmitted via dust and aerosols. Lung involvement is the most common, with a varied clinical presentation. Although it is not the only source of infection, H. capsulatum is frequently found in bat guano, which is the reason why it is highly prevalent among caving practitioners. The solitary histoplasmoma of the lung is an unusual and chronic manifestation of this entity, which mimics, or at least is frequently misconstrued, as a malignancy. Almost invariably, the diagnosis of this type of histoplasmosis presentation is achieved after lung biopsy. The authors present the case of a young woman who sought medical care because of chest pain. The diagnostic work-up revealed the presence of a pulmonary nodule. She was submitted to a thoracotomy and wedge pulmonary resection. The histologic analysis rendered the diagnosis of histoplasmoma. This report aims to call attention to this diagnosis as the differential diagnosis of a pulmonary nodule.

Bone marrow necrosis and fat embolism syndrome: a dreadful complication of hemoglobin sickle cell disease.

Sickle cell disease encompasses a wide range of genotypic presentation with particular clinical features. The entity affects millions of people, particularly those whose ancestors came from sub-Saharan Africa and other countries in the Western Hemisphere, Saudi Arabia, and India. Currently, the high frequency of S and C genes reflects natural selection through the protection of heterozygotes against severe malaria, the high frequency of consanguineous marriages, improvement of some public health policies and the nutritional standards in the poorer countries where newborns are now living long enough to present for diagnosis and management. Although there is a high burden of the disease, in many countries, the new-born sickle cell screening test is being performed and is rendering an early diagnosis; however, it is still difficult for sickle cell patients to find proper treatment and adequate follow-up. Moreover, in many countries, patients are neither aware of their diagnosis nor the care they should receive to prevent complications; also, they do not receive adequate genetic counseling. Hemoglobin SC (HbSC) disease is the most frequent double sickle cell heterozygosis found in Brazil. The clinical course tends to be more benign with fewer hospitalizations compared with double homozygotic SS patients. However, HbSC patients may present severe complications with a fatal outcome. We report the case of a 36-year-old man who presented to the emergency care facility with symptoms consistent with the diagnosis of sickling crisis. The outcome was unfavorable and death occurred just hours after admission. The autopsy revealed a generalized vaso-occlusive crisis by sickled red cells, bone marrow necrosis, and fat embolism syndrome.

Bone marrow necrosis and fat embolism syndrome: a dreadful complication of hemoglobin sickle cell disease

Sickle cell disease encompasses a wide range of genotypic presentation with particular clinical features. The entity affects millions of people, particularly those whose ancestors came from sub-Saharan Africa and other countries in the Western Hemisphere, Saudi Arabia, and India. Currently, the high frequency of S and C genes reflects natural selection through the protection of heterozygotes against severe malaria, the high frequency of consanguineous marriages, improvement of some public health policies and the nutritional standards in the poorer countries where newborns are now living long enough to present for diagnosis and management. Although there is a high burden of the disease, in many countries, the new-born sickle cell screening test is being performed and is rendering an early diagnosis; however, it is still difficult for sickle cell patients to find proper treatment and adequate follow-up. Moreover, in many countries, patients are neither aware of their diagnosis nor the care they should receive to prevent complications; also, they do not receive adequate genetic counseling. Hemoglobin SC (HbSC) disease is the most frequent double sickle cell heterozygosis found in Brazil. The clinical course tends to be more benign with fewer hospitalizations compared with double homozygotic SS patients. However, HbSC patients may present severe complications with a fatal outcome. We report the case of a 36-year-old man who presented to the emergency care facility with symptoms consistent with the diagnosis of sickling crisis. The outcome was unfavorable and death occurred just hours after admission. The autopsy revealed a generalized vaso-occlusive crisis by sickled red cells, bone marrow necrosis, and fat embolism syndrome.

Bicytopenia and leukoerythroblastosis: a rare initial presentation of signet ring cell gastric adenocarcinoma.

Gastric adenocarcinoma is a common neoplasia and is responsible for up to 30% of the overall deaths due to cancer. Advanced disease is mostly characterized by peritoneum, liver, and lung involvement. The spread of the disease to the bone is rare, and bone marrow dissemination is even rarer. In this setting, leukoerythroblastosis may be the initial manifestation of the disease. The authors report the case of a 64-year-old Caucasian man who sought medical care complaining of back pain, weakness, and weight loss. The physical examination revealed pallor, and the laboratory work-up depicted severe anemia and thrombocytopenia; the peripheral blood smear was consistent with leukoerythroblastosis. The ongoing investigation through a bone marrow biopsy showed massive involvement of the bone marrow by a signet ring cell adenocarcinoma. During hospitalization, the patient presented melena, and an upper digestive endoscopy depicted an ulcerated and infiltrative lesion in the cardia, upon which the histological examination revealed a signet ring cell adenocarcinoma. This case highlights the bone marrow invasion represented by bicytopenia and leukoerythroblastosis as the initial manifestation of this histological type of gastric cancer. Although treatment attempts were made with chemotherapy and radiotherapy, the patient died early on, showing the aggressive behavior of this form of tumoral presentation.

Severe pulmonary hypertension due to combined pulmonary fibrosis and emphysema: another cause of death among smokers.

In 2005, the combined pulmonary fibrosis and emphysema (CPFE) was first defined as a distinct entity, which comprised centrilobular or paraseptal emphysema in the upper pulmonary lobes, and fibrosis in the lower lobes accompanied by reduced diffused capacity of the lungs for carbon monoxide (DLCO). Recently, the fibrosis associated with the connective tissue disease was also included in the diagnosis of CPFE, although the exposure to tobacco, coal, welding, agrochemical compounds, and tire manufacturing are the most frequent causative agents. This entity characteristically presents reduced DLCO with preserved lung volumes and severe pulmonary hypertension, which is not observed in emphysema and fibrosis alone. We present the case of a 63-year-old woman with a history of heavy tobacco smoking abuse, who developed progressive dyspnea, severe pulmonary hypertension, and cor pulmonale over a 2-year period. She attended the emergency facility several times complaining of worsening dyspnea that was treated as decompensate chronic obstructive pulmonary disease (COPD). The imaging examination showed paraseptal emphysema in the upper pulmonary lobes and fibrosis in the middle and lower lobes. The echo Doppler cardiogram revealed the dilation of the right cardiac chambers and pulmonary hypertension, which was confirmed by pulmonary trunk artery pressure measurement by catheterization. During this period, she was progressively restricted to the minimal activities of daily life and dependent on caregivers. She was brought to the hospital neurologically obtunded, presenting anasarca, and respiratory failure, which led her to death. The autopsy showed signs of pulmonary hypertension and findings of fibrosis and emphysema in the histological examination of the lungs. The authors highlight the importance of the recognition of this entity in case of COPD associated with severe pulmonary hypertension of unknown cause.

Severe pulmonary hypertension due to combined pulmonary fibrosis and emphysema: another cause of death among smokers

In 2005, the combined pulmonary fibrosis and emphysema (CPFE) was first defined as a distinct entity, which comprised centrilobular or paraseptal emphysema in the upper pulmonary lobes, and fibrosis in the lower lobes accompanied by reduced diffused capacity of the lungs for carbon monoxide (DLCO). Recently, the fibrosis associated with the connective tissue disease was also included in the diagnosis of CPFE, although the exposure to tobacco, coal, welding, agrochemical compounds, and tire manufacturing are the most frequent causative agents. This entity characteristically presents reduced DLCO with preserved lung volumes and severe pulmonary hypertension, which is not observed in emphysema and fibrosis alone. We present the case of a 63-year-old woman with a history of heavy tobacco smoking abuse, who developed progressive dyspnea, severe pulmonary hypertension, and cor pulmonale over a 2-year period. She attended the emergency facility several times complaining of worsening dyspnea that was treated as decompensate chronic obstructive pulmonary disease (COPD). The imaging examination showed paraseptal emphysema in the upper pulmonary lobes and fibrosis in the middle and lower lobes. The echo Doppler cardiogram revealed the dilation of the right cardiac chambers and pulmonary hypertension, which was confirmed by pulmonary trunk artery pressure measurement by catheterization. During this period, she was progressively restricted to the minimal activities of daily life and dependent on caregivers. She was brought to the hospital neurologically obtunded, presenting anasarca, and respiratory failure, which led her to death. The autopsy showed signs of pulmonary hypertension and findings of fibrosis and emphysema in the histological examination of the lungs. The authors highlight the importance of the recognition of this entity in case of COPD associated with severe pulmonary hypertension of unknown cause.

Bicytopenia and leukoerythroblastosis: a rare initial presentation of signet ring cell gastric adenocarcinoma

Gastric adenocarcinoma is a common neoplasia and is responsible for up to 30% of the overall deaths due to cancer. Advanced disease is mostly characterized by peritoneum, liver, and lung involvement. The spread of the disease to the bone is rare, and bone marrow dissemination is even rarer. In this setting, leukoerythroblastosis may be the initial manifestation of the disease. The authors report the case of a 64-year-old Caucasian man who sought medical care complaining of back pain, weakness, and weight loss. The physical examination revealed pallor, and the laboratory work-up depicted severe anemia and thrombocytopenia; the peripheral blood smear was consistent with leukoerythroblastosis. The ongoing investigation through a bone marrow biopsy showed massive involvement of the bone marrow by a signet ring cell adenocarcinoma. During hospitalization, the patient presented melena, and an upper digestive endoscopy depicted an ulcerated and infiltrative lesion in the cardia, upon which the histological examination revealed a signet ring cell adenocarcinoma. This case highlights the bone marrow invasion represented by bicytopenia and leukoerythroblastosis as the initial manifestation of this histological type of gastric cancer. Although treatment attempts were made with chemotherapy and radiotherapy, the patient died early on, showing the aggressive behavior of this form of tumoral presentation.

Sex differences in DNA methylation of the cord blood are related to sex-bias psychiatric diseases.

Sex differences in the prevalence of psychiatric disorders are well documented, with exposure to stress during gestation differentially impacting females and males. We explored sex-specific DNA methylation in the cord blood of 39 females and 32 males born at term and with appropriate weight at birth regarding their potential connection to psychiatric outcomes. Mothers were interviewed to gather information about environmental factors (gestational exposure) that could interfere with the methylation profiles in the newborns. Bisulphite converted DNA was hybridized to Illumina HumanMethylation450 BeadChips. Excluding XYS probes, there were 2,332 differentially methylated CpG sites (DMSs) between sexes, which were enriched within brain modules of co-methylated CpGs during brain development and also differentially methylated in the brains of boys and girls. Genes associated with the DMSs were enriched for neurodevelopmental disorders, particularly for CpG sites found differentially methylated in brain tissue between patients with schizophrenia and controls. Moreover, the DMS had an overlap of 890 (38%) CpG sites with a cohort submitted to toxic exposition during gestation. This study supports the evidences that sex differences in DNA methylation of autosomes act as a primary driver of sex differences that are found in psychiatric outcomes.

Fatal hemoperitoneum due to segmental arterial mediolysis.

Spontaneous hemoperitoneum due to vascular injury is a life-threatening condition mostly associated with aortic or splanchnic arterial disease, which stems from atherosclerotic, inflammatory, or infectious origin. However, in 1976, Slavin and Gonzales described a nonatherosclerotic arterial disease that may render aneurysmal formation predominantly in the splanchnic arterial bed. The clinical presentation is diverse, but abdominal pain and shock prevail. We report the case of a middle-aged man who presented a hemoperitoneum due to a middle colic artery aneurysm rupture and died after undergoing a surgical treatment attempt. The preoperative imaging study revealed the presence of a huge hematoma in the epiplon retrocavity, and abdominal free liquid as well as extensive arterial disease with multiple aneurysms. The autopsy findings included hemoperitoneum, hematoma in the upper left abdominal quadrant, the surgical ligature of the middle colic artery, and histologic features consistent with segmental arterial mediolysis. The authors call attention to this rare entity and highlight the autopsy as a fundamental examination to accurately reach this diagnosis.