Management of typical and atypical metastatic lung carcinoids: present and future perspectives.

Lung carcinoids are rare tumors representing 1-2% of all invasive lung malignancies. They include typical and atypical carcinoids, whose distinction is made based on the mitotic index and presence or absence of necrosis. The 10-year overall survival for stage IV typical carcinoid is 47% and 18% for atypical carcinoid, reflecting the indolent growth of these tumors. There are limited approved treatment options for them and most of the evidence comes from retrospective analyses, single-arm trials, subgroup analysis of phase II/III trials for metastatic neuroendocrine tumors and extrapolation of data from phase III trials for gastroenteropancreatic neuroendocrine tumors. Management of metastatic lung carcinoids requires a multidisciplinary standardized approach in specialized centers. Treatment should have a dual objective, control of tumor growth and control of symptoms related to hypersecretion syndromes, aiming to improve quality of life and survival. In the continuum of treatment disease, locoregional treatment options need to be considered in parallel with systemic treatments. In this paper, we review the present treatment options and their rational and we give an insight into future alternatives.

Non-Small-Cell Lung Cancer Patients Harboring ROS1 Rearrangement: Real World Testing Practices, Characteristics and Treatment Patterns (ROS1REAL Study).

ROS1 rearrangements are considered rare in non-small-cell lung cancer (NSCLC). This retrospective real-world study aimed to evaluate first-line treatment with crizotinib, a tyrosine kinase inhibitor (TKI) standard of care vs. new generation ROS1 anti-cancer agents. Forty-nine ROS1-expressing NSCLC patients, diagnosed with advanced metastatic disease, were included. Molecular profiling using either FISH/CISH or NGS was performed on tissue samples. Twenty-eight patients were treated with crizotinib, while fourteen patients were administered newer drugs (entrectinib, repotrectinib) and seven patients received platinum-doublet chemotherapy in a first-line setting. Overall response rate and disease control rate for the crizotinib and entrectinb/repotrectinib cohort were 68% and 82% vs. 86% and 93%, respectively. Median progression free survival was 1.6 years (95% CI 1.15-2.215) for the crizotinib treatment vs. 2.35 years for the entrectinib/repotrectinib cohort (95% CI 1.19-3.52). Central nervous system progression was noted in 20% and 25% of the crizotinib and entrectinib/repotrectinib cohorts, respectively. This multi-center study presents real-world treatment patterns of ROS1 NSCLC population, indicating that crizotinib exhibited comparable results to entrectinib/repotrectinib in a first-line setting, although both response rate and survival was numerically longer with treatment with newer agents.

Neuroendocrine breast carcinoma.

Neuroendocrine breast cancer (NEBC) is a rare and heterogeneous entity. It most commonly presents a luminal phenotype and a worse prognosis. When diagnosed in an advanced stage, metastasis from another neuroendocrine tumor should be excluded. This case features a premenopausal woman with an oligometastatic breast large cell neuroendocrine carcinoma, estrogen receptor (ER) positive, and human epidermal growth factor receptor 2 (HER2) negative. Since the patient was very symptomatic at the presentation of the disease, chemotherapy was started. Complete radiological response of the metastatic disease was achieved, and the patient was then submitted to radical breast surgery and bilateral oophorectomy. She subsequently underwent radiation therapy. Since then and to date, she has been under endocrine therapy (ET) and a CDK4/6 inhibitor (CDK4/6i), with no evidence of malignant disease. Evidence to guide the choice of treatment for these tumors is currently scarce. In cases with oligometastatic disease, radical treatment should be considered. Given that this entity is rare, its reporting should be encouraged.

The Contribution of Inherited Thrombophilia to Venous Thromboembolism in Cancer Patients.

Although the relationship between venous thromboembolism (VTE) and cancer has been a subject of study, knowledge of the contribution of thrombophilia to thrombosis in patients with cancer is still very limited. The aim of this article is to collect present knowledge on the contribution of inherited thrombophilia to VTE in cancer patients. We performed a search in Google Scholar and PubMed and selected 21 from 76 returned articles. Then we made a narrative review of the selected articles. We describe 11 studies on the contribution of inherited thrombophilia to VTE in cancer patients in general and 10 on that contribution in specific types of cancer: 1 in colorectal cancer, 4 in breast cancer, 1 in gynecologic cancer and 4 in hematopoietic malignancies. All studies investigate the relation of factor V Leiden (FVL) to VTE, 13 that of the prothrombin G20210A mutation (PTG20210A) and 7 studies also investigate other inherited thrombophilias, such methylenetetrahydrofolate reductase gene mutations, although only 2 investigate the contribution of deficiencies of the natural anticoagulants. Studies are very heterogeneous, in design and sample size and conclusions differ considerably. There is no consensus on the contribution of inherited thrombophilia to VTE in cancer patients except for acute lymphoblastic leukemia in children. Probably, that contribution is not the same for all types of cancer and more studies are needed to bring more knowledge on this subject.

What's new about the tumor microenvironment of urothelial carcinoma?

Urothelial carcinoma is a significant global health concern that accounts for a substantial part of cancer diagnoses and deaths worldwide. The tumor microenvironment is a complex ecosystem composed of stromal cells, soluble factors, and altered extracellular matrix, that mutually interact in a highly immunomodulated environment, with a prominent role in tumor development, progression, and treatment resistance. This article reviews the current state of knowledge of the different cell populations that compose the tumor microenvironment of urothelial carcinoma, its main functions, and distinct interactions with other cellular and non-cellular components, molecular alterations and aberrant signaling pathways already identified. It also focuses on the clinical implications of these findings, and its potential to translate into improved quality of life and overall survival. Determining new targets or defining prognostic signatures for urothelial carcinoma is an ongoing challenge that could be accelerated through a deeper understanding of the tumor microenvironment.

Vitiligo-like Lesions as a Predictor of Response to Immunotherapy in Non-Small Cell Lung Cancer: Comprehensive Review and Case Series from a University Center.

The reference to vitiligo-like lesions (VLLs) induced by immune checkpoint inhibitors (ICIs) as a valuable predictive marker of treatment success of immunotherapy with ICIs in melanoma has been mentioned in the literature. Its role in non-small cell lung cancer (NSCLC)-treated patients remains a poorly recognized phenomenon with uncertain significance regarding its predictive value. A retrospective, observational, single-center report was performed, with descriptive analysis of clinicopathological and treatment characteristics of patients with stage IV NSCLC who developed ICI-induced VLL between January 2018 and December 2022, contextualized in a comprehensive review of the literature and reported cases regarding this phenomenon. During the first 5 years' experience of ICI use in stage IV NSCLC treatment, three cases of ICI-induced VLLs were diagnosed. In line with the previous reports, two of the three presented cases exhibited treatment response and favorable prognosis. The recognition and understanding of the pathophysiological processes underlying ICI-induced VLLs may represent a promising opportunity to identify a predictive marker of tumor response to ICIs, with impact in treatment selection and patient management. It also may contribute to the recognition of new patterns of molecular expression that could lead to improvements in therapeutic development.

BMP6 and VDR gene polymorphisms are associated with osteonecrosis in a sickle cell anaemia cohort.

The occurrence and severity of osteonecrosis in sickle cell anaemia (SCA) vary due to risk factors, including genetic modifiers. Bone morphogenetic proteins (BMPs), particularly BMP6, and the vitamin D receptor (VDR) play key roles in cartilage and bone metabolism, making them potential contributors to orthopaedic outcomes in SCA. Here, we evaluated the association of polymorphisms in BMP6 (rs3812163, rs270393 and rs449853) and VDR (FokI rs2228570 and Cdx2 rs11568820) genes with osteonecrosis risk in a Brazilian SCA cohort. A total of 177 unrelated SCA patients were selected. The AA genotype of BMP6 rs3812163 was independently associated with a lower osteonecrosis risk (p = 0.015; odds ratio (OR): 0.38; 95% confidence interval (CI): 0.18-0.83) and with the long-term cumulative incidence of osteonecrosis (p = 0.029; hazard ratio: 0.56, 95% CI: 0.34-0.94). The VDR rs2228570 TT genotype was independently associated with a lower osteonecrosis risk (p = 0.039; OR: 0.14; 95% CI: 0.02-0.90). In summary, our results provide evidence that BMP6 rs3812163 and the VDR rs2228570 might be implicated in osteonecrosis pathophysiology in SCA and might help identify individuals at high risk.

O impacto da depressão pós-parto no desenvolvimento cognitivo infantil / The impact of postpartum depression on child cognitive development

Objetivo: avaliar as consequências da depressão pós-parto no desenvolvimento cognitivo infantil. Métodos: trata-se de uma revisão narrativa, com caráter analítico quantitativo, realizada por meio da busca de artigos científicos publicados, nas plataformas Google Acadêmico, Scielo e PubMed, sobre a relação entre depressão pós-parto e desenvolvimento infantil. Resultados: foi selecionado um total de 23 artigos entre os três bancos de dados. Os resultados apontam que filhos de mães deprimidas são mais propensos a ter alterações no desenvolvimento cognitivo, social e linguístico do que filhos de mães não deprimidas. Entretanto, deve-se lembrar que essa alteração não acontece exclusivamente pela depressão pós-parto, uma vez que ela pode estar associada a outros fatores de risco, como condições socioeconômicas e apoio marital. Conclusão: a depressão pós-parto como fator isolado afeta o bebê de maneira sutil, mas, diante de diversos fatores ambientais e conduta parental, o efeito nocivo pode ser intensificado, o que pode prejudicar os desempenhos nos testes cognitivos, de atenção e aprendizagem. Desse modo, compreende-se que é importante incentivar um acompanhamento pré-natal que valorize a saúde mental das gestantes, para que qualquer manifestação psicológica negativa seja prontamente identificada e receba o apoio necessário o mais rápido possível.

Objective: to evaluate the consequences of postpartum depression on child cognitive development. Methods: this is a narrative review, with a quantitative analytical character, carried out by searching for scientific articles published on the Google Scholar, Scielo and PubMed platforms on the relationship between postpartum depression and child development. Results: a total of 23 articles were selected from the three databases. The results indicate that children of depressed mothers are more likely to have changes in cognitive, social and linguistic development than children of non-depressed mothers. However, it should be remembered that this change does not occur exclusively due to postpartum depression, as it may be associated with other risk factors, such as socioeconomic conditions and marital support. Conclusion: postpartum depression as an isolated factor affects the baby in a subtle way, but, given several environmental factors and parental behavior, the harmful effect can be intensified, which can harm performance in cognitive, attention and learning tests. Therefore, it is understood that it is important to encourage prenatal care that values the mental health of pregnant women, so that any negative psychological manifestations are promptly identified and receive the necessary support as quickyl as possible.

Lung Cancer Related Thrombosis (LCART): Focus on Immune Checkpoint Blockade.

Cancer-associated thrombosis (CAT) is a common complication in lung cancer patients. Lung cancer confers an increased risk of thrombosis compared to other solid malignancies across all stages of the disease. Newer treatment agents, including checkpoint immunotherapy and targeted agents, may further increase the risk of CAT. Different risk-assessment models, such as the Khorana Risk Score, and newer approaches that incorporate genetic risk factors have been used in lung cancer patients to evaluate the risk of thrombosis. The management of CAT is based on the results of large prospective trials, which show similar benefits to low-molecular-weight heparins (LMWHs) and direct oral anticoagulants (DOACs) in ambulatory patients. The anticoagulation agent and duration of therapy should be personalized according to lung cancer stage and histology, the presence of driver mutations and use of antineoplastic therapy, including recent curative lung surgery, chemotherapy or immunotherapy. Treatment options should be evaluated in the context of the COVID-19 pandemic, which has been shown to impact the thrombotic risk in cancer patients. This review focuses on the epidemiology, pathophysiology, risk factors, novel predictive scores and management of CAT in patients with active lung cancer, with a focus on immune checkpoint inhibitors.

A-296G variant of THBS1 gene (rs1478605) is associated with a lower frequency of stroke in a Brazilian population with sickle cell anemia.

OBJECTIVES: Stroke is a devastating clinical outcome that significantly contributes to the morbidity and mortality of sickle cell anemia (SCA) patients. Despite its advantages in predicting stroke risk, transcranial Doppler screening has limitations that restrict its applicability, highlighting the need for emerging prognostic tools. Thrombospondin-1 plays a crucial role in endothelial injury, platelet adhesion, and nitric oxide metabolism and may be implicated in stroke pathophysiology. Here, we aimed to evaluate the association of THBS1 genetic variations with the occurrence of stroke in SCA patients MATERIALS AND METHODS: By real-time PCR, 512 SCA patients were fully genotyped for THBS1 A-296G (rs1478605) polymorphism RESULTS: THBS1 GG genotype was associated with a lower risk for stroke occurrence [odds ratio (OR): 0.30; 95% confidence interval (CI): 0.11-0.78; P = 0.011], although these findings were not consistent with multivariate logistic regression analysis (OR: 0.73, 95% CI: 0.12 - 4.37; P = 0.736). In agreement, the cumulative incidence of stroke for patients with AG/AA genotypes was higher when compared to the GG genotype (P = 0.018). However, the association was not maintained in the multivariate proportional hazards model (hazard ratio: 0.67, 95% CI: 0.12-3.61; P = 0.643) CONCLUSIONS: In summary, the present study shows that the THBS1 A-296G (rs1478605) polymorphism may be a potential modifier for stroke in SCA.

Occurrence and evolutionary conservation analysis of α-helical cationic amphiphilic segments in the human proteome.

The existence of encrypted fragments with antimicrobial activity in human proteins has been thoroughly demonstrated in the literature. Recently, algorithms for the large-scale identification of these segments in whole proteomes were developed, and the pervasiveness of this phenomenon was stated. These algorithms typically mine encrypted cationic and amphiphilic segments of proteins, which, when synthesized as individual polypeptide sequences, exert antimicrobial activity by membrane disruption. In the present report, the human reference proteome was submitted to the software kamal for the uncovering of protein segments that correspond to putative intragenic antimicrobial peptides (IAPs). The assessment of the identity of these segments, frequency, functional classes of parent proteins, structural relevance, and evolutionary conservation of amino acid residues within their corresponding proteins was conducted in silico. Additionally, the antimicrobial and anticancer activity of six selected synthetic peptides was evaluated. Our results indicate that cationic and amphiphilic segments can be found in 2% of all human proteins, but are more common in transmembrane and peripheral membrane proteins. These segments are surface-exposed basic patches whose amino acid residues present similar conservation scores to other residues with similar solvent accessibility. Moreover, the antimicrobial and anticancer activity of the synthetic putative IAP sequences was irrespective to whether these are associated to membranes in the cellular setting. Our study discusses these findings in light of the current understanding of encrypted peptide sequences, offering some insights into the relevance of these segments to the organism in the context of their harboring proteins or as separate polypeptide sequences.

Feasibility and User Experience of Digital Patient Monitoring for Real-World Patients With Lung or Breast Cancer.

BACKGROUND: Digital patient monitoring (DPM) tools can facilitate early symptom management for patients with cancer through systematic symptom reporting; however, low adherence can be a challenge. We assessed patient/healthcare professional (HCP) use of DPM in routine clinical practice. MATERIALS AND METHODS: Patients with locally advanced/metastatic lung cancer or HER2-positive breast cancer received locally approved/reimbursed drugs alongside DPM, with elements tailored by F. Hoffmann-La Roche Ltd, on the Kaiku Health DPM platform. Patient access to the DPM tool was through their own devices (eg, laptops, PCs, smartphones, or tablets), via either a browser or an app on Apple iOS or Android devices. Coprimary endpoints were patient DPM tool adoption (positive threshold: 60%) and week 1-6 adherence to weekly symptom reporting (positive threshold: 70%). Secondary endpoints included experience and clinical impact. RESULTS: At data cutoff (June 9, 2022), adoption was 85% and adherence was 76%. Customer satisfaction and effort scores for patients were 76% and 82%, respectively, and 83% and 79% for HCPs. Patients spent approximately 10 minutes using the DPM tool and completed approximately 1.0 symptom questionnaires per week (completion time 1-4 minutes). HCPs spent approximately 1-3 minutes a week using the tool per patient. Median time to HCP review for alerted versus non-alerted symptom questionnaires was 19.6 versus 21.5 hours. Most patients and HCPs felt that the DPM tool covered/mostly covered symptoms experienced (71% and 75%), was educational (65% and 92%), and improved patient-HCP conversations (70% and 83%) and cancer care (51% and 71%). CONCLUSION: The DPM tool demonstrated positive adoption, adherence, and user experience for patients with lung/breast cancer, suggesting that DPM tools may benefit clinical cancer care.

Sequence-dependent and -independent information in a combined random energy model for protein folding and coding.

Random energy models (REMs) provide a simple description of the energy landscapes that guide protein folding and evolution. The requirement of a large energy gap between the native structure and unfolded conformations, considered necessary for cooperative, protein-like, folding behavior, indicates that proteins differ markedly from random heteropolymers. It has been suggested, therefore, that natural selection might have acted to choose nonrandom amino acid sequences satisfying this particular condition, implying that a large fraction of possible, unselected random sequences, would not fold to any structure. From an informational perspective, however, this scenario could indicate that protein structures, regarded as messages to be transmitted through a communication channel, would not be efficiently encoded in amino acid sequences, regarded as the communication channel for this transmission, since a large fraction of possible channel states would not be used. Here, we use a combined REM for conformations and sequences, with previously estimated parameters for natural proteins, to explore an alternative possibility in which the appropriate shape of the landscape results mainly from the deviation from randomness of possible native structures instead of sequences. We observe that this situation emerges naturally if the distribution of conformational energies happens to arise from two independent contributions corresponding to sequence-dependent and -independent terms. This construction is consistent with the hypothesis of a protein burial folding code, with native structures being determined by a modest amount of sequence-dependent atomic burial information with sequence-independent constraints imposed by unspecific hydrogen bond formation. More generally, an appropriate combination of sequence-dependent and -independent information accommodates the possibility of an efficient structural encoding with the main physical requirement for folding, providing possible insight not only on the folding process but also on several aspects sequence evolution such as neutral networks, conformational coverage, and de novo gene emergence.

Neuroendocrine breast carcinoma

ABSTRACT Neuroendocrine breast cancer (NEBC) is a rare and heterogeneous entity. It most commonly presents a luminal phenotype and a worse prognosis. When diagnosed in an advanced stage, metastasis from another neuroendocrine tumor should be excluded. This case features a premenopausal woman with an oligometastatic breast large cell neuroendocrine carcinoma, estrogen receptor (ER) positive, and human epidermal growth factor receptor 2 (HER2) negative. Since the patient was very symptomatic at the presentation of the disease, chemotherapy was started. Complete radiological response of the metastatic disease was achieved, and the patient was then submitted to radical breast surgery and bilateral oophorectomy. She subsequently underwent radiation therapy. Since then and to date, she has been under endocrine therapy (ET) and a CDK4/6 inhibitor (CDK4/6i), with no evidence of malignant disease. Evidence to guide the choice of treatment for these tumors is currently scarce. In cases with oligometastatic disease, radical treatment should be considered. Given that this entity is rare, its reporting should be encouraged.

Blood components requirement in Brazilian dengue outbreaks: A retrospective analysis between 2008 to 2019.

INTRODUCTION: Dengue is the most fatal virus disease spread by mosquito bites and Aedes aegypti is the main transmitting agent. It is an endemic disease in the tropical and subtropical regions, currently affecting more than 100 countries. Although most patients present mild forms of the disease, a considerable proportion of individuals has severe alterations in the blood count. The aim of this study was to evaluate the consumption pattern of blood components in epidemic and non-epidemic periods and to verify if there was an impact on dengue cases and the death rate. METHOD: This is a retrospective cross-sectional study conducted through the collection and analysis of data from the Brazilian Ministry of Health from 2008 to 2019 on new cases and deaths from dengue, as well as the consumption of blood components in the period mentioned by hemovigilance bulletins of the Brazilian authority. RESULTS: Regarding the results, no significant difference was found between the absolute amount of blood components used in years with an epidemic peak. Regarding the relative values, an important variation was shown among the distributive consumption patterns of blood components in the outbreak years. In the univariate linear regression analysis, there was statistical significance between the increase in the number of dengue cases and deaths from dengue with the increase in the consumption of red blood cell concentrates (RBP), platelet concentrates (PP), fresh frozen plasma (FFP) and cryoprecipitate (Cryo) (p-value < 0.05). The increase in dengue cases was related to the increase in Cryo consumption with clinical significance (R² > 0.5), but dengue deaths were not correlated to the same. In multivariate analysis, all regression models had clinical and statistical significance. CONCLUSION: The data obtained in the present study demonstrate that there is a relevant relationship between the increase in cases and deaths from dengue with the blood components usage, especially PP, FFP and cryoprecipitate.

Real-World Experience in Treatment of Patients with Non-Small-Cell Lung Cancer with BRAF or cMET Exon 14 Skipping Mutations.

BRAF and cMET exon 14 skipping are rare mutations of NSCLC. The treatment sequence in these cases for the first and second line is not clear. An international registry was created for patients with advanced NSCLC harboring BRAF or cMET exon 14 skipping mutations, diagnosed from January 2017 to June 2022. Clinicopathological and molecular data and treatment patterns were recorded. Data on 58 patients, from eight centers across five countries, were included in the final analysis. We found that 40 patients had the cMET exon 14 skipping mutation and 18 had the BRAF V600E mutation. In total, 53 and 28 patients received first- and second-line treatments, respectively, among which 52.8% received targeted therapy (TT) in the first line and 53.5% in the second line. The overall response rate (ORR) and disease control rate (DCR) for first-line treatment with TT vs. other treatment such as immune checkpoint inhibitors ± chemotherapy (IO ± CT) were 55.6% vs. 21.7% (p = 0.0084) and 66.7% vs. 39.1% (p = 0.04), respectively. The type of treatment in first-line TT vs. other affected time to treatment discontinuation (TTD) was 11.6 m vs. 4.6 m (p= 0.006). The overall survival for the whole group was 15.4 m and was not statistically affected by the type of treatment (19.2 m vs. 13.5 m; p = 0.83).

Aumolertinib in NSCLC with leptomeningeal involvement, harbouring concurrent EGFR exon 19 deletion and TP53 comutation: a case report.

Background: Aumolertinib (HS-10296), a 3rd-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI), has been shown to have efficacy in treating tumors harboring EGFR sensitive mutations: EGFR in-frame deletions or insertions within exon 19 deletion (19Del) and the exon 21 L858R mutation and EGFR T790M resistance mutation. Research has shown that tumor protein p53 (TP53) mutations and leptomeningeal metastases (LM) are associated with reduced responsiveness and a poor prognosis in patients with advanced non-small cell lung cancer (NSCLC) who have received targeted therapy with EGFR-TKIs. The TP53 mutation is a common concomitant mutation of EGFR amplification in solid tumors. First-line aumolertinib treatment is effective in EGFR concurrent mutated NSCLC, however, the efficacy and survival outcomes in these patients with leptomeningeal metastasis remain unknown. Case Description: We retrospectively examined the data of a lung adenocarcinoma patient, 51 years old, male, multi-mutations of EGFR and TP53, who received 1st-line treatment with a 1st-generation TKI followed by 2nd-line treatment with aumolertinib. Before the 1st-line treatment, the patient underwent a lung biopsy to examine the 520 genes of all cancers using illumia high-throughput sequencing. The sequencing results showed that the patient had the EGFR 19del (p.Leu747_Thr751del)/TP53 (p.lys120fs)/EGFR amplified multiple mutation with a low tumor mutational burden. The patient was treated with gefitinib and achieved progression-free survival (PFS) for 10 months until secondary malignancy of the lymph nodes. The first-generation TKI combined with chemotherapy was applied and then the patient was diagnosed with leptomeningeal metastases. Subsequently, the patient was treated with aumolertinib for 12 months without disease progression. The efficacy evaluation was partial response (PR) with grade 2 rash. Adenocarcinoma cells were found in the cerebrospinal fluid (CSF). CSF-derived circulating tumor deoxyribonucleic acid was detected using the target area probe capture and 2nd-generation high-throughput sequencing technology. The CSF gene detection showed the EGFR p. L747_T751 del, TP53 p. K120fs and EGFR amplification mutations. Conclusions: This is the first reported case in which aumolertinib was used to treat a patient with the multi-mutations of EGFR 19Del, TP53, and EGFR amplification and leptomeningeal metastases. The findings suggested that almonertinib may result in long-period clinical improvement and tolerable safety in concurrent mutated LM NSCLC.