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Anomalous expression of potassium channels in cancer tissues is associated with several cancer hallmarks that support deregulated proliferation and tumor progression. Ion channels seem to influence cell proliferation; however, the crucial molecular mechanisms involved remain elusive. Some results show how extracellular mitogenic signals modulate ion channel activity through intracellular secondary messengers. It is relevant because we are beginning to understand how potassium channels can affect the proliferative capacity of cells, either in normal mitogen-dependent proliferation or in mitogen-unresponsive proliferation. Calciumdependent potassium channels have been implicated in cell cycle signaling in many cancerous cell lines. In particular, the so-called intermediate conductance KCa3.1 (IKCa) is reported to play a significant role in uncontrolled cell cycle signaling, among other malignant processes driven by cancer hallmarks. In addition to these features, this channel can be subjected to specific pharmacological regulation, making it a promising cornerstone for understanding the signaling behavior of several types of cancer and as a target for chemotherapeutic approaches. This review is dedicated to the connection of KCa3.1 activity, in canonical and non-canonical ways, to the cell cycle signaling, including the cooperation with calcium channels to generate calcium signals and its role as a mediator of proliferative signals., Competing Interests: The authors have nothing to disclose., (© Copyright by the Author(s). Published by Cell Physiol Biochem Press.)

Huntington's disease (HD) is caused by an aberrant expansion of CAG repeats in the HTT gene that mainly affects basal ganglia. Although striatal dysfunction has been widely studied in HD mouse models, other brain areas can also be relevant to the pathology. In this sense, we have special interest on the retina as this is the most exposed part of the central nervous system that enable health monitoring of patients using noninvasive techniques. To establish the retina as an appropriate tissue for HD studies, we need to correlate the retinal alterations with those in the inner brain, i.e., striatum. We confirmed the malfunction of the transgenic R6/1 retinas, which underwent a rearrangement of their transcriptome as extensive as in the striatum. Although tissue-enriched genes were downregulated in both areas, a neuroinflammation signature was only clearly induced in the R6/1 retina in which the observed glial activation was reminiscent of the situation in HD patient's brains. The retinal neuroinflammation was confirmed in the slow progressive knock-in zQ175 strain. Overall, these results demonstrated the suitability of the mouse retina as a research model for HD and its associated glial activation., (© 2024. The Author(s).)

Introduction: The addition of taxanes to anthracycline-based chemotherapy is considered standard of care in the treatment of breast cancer. However, there are insufficient data regarding the safety of taxanes during pregnancy. The aim of this study was to describe the incidence of obstetric and neonatal adverse events associated with the use of taxane-containing chemotherapy regimens for the treatment of breast cancer during pregnancy., Methods: This is a multicenter, international cohort study of breast cancer patients treated with taxanes during pregnancy. A descriptive analysis was undertaken to synthetize available data., Results: A total of 103 patients were included, most of whom were treated with paclitaxel and anthracyclines given in sequence during gestation (90.1%). The median gestational age at taxane initiation was 28 weeks (range = 12-37 weeks). Grade 3-4 adverse events were reported in 7 of 103 (6.8%) patients. The most common reported obstetric complications were intrauterine growth restriction (n = 8 of 94, 8.5%) and preterm premature rupture of membranes (n = 5 of 94, 5.3%). The live birth rate was 92 of 94 (97.9%), and the median gestational age at delivery was 37 weeks (range = 32-40 weeks). Admission to an intensive care unit was reported in 14 of 88 (15.9%) neonates, and 17 of 70 (24.3%) live births resulted in small for gestational age neonates. Congenital malformations were reported in 2 of 93 (2.2%)., Conclusion: Obstetric and neonatal outcomes after taxane exposure during pregnancy were generally favorable and did not seem to differ from those reported in the literature with standard anthracycline-based regimens. This study supports the use of taxanes during gestation when clinically indicated., (© The Author(s) 2023. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Introduction: reconstruction of large bone defects using modular knee arthroplasty (MKA) presents a significant challenge in terms of functionality. The objective of the present work was to identify the different prognostic factors associated with failure of MKA in cancer patients., Material and Methods: a retrospective cohort study was conducted, including patients with a diagnosis of musculoskeletal tumor in the distal femur or proximal tibia, who underwent MKA between January 1, 2010, and December 31, 2021., Results: 49 patients were included, of which 25 (51.02%) were women and 24 (48.98%) men, with a mean age of 29.57 years. Of these, 14 (28.57%) patients experienced some type of MKA failure. The most frequent complication that led to failure was periprosthetic infection, observed in seven (14.29%) patients. Variables associated with MKA failure included biopsies performed outside our hospital (HR 3.2, 95% CI 1.4-6.4, p = 0.02), the length of the long axis of the tumor (HR 2.1, 95% CI 1.2-4.6, p = 0.01) and a prolonged surgical time (HR 3.37, 95% CI 1.1-8.6, p = 0.04)., Conclusion: the most significant prognostic factors associated with MKA failure in our cohort were tumor size, prolonged surgical time, and performance of the diagnostic biopsy in a center not specialized in the management of this type of patient. These findings highlight the importance of considering these variables to improve outcomes in patients undergoing MKA.

Purpose: Urothelial cancer accounts for approximately 3% of new cancer cases worldwide, with a high burden of disease in countries with medium and low human development indexes where its incidence and mortality are increasing. The purpose of this consensus is to develop statements on the evaluation and treatment of locally advanced and metastatic urothelial carcinoma that would further guide the clinical practice in Latin America., Methods: A systematic review of the literature was conducted by an independent team of methodologists. Then, a modified Delphi method was developed with clinical specialists from different Latin American countries., Results: Forty-two consensus statements, based on evidence, were developed to address the staging, the evaluation (suitability for chemotherapy, risk assessment, and biomarkers), and systemic treatment (first-line and subsequent therapies) of locally advanced or metastatic urothelial carcinoma. The statements made in this consensus are suggested practice recommendations in the Latin American context; however, the importance of a complete and individualized patient evaluation as a guide for therapeutic selection is highlighted. The availability and affordability of support tools for the evaluation of the disease, as well as specific therapies, may limit the application of the best practices suggested., Recommendations: Therapeutic decisions need to be tailored to the context-specific clinical setting and availability of resources. Local research is promoted to improve outcomes for patients with this challenging cancer in Latin America.

Introduction: Multiple scales have been designed to stratify the severity and predict the prognosis in the initial evaluation of patients with aneurysmal subarachnoid hemorrhage (aSAH). Our study aimed to validate the most commonly used prognostic scales for aSAH in our population: Hunt-Hess, modified Hunt-Hess, World Federation of Neurosurgical Societies (WFNS), Prognosis on Admission of Aneurysmal Subarachnoid Hemorrhage (PAASH), and Barrow Aneurysm Institute (BAI) scales., Methods: This study includes all aSAH cases treated at our institution between June 2019 and December 2020. We developed a retrospective cohort by reviewing medical records and radiologic images performed during hospitalization. The outcome was evaluated using the modified Rankin scale (mRS). It was defined as a poor outcome (mRS 4-5) and mortality (mRS 6). The ROC curves and the area under the curve (AUC) of each of the prognostic scales were calculated to evaluate their prognostic prediction capacity., Results: A total of 142 patients were diagnosed with aSAH. A poor outcome occurred in 52.1% of the patients, whereas mortality was 27.5%. The AUC of the scales studied was similar and no significant difference was found between them for predicting a poor outcome (P = .709) or mortality (P = .715)., Conclusion: We determined that the prognostic scales for aSAH had a similar predictive value for poor clinical outcomes and mortality in our institution, with no significant difference. Thus, we recommend the most simple and well-known scale used institutionally., (Copyright © 2023 Sociedad Española de Neurocirugía. Published by Elsevier España, S.L.U. All rights reserved.)

Introduction: The investigation of small bowel (SB) intussusception is variable, reflecting the lack of existing standards. The aim of this study was to understand the role of small bowel capsule endoscopy (SBCE) to investigate this pathology., Methodology: This was a retrospective multi-centre study. Patients with intussusception on SBCE and those where SBCE was carried out due to findings of intussusception on radiological investigations were included. Relevant information was collected., Results: Ninety-five patients (median age 39+/-SD19.1 years, IQR 30) were included. Radiological investigations were carried out in 71 patients (74.7%) prior to SBCE with intussusception being present in 60 patients on radiological investigations (84.5%). Thirty patients (42.2%) had intussusception on radiological investigations followed by a normal SBCE. Ten patients (14.1%) had findings of intussusception on radiological investigations, a normal SBCE and repeat radiological investigations that were also normal. Abnormal findings were noted on SBCE that could explain intussusception on imaging in (16 patients) 22.5% of patients. Five patients (5.3%) underwent radiological investigations and SBCE to investigate coeliac disease and intussusception. None had associated malignancy. Four patients (4.2%) underwent SBCE to investigate familial polyposis syndromes and went on to SB enteroscopy and surgery accordingly. Most patients (n = 14; 14.8%) with intussusception on initial SBCE (without prior radiological imaging) had suspected SB bleeding (n = 10, 10.5%). Four patients (4.2%) had additional findings of a mass on CT scan and went on to have surgery., Conclusion: SBCE should be used to complement radiology when investigating intussusception. It is a safe non-invasive test that will minimise unnecessary surgery. Additional radiological investigations following a negative SBCE in cases of intussusception noted on initial radiological investigations are unlikely to yield positive findings. Radiological investigations following intussusception noted on SBCE in case of patients presenting with obscure gastrointestinal bleeding, may yield additional findings., Competing Interests: Conflict of interest None., (Copyright © 2023 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.)

Inhibition of enzymes responsible for endocannabinoid hydrolysis represents an invaluable emerging tool for the potential treatment of neurodegenerative disorders. Monoacylglycerol lipase (MAGL) is the enzyme responsible for degrading 2-arachydonoylglycerol (2-AG), the most abundant endocannabinoid in the central nervous system (CNS). Here, we tested the effects of the selective MAGL inhibitor JZL184 on the 3-nitropropinic acid (3-NP)-induced short-term loss of mitochondrial reductive capacity/viability and oxidative damage in rat brain synaptosomal/mitochondrial fractions and cortical slices. In synaptosomes, while 3-NP decreased mitochondrial function and increased lipid peroxidation, JZL184 attenuated both markers. The protective effects evoked by JZL184 on the 3-NP-induced mitochondrial dysfunction were primarily mediated by activation of cannabinoid receptor 2 (CB2R), as evidenced by their inhibition by the selective CB2R inverse agonist JTE907. The cannabinoid receptor 1 (CB1R) also participated in this effect in a lesser extent, as evidenced by the CB1R antagonist/inverse agonist AM281. In contrast, activation of CB1R, but not CB2R, was responsible for the protective effects of JZL184 on the 3-NP-iduced lipid peroxidation. Protective effects of JZL184 were confirmed in other toxic models involving excitotoxicity and oxidative damage as internal controls. In cortical slices, JZL184 ameliorated the 3-NP-induced loss of mitochondrial function, the increase in lipid peroxidation, and the inhibition of succinate dehydrogenase (mitochondrial complex II) activity, and these effects were independent on CB1R and CB2R, as evidenced by the lack of effects of AM281 and JTE907, respectively. Our novel results provide experimental evidence that the differential protective effects exerted by JZL184 on the early toxic effects induced by 3-NP in brain synaptosomes and cortical slices involve MAGL inhibition, and possibly the subsequent accumulation of 2-AG. These effects involve pro-energetic and redox modulatory mechanisms that may be either dependent or independent of cannabinoid receptors' activation., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Introduction: chondrosarcoma is the second most common primary malignant tumor, constitutes approximately one quarter of all primary bone sarcomas. Surgical margins in pelvic chondrosarcoma have a direct impact as a prognostic factor, both on overall survival and on recurrence-free survival of this disease., Objectives: to analyze the impact of surgical margins as a prognostic factor in pelvic chondrosarcoma., Material and Methods: a retrospective database cohort with prospective follow-up of sarcomas in patients diagnosed with primary pelvic chondrosarcoma who underwent surgical treatment. Clinical-demographic variables were obtained, a descriptive analysis of each variable was performed, and these were contrasted with the outcome variables., Results: seventeen patients were included, of which nine were female. The median age was 41 years, ranging from 23 to 65 years. The average tumor size was 20.9 cm (range 5 to 46 cm). The average surgical margin was 5.3 mm, ranging from 1 to 30 mm, with 58% positive margins. The average overall survival was 64 months (range 7 to 108 months). The distribution of pelvic involvement was as follows: zone I in nine patients (52.9%), zone II in two (11.8%), a combination of zones I-III in two (11.8%), I+II in one (5.9%), II+III in one (5.9%), I-III plus sacrum in one (5.9%) and I plus sacrum in one (5.9%). Tumor grades were classified as low in seven patients (41.2%), intermediate in sven (41.2%), high in two (11.8%), and dedifferentiated in one (5.9%). Regarding the type of resection, 12 patients (70.6%) underwent internal hemipelvectomy and five (29.4%) external hemipelvectomy. Recurrence was recorded in five cases (29.4%), metastasis in three (17.6%), and mortality in four (23.5%)., Conclusions: this series represents the largest cohort reported in Latin America of primary pelvic chondrosarcomas. A more favorable prognosis was observed in patients with surgical margins greater than 1 mm. The presence of chondrosarcoma in multiple pelvic zones was associated with a worse oncological prognosis. Additionally, a higher incidence of positive surgical margins and local recurrence rates were identified in pelvic chondrosarcomas compared to those located in the extremities.

Pesticides are compounds known to cause immunetoxicity in exposed individuals, which have a potential to substantially modify the prognosis of pathologies dependent on an efficient immune response, such as breast cancer. In this context, we examined the circulating cytokine profile of Th1/Th2/Th17 patterns in women occupationally exposed to pesticides and their correlation with worse prognostic outcomes. Peripheral blood samples were collected from 187 rural working women with breast cancer, occupationally exposed or not to pesticides, to quantify the levels of cytokines IL-1β, IL-12, IL-4, IL-17-A, and TNF -α. Data on the disease profile and clinical outcomes were collected through medical follow-up. IL-12 was reduced in exposed women with tumors larger than 2 cm and in those with lymph node metastases. Significantly reduced levels of IL-17A were observed in exposed patients with Luminal B subtype tumors, with high ki67 proliferation rates, high histological grade, and positive for the progesterone receptor. Reduced IL-4 was also seen in exposed women with lymph node invasion. Our data show that occupational exposure to pesticides induces significant changes in the levels of cytokines necessary for tumor control and correlates with poor prognosis clinical outcomes in breast cancer., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Santos, da Silva, Jaques, Dalla Vecchia, Ferreira, Rech, Sierota da Silva, Santos, Panis and Benvegnú.)

Recent evidence has pointed out that the cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) expression is a poor prognosis factor. However, the implications of CTLA-4 expression on circulating inflammatory mediators are unclear for breast cancer. Tumor biopsies and blood samples were collected from 117 breast cancer patients. Oxidative stress parameters were evaluated in plasma samples by measuring the lipoperoxidation profile and nitric oxide metabolites (NOx). Interleukins 12 (IL-12) and 4 (IL-4) were assessed by ELISA. CTLA-4 expression was determined by immunofluorescence assessed by its labeling in tumor-infiltrating leukocytes (TILs) or breast tumors. Correlations between CTLA-4 expression in breast tumors with TCD4/TCD8 infiltrating lymphocyte and inflammation-related genes were performed using data from TIMER 2.0/TCGA databases (n = 2160). CTLA-4 expression in TILs significantly correlated to triple-negative breast tumors. Patients carrying CTLA-4-positive tumors exhibited lower plasmatic NOx levels, and those expressing CTLA-4 in TILs had reduced levels of IL-12 in plasma. No changes in either IL-4 or lipid peroxidation profiles were detected concerning any CTLA4 status. Compared to the Luminal A ones, oxidative stress parameters and cytokines were observed in patients bearing triple-negative tumors. CTLA-4 expression in all breast cancer subtypes positively correlated to TCD4/TCD8 lymphocyte infiltrates, as well as to the pro-inflammatory genes IL12A, IL4, NFKB1, NFKB2, NOS1, NOS2, and NOS3. CTLA-4 expression in both tumor and TILs can affect the systemic inflammatory status of breast cancer patients, especially antitumor molecules such as IL-12 and NOx that correlate to more aggressive disease., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

High-grade gliomas (HGG) are the most common primary brain malignancies and account for more than half of all malignant primary brain tumors. The new 2021 WHO classification divides adult HGG into four subtypes: grade 3 oligodendroglioma (1p/19 codeleted, IDH-mutant); grade 3 IDH-mutant astrocytoma; grade 4 IDH-mutant astrocytoma, and grade 4 IDH wild-type glioblastoma (GB). Radiotherapy (RT) and chemotherapy (CTX) are the current standard of care for patients with newly diagnosed HGG. Several clinically relevant molecular markers that assist in diagnosis and prognosis have recently been identified. The treatment for recurrent high-grade gliomas is not well defined and decision-making is usually based on prior strategies, as well as several clinical and radiological factors. Whereas the prognosis for GB is grim (5-year survival rate of 5-10%) outcomes for the other high-grade gliomas are typically better, depending on the molecular features of the tumor. The presence of neurological deficits and seizures can significantly impact quality of life., (© 2023. The Author(s).)

Posttranslational modifications of epigenetic modifiers provide a flexible and timely mechanism for rapid adaptations to the dynamic environment of cancer cells. SIRT1 is an NAD + -dependent epigenetic modifier whose activity is classically associated with healthy aging and longevity, but its function in cancer is not well understood. Here, we reveal that 1α,25-dihydroxyvitamin D 3 (1,25(OH) 2 D 3, calcitriol), the active metabolite of vitamin D (VD), promotes SIRT1 activation through auto-deacetylation in human colon carcinoma cells, and identify lysine 610 as an essential driver of SIRT1 activity. Remarkably, our data show that the post-translational control of SIRT1 activity mediates the antiproliferative action of 1,25(OH) 2 D 3 . This effect is reproduced by the SIRT1 activator SRT1720, suggesting that SIRT1 activators may offer new therapeutic possibilities for colon cancer patients who are VD deficient or unresponsive. Moreover, this might be extrapolated to inflammation and other VD deficiency-associated and highly prevalent diseases in which SIRT1 plays a prominent role., Competing Interests: JG, AC, JM, MF, MF, JC, AD, AB, AM, ML, CG No competing interests declared, (© 2023, García-Martínez et al.)

Background: The COVID-19 pandemic had global catastrophic effects on the management of non-communicable diseases including paediatric cancers. Restrictions during the start of 2020 complicated timely referrals of patients to specialized centres. We aimed to evaluate the pandemic's impact on the number of new diagnoses, disease characteristics and management delay for paediatric renal tumour patients included in the SIOP-RTSG-UMBRELLA study, as compared with data from a historical SIOP-RTSG trial (2005-2009)., Methods: The number of intensive care admissions, population mobility rates and national lockdown periods/restrictions were used as proxies of the pandemic's severity and impact on societies. Clinical and tumour data were extracted from the SIOP-RTSG-UMBRELLA study and from historical SIOP-RTSG trials., Results: During the first lockdown in Europe, the number of newly diagnosed patients decreased following restrictions and population immobilisation. Additionally, there was a higher proportion of advanced disease (37% vs. 17% before and after COVID-9, p < 0.001) and larger median tumour volume (559 cm 3 vs. 328 and 434 cm 3 before and after, p < 0.0001). Also in Brazil, the proportion of advanced disease was higher during the national decrease in mobilisation and start of restrictions (50% and 24% vs. 11% and 18% before and after, p < 0.01). Tumour volume in Brazil was also higher during the first months of COVID-19 (599 cm 3 vs. 459 and 514 cm 3 ), although not significant (p = 0.17). We did not observe any delays in referral time nor in time to start treatment, even though COVID-19 restrictions may have caused children to reach care later., Conclusion: The COVID-19 pandemic briefly changed the tumour characteristics of children presenting with renal tumours. The longer-term impact on clinical outcomes will be kept under review., (© 2023 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Purpose: The present study aims to assess the agreement between clinical and pathological diagnosis in conjunctival tumours in a specialist ocular oncology unit., Methods: retrospective study of consecutive patients with conjunctival tumours diagnosed at the Ocular Oncology Unit of the University Hospital of Valladolid was performed from 1992 to 2017. Tumours were classified according to their origin (epithelial, melanocytic, lymphoid and others) and degree of malignancy (benign, premalignant, malignant). A biopsy was performed in cases of symptomatic or growing lesions. Cohen´s kappa (κ) statistics was used as an indicator of agreement between clinical and pathological diagnosis., Results: Of 462 consecutive patients, a biopsy was required in 195 (42.2%). The agreement with the pathological diagnosis was successful in 154 (79.0%) cases. Analysis according to the grade of malignancy showed the lowest rate of agreement among benign (n = 83; 91.6%) and premalignant (n = 62; 90.3%) lesions, with a total agreement in malignant lesions (n = 50; 100%); the Cohen´s kappa coefficient (κ) was 0.90. The highest rates of concordance were found in epithelial, melanocytic and soft tissue lesions with κ values of 1, 0.8 and 1 respectively. The worst rate of concordance was found in lymphoid lesions with a κ value of 0.3., Conclusion: Most of the conjunctival tumours were correctly identified clinically; benign and malignant lesions showed the highest rate of accuracy; however, premalignant tumours can hide micro-invasive diseases that can go unnoticed on clinical examination. The biopsy is essential for accurate diagnosis and treatment., (Copyright © 2023 Sociedad Española de Oftalmología. All rights reserved.)

Background: Currently, epithelial ovarian cancer is diagnosed in advanced stages (EC IIIC) in 75-80% of cases worldwide. In this group of patients treatment with neoadjuvant chemotherapy is started, followed by interval cytoreduction of residual disease and even require peritonectomy with application of hyperthermic intraperitoneal chemotherapy (HIPEC)., Objective: To identify the overall survival and progression-free survival associated with peritonectomy, in patients with peritoneal carcinomatosis secondary to ovarian cancer treated in the oncology gynecology service from January 2009 to January 2019 at the UMAE Hospital de Oncología Centro Médico Nacional Siglo XXI., Material and Methods: Observational, descriptive, cross-sectional, retrospective study, information was obtained from the clinical file of patients treated with peritonectomy with the use of hyperthermic intraperitoneal chemotherapy in the gynecological oncology service from January 2009 to January 2019 at the UMAE Hospital de Oncología Centro Médico Nacional Siglo XXI., Results: Information was obtained from a total of 36 patients (n=100%), 36.1% received intraperitoneal chemotherapy and 63.8% underwent cytoreduction without the application of intraoperative chemotherapy. The most frequently used drug was cisplatin followed by mitomycin. There was no statistical significance when comparing both groups, however there was a trend in favor of the use of intraoperative chemotherapy by obtaining a greater number of months in terms of overall survival., Conclusion: Peritonectomy with hyperthermic intraperitoneal chemotherapy is an option in selected patients with advanced stage ovarian cancer in primary and recurrent surgery, as well as in patients with platinum-resistant ovarian cancer., (Licencia CC 4.0 (BY-NC-ND) © 2023 Revista Médica del Instituto Mexicano del Seguro Social.)

The chimeric EWSR1::FLI1 transcription factor is the main oncogenic event in Ewing sarcoma. Recently, it has been proposed that EWSR1::FLI1 levels can fluctuate in Ewing sarcoma cells, giving rise to two cell populations. EWSR1::FLI1 low cells present a migratory and invasive phenotype, while EWSR1::FLI1 high cells are more proliferative. In this work, we described how the CD44 standard isoform (CD44s), a transmembrane protein involved in cell adhesion and migration, is overexpressed in the EWSR1::FLI1 low phenotype. The functional characterization of CD44s (proliferation, clonogenicity, migration, and invasion ability) was performed in three doxycycline-inducible Ewing sarcoma cell models (A673, MHH-ES1, and CADO-ES1). As a result, CD44s expression reduced cell proliferation in all the cell lines tested without affecting clonogenicity. Additionally, CD44s increased cell migration in A673 and MHH-ES1, without effects in CADO-ES1. As hyaluronan is the main ligand of CD44s, its effect on migration ability was also assessed, showing that high molecular weight hyaluronic acid (HMW-HA) blocked cell migration while low molecular weight hyaluronic acid (LMW-HA) increased it. Invasion ability was correlated with CD44 expression in A673 and MHH-ES1 cell lines. CD44s, upregulated upon EWSR1::FLI1 knockdown, regulates cell migration and invasion in Ewing sarcoma cells.

Poorly differentiated gastroenteropancreatic neuroendocrine carcinomas are aggressive neoplasms of challenging clinical management. A small proportion of patients with early-stage disease may achieve long-term survival, but the majority of patients present with rapidly lethal metastatic disease. Current standard of care still follows the treatment paradigm of small cell lung cancer, a far more common G3 neuroendocrine neoplasm, although emerging molecular and clinical data increasingly question this approach. In this article, we will briefly summarize epidemiology and prognosis of gastroenteropancreatic neuroendocrine carcinomas to emphasize the very low incidence, aggressive nature, and orphan status of this tumor entity. We will also discuss the current pathological classification and its limitations, as well as recent data on their differential biological background compared with small cell lung cancer, and its potential implications for patients care. Then, we will review the standard of care of systemic therapy, basically focused on platinum-based cytotoxic chemotherapy, including some recent randomized trials providing evidence regarding efficacy of irinotecan vs etoposide platinum doublets. Finally, we will present a comprehensive overview of novel therapeutic strategies in current clinical development, including recently reported data on immunotherapy, tumor-agnostic therapies (microsatellite instability, high tumor mutational burden, NTRK and RET gene fusions, BRAF or KRAS inhibitors), and additional treatment strategies targeting other tumor vulnerabilities (ie, Notch pathway, novel targets for radioligand therapy), and provide some insights regarding unmet needs and future perspectives to improve patient's care and prognosis., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Endocrine Society.)

Purpose: TMEM176B was recently described as a negative modulator of Nlrp3 inflammasome activation in mice. In the mouse model, the inhibition of TMEM176B leads to an increased anti-tumoral activity which is dependent on Nlrp3. Since we have recently shown that single nucleotide variants (SNPs) in inflammasome genes, including NLRP3, significantly affect colorectal cancer (CRC) prognosis, we proposed to investigate here the association between genetic variants in TMEM176B and CRC prognosis., Methods: Considering that, up to now, no genetic study analyzing this gene in humans exists, we selected possible functional SNPs and genotyped them in a cohort of CRC patients submitted to surgery and followed up for more than 10 years. Genotype-guided assays were realized to evaluate the effect of the variant on NLRP3 inflammasome activation. Gene expression from The Cancer Genome Atlas (TCGA) cohort was analyzed to valid possible prognostic and predictive features., Results: We identified the Ala134Thr variant (rs2072443) in TMEM176B as a protective factor for CRC prognosis. This SNP is associated with decreased gene expression and with an increased activation of NLRP3 inflammasome, at least in monocytes and dendritic cells. Furthermore, low TMEM176B expression is associated with higher overall survival., Conclusion: Altogether, these findings supported the role of TMEM176B in NLRP3 inflammasome biology and for the first time demonstrated the genetic association between rs2072443 and CRC in humans., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: The present study assesses the time intervals from symptom discovery to treatment start and describes the health service use experiences of uninsured patients with cancer of the breast, cervix uteri, testicle, and prostate before their arrival to the cancer hospital., Methods: This cross-sectional study included 1468 patients who were diagnosed between June 2016 and May 2017 and received treatment for the selected cancers in two of the largest public cancer hospitals in Mexico City, financed through Seguro Popular. Data was collected through a survey administered via face-to-face interviews with patients and a review of their medical files., Results: The median time between detection (symptom discovery or first abnormal screening test) and treatment start was 6.6 months. For all types of cancer, the longest interval was the diagnostic interval -between the first use of healthcare services and the confirmation of cancer. Less than 20% cancer patients were diagnosed in the earliest stages that are associated with the best chances of long-term survival. The participants described a high use of private services for their first consultation, the use of several different types of health services and multiple consultations before arrival to the cancer centers, and 35% perceived being misdiagnosed by the first doctor they consulted., Conclusions: Most cancer patients treated in the two largest public institutions available for the uninsured faced long delays to get diagnosed and started treatment at advanced stages. Strengthening quality and access for effective early cancer diagnosis and treatment is key to improve patient outcomes in low and middle-income settings., Competing Interests: Declaration of Competing Interest The authors declare no conflict of interest., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

In Costa Rica (CR), only one report on head and neck cancer (HNC) incidence trends (1985-2007) has been published and no investigations on the epidemiology of potentially human papillomavirus (HPV)-related and HPV-unrelated HNCs have been done. We examined the age-standardized incidence rates (IRs) and trends of head and neck squamous cell carcinomas (HNSCC) and compared incidence trends of potentially HPV-related and HPV-unrelated HNSCCs. We obtained all available HNC cases for the period 2006-2015 from the Costa Rican National Cancer Registry of Tumors and the population estimates from the Costa Rican National Institute of Statistics and Census. The analysis was restricted to invasive HNSCCs (n = 1577). IRs and incidence rate ratios were calculated using SEER*Stat software and were age-standardized for the 2010 Costa Rican population. Joinpoint regression analysis program was used to calculate trends and annual percent changes (APCs) in rates. For all HNSCCs, the age-standardized IR was 34.0/million person-years; 95% CI 32.4, 35.8. There was a significant decline in the incidence of nasopharyngeal cancer (APC: -5.9% per year; 95% CI -10.8, -0.7) and laryngeal cancer (APC: -5.4% per year; -9.2, 1.5). The incidence trends for hypopharyngeal, oropharyngeal and oral cavity cancers each remained stable over time. HNSCCs were categorized by their potential relatedness to HPV infection. Though the APCs were not statistically significant, IRs of potentially HPV-related HNSCCs trended upward, while HPV-unrelated HNSCCs trended downward. HNSCCs are uncommon in CR and decreased over time. We observed a divergent pattern of decreasing HPV-unrelated with increasing HPV-related HNSCCs that should be further informed by HPV genotyping tumor samples., (© 2023 The Authors. International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC. This article has been contributed to by U.S. Government employees and their work is in the public domain in the USA.)

Introduction: Metastatic breast cancer causes the most breast cancer-related deaths around the world, especially in countries where breast cancer is detected late into its development. Genetic testing for cancer susceptibility started with the BRCA 1 and 2 genes. Still, recent research has shown that variations in other members of the DNA damage response (DDR) are also associated with elevated cancer risk, opening new opportunities for enhanced genetic testing strategies., Methods: We sequenced BRCA1/2 and twelve other DDR genes from a Mexican-mestizo population of 40 metastatic breast cancer patients through semiconductor sequencing., Results: Overall, we found 22 variants -9 of them reported for the first time- and a strikingly high proportion of variations in ARID1A. The presence of at least one variant in the ARID1A, BRCA1, BRCA2, or FANCA genes was associated with worse progression-free survival and overall survival in our patient cohort., Discussion: Our results reflected the unique characteristics of the Mexican-mestizo population as the proportion of variants we found differed from that of other global populations. Based on these findings, we suggest routine screening for variants in ARID1A along with BRCA1/2 in breast cancer patients from the Mexican-mestizo population., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Vázquez-Romo, Millan-Catalan, Ruíz-García, Martínez-Gutiérrez, Alvarado-Miranda, Campos-Parra, López-Camarillo, Jacobo-Herrera, López-Urrutia, Guardado-Estrada, Cantú de León and Pérez-Plasencia.)

To describe access to complete treatment in women with cervical cancer and state-sponsored insurance versus no insurance. We conducted a retrospective observational study. The source population consisted of women treated for cervical cancer from January 2000 to December 2015 in a tertiary care hospital. We included 411 women with state-sponsored insurance and 400 without insurance. We defined access to cervical cancer treatment as complete treatment (according NCCN/ESMO (National Comprehensive Cancer Network/European Society for Medical Oncology) standards) and timely initiation of treatment (less than 4 weeks). Clinical and sociodemographic characteristics were described and analyzed with logistic regression using complete treatment as the main outcome. A total of 811 subjects were included, the median age was 46 (IQR (Interquartile range) 42-50) years. Most of them were married (36.1%), unemployed (50.4%), and had completed primary school (44.0%). The most common clinical stages at diagnosis were II (38.2%) and III (24.7%). In the adjusted regression model, being married (OR (odds ratio): 4.3, 95% CI (confidence interval): 1.74-10.61) and having paid employment (OR: 2.79, 95% CI: 1.59-4.90) or state-sponsored insurance (OR: 1.54, 95% CI: 1.04-2.26) were positively associated with the possibility of having a complete treatment. Women with insurance were likely to be younger and receive timely treatment compared with uninsured women. Complete treatment was associated to insurance status and advanced stages of cervical cancer. State-sponsored insurance improves access to complete treatment. Government policies are needed to avoid social and economic inequity and provide better management of cervical cancer in our country., Competing Interests: The authors have no funding and conflicts of interest to disclose., (Copyright © 2023 the Author(s). Published by Wolters Kluwer Health, Inc.)

Given their tumor-specific and stage-specific gene expression, long non-coding RNAs (lncRNAs) have demonstrated to be potential molecular biomarkers for diagnosis, prognosis, and treatment response. Particularly, the lncRNAs DSCAM-AS1 and GATA3-AS1 serve as examples of this because of their high subtype-specific expression profile in luminal B-like breast cancer. This makes them candidates to use as molecular biomarkers in clinical practice. However, lncRNA studies in breast cancer are limited in sample size and are restricted to the determination of their biological function, which represents an obstacle for its inclusion as molecular biomarkers of clinical utility. Nevertheless, due to their expression specificity among diseases, such as cancer, and their stability in body fluids, lncRNAs are promising molecular biomarkers that could improve the reliability, sensitivity, and specificity of molecular techniques used in clinical diagnosis. The development of lncRNA-based diagnostics and lncRNA-based therapeutics will be useful in routine medical practice to improve patient clinical management and quality of life.

Neuroendocrine neoplasms (NENs) are mutationally quiet (low number of mutations/Mb), and epigenetic mechanisms drive their development and progression. We aimed at comprehensively characterising the microRNA (miRNA) profile of NENs, and exploring downstream targets and their epigenetic modulation. In total, 84 cancer-related miRNAs were analysed in 85 NEN samples from lung and gastroenteropancreatic (GEP) origin, and their prognostic value was evaluated by univariate and multivariate models. Transcriptomics (N = 63) and methylomics (N = 30) were performed to predict miRNA target genes, signalling pathways and regulatory CpG sites. Findings were validated in The Cancer Genome Atlas cohorts and in NEN cell lines. We identified a signature of eight miRNAs that stratified patients in three prognostic groups (5-year survival of 80%, 66% and 36%). Expression of the eight-miRNA gene signature correlated with 71 target genes involved in PI3K-Akt and TNFα-NF-kB signalling. Of these, 28 were associated with survival and validated in silico and in vitro. Finally, we identified five CpG sites involved in the epigenetic regulation of these eight miRNAs. In brief, we identified an 8-miRNA signature able to predict survival of patients with GEP and lung NENs, and identified genes and regulatory mechanisms driving prognosis in NEN patients., (© 2023 The Authors. Molecular Oncology published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies.)

Inflammation is a common feature in neurodegenerative diseases that contributes to neuronal loss. Previously, we demonstrated that the basal inflammatory tone differed between brain regions and, consequently, the reaction generated to a pro-inflammatory stimulus was different. In this study, we assessed the innate immune reaction in the midbrain and in the striatum using an experimental model of Parkinson's disease. An adeno-associated virus serotype 9 expressing the α-synuclein and mCherry genes or the mCherry gene was administered into the substantia nigra. Myeloid cells (CD11b + ) and astrocytes (ACSA2 + ) were purified from the midbrain and striatum for bulk RNA sequencing. In the parkinsonian midbrain, CD11b + cells presented a unique anti-inflammatory transcriptomic profile that differed from degenerative microglia signatures described in experimental models for other neurodegenerative conditions. By contrast, striatal CD11b + cells showed a pro-inflammatory state and were similar to disease-associated microglia. In the midbrain, a prominent increase of infiltrated monocytes/macrophages was observed and, together with microglia, participated actively in the phagocytosis of dopaminergic neuronal bodies. Although striatal microglia presented a phagocytic transcriptomic profile, morphology and cell density was preserved and no active phagocytosis was detected. Interestingly, astrocytes presented a pro-inflammatory fingerprint in the midbrain and a low number of differentially displayed transcripts in the striatum. During α-synuclein-dependent degeneration, microglia and astrocytes experience context-dependent activation states with a different contribution to the inflammatory reaction. Our results point towards the relevance of selecting appropriate cell targets to design neuroprotective strategies aimed to modulate the innate immune system during the active phase of dopaminergic degeneration., (© 2022 The Authors. GLIA published by Wiley Periodicals LLC.)

Introduction: Breast cancer is a heterogeneous disease, and the distribution of the different subtypes varies by race/ethnic category in the United States and by country. Established breast cancer-associated factors impact subtype-specific risk; however, these included limited or no representation of Latin American diversity. To address this gap in knowledge, we report a description of demographic, reproductive, and lifestyle breast cancer-associated factors by age at diagnosis and disease subtype for The Peruvian Genetics and Genomics of Breast Cancer (PEGEN-BC) study., Methods: The PEGEN-BC study is a hospital-based breast cancer cohort that includes 1943 patients diagnosed at the Instituto Nacional de Enfermedades Neoplásicas in Lima, Peru. Demographic and reproductive information, as well as lifestyle exposures, were collected with a questionnaire. Clinical data, including tumor Hormone Receptor (HR) status and Human Epidermal Growth Factor Receptor 2 (HER2) status, were abstracted from electronic medical records. Differences in proportions and mean values were tested using Chi-squared and one-way ANOVA tests, respectively. Multinomial logistic regression models were used for multivariate association analyses., Results: The distribution of subtypes was 52% HR+HER2-, 19% HR+HER2+, 16% HR-HER2-, and 13% HR-HER2+. Indigenous American (IA) genetic ancestry was higher, and height was lower among individuals with the HR-HER2+ subtype (80% IA vs. 76% overall, p =0.007; 152 cm vs. 153 cm overall, p =0.032, respectively). In multivariate models, IA ancestry was associated with HR-HER2+ subtype (OR=1.38,95%CI=1.06-1.79, p =0.017) and parous women showed increased risk for HR-HER2+ (OR=2.7,95%CI=1.5-4.8, p <0.001) and HR-HER2- tumors (OR=2.4,95%CI=1.5-4.0, p <0.001) compared to nulliparous women. Multiple patient and tumor characteristics differed by age at diagnosis (<50 vs. >=50), including ancestry, region of residence, family history, height, BMI, breastfeeding, parity, and stage at diagnosis ( p <0.02 for all variables)., Discussion: The characteristics of the PEGEN-BC study participants do not suggest heterogeneity by tumor subtype except for IA genetic ancestry proportion, which has been previously reported. Differences by age at diagnosis were apparent and concordant with what is known about pre- and post-menopausal-specific disease risk factors. Additional studies in Peru should be developed to further understand the main contributors to the specific age of onset and molecular disease subtypes in this population and develop population-appropriate predictive models for prevention., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Zavala, Casavilca-Zambrano, Navarro-Vásquez, Tamayo, Castañeda, Valencia, Morante, Calderón, Abugattas, Gómez, Fuentes, Liendo-Picoaga, Cotrina, Neciosup, Roque, Vásquez, Mas, Gálvez-Nino, Fejerman and Vidaurre.)

Introduction: PARK7/DJ-1 is an oncogene that is associated with tumorigenesis in many cancers. Recent studies have demonstrated the importance of DJ-1 in the origin and development of uveal melanoma (UM). We present an analysis of the role of the DJ-1 protein in UM cells, especially in its effect on proliferation and migration., Methods: UM cells from a primary tumor, Mel 270, and its liver metastasis, OMM2.5, were transfected with lentiviral-delivered shRNA against PARK7/DJ-1. Evaluation of cell migration and proliferation was performed using the xCELLigence real-time cell analyzer (RTCA). The effect of DJ-1 inhibition on the PTEN-Akt signaling pathway was also studied by immunoblotting., Results: The silencing of PARK7/DJ-1 oncoprotein expression produced a significant decrease of phosphorylated Akt (S473) in Mel270 and in metastatic OMM2.5 UM cells with no alteration on tumor suppressor PTEN expression. The diminution of PARK7/DJ-1 expression significantly inhibited real-time proliferation and invasion of Mel270 and OMM2.5 and the invasion potential of the metastatic cells., Conclusion: DJ-1 appears to play a key role on the PTEN/Akt pathway in UM. DJ-1 inhibition appears to have a negative effect on proliferation and invasion of UM cells. This suggests DJ-1 as a potential therapeutic target in UM.

Background: In breast cancer (BC), hypoxia is associated with poor prognosis. Protein Salvador homolog 1 (SAV1) acts as a tumor suppressor and is downregulated in the cancer cells. However, there is limited data on the expression profile of SAV1 and its importance in BC. It has not been studied to evaluate this phenomenon in a hypoxic microenvironment yet., Aim: This study aimed to investigate SAV1 expression profiles under normoxia and hypoxia, and the potential of SAV1 in BC prognosis., Methods: Gene and protein expression analyses were performed using Real-Time quantitative PCR (RT-qPCR) and immunocytochemistry (ICC), respectively, and in silico analyses were performed using The Cancer Genome Atlas (TCGA). The survival curves were constructed using KMplotter., Results: SAV1 expression was lower in BC samples and tumor cell lines than in normal samples. The SAV1 mRNA levels were reduced in hypoxic estrogen receptor positive (ER + ) tumors, which were associated with a lower survival probability as compared to normoxic ER + tumors. Furthermore, lower levels of SAV1 were found in advanced cancer stage samples, which are associated with worse survival curves and can be a risk factor for BC., Conclusions: These data suggest a potential prognostic role of SAV1 in BC, with lower expressions associated with worse prognosis., Competing Interests: Conflicts of Interest The authors declare that they have no conflict of interest., (Copyright © 2023 Instituto Mexicano del Seguro Social (IMSS). Published by Elsevier Inc. All rights reserved.)

HOX genes have been associated with carcinogenesis. However, the molecular mechanism by which tumors are generated remains unclear. The HOXC13 and HOXD13 genes are of interest for their involvement in the development of genitourinary structures. The aim of this first study in the Mexican population was to search for and analyze variants in the coding region of the HOXC13 and HOXD13 genes in women with cervical cancer. Samples from Mexican women with cervical cancer and healthy women were sequenced (50/50). Allelic and genotypic frequencies were compared between groups. The functional impact of the proteins was determined with two bioinformatics servers (SIFT and PolyPhen-2), and the oncogenic potential of the identified nonsynonymous variants was determined using the CGI server. We identified five unreported gene variants: c.895C>A p.(Leu299Ile) and c.777C>T p.(Arg259Arg) in the HOXC13 gene and c.128T>A p.(Phe43Tyr), c.204G>A p.(Ala68Ala), and c.267G>A p.(Ser89Ser) in the HOXD13 gene. In this study, we suggest that the non-synonymous variants c.895C>A p.(Leu299Ile) and c.128T>A p.(Phe43Tyr) could represent a risk factor for the development of the disease, although additional studies in larger patient populations and in different ethnic groups are needed in order to support the results observed.

Glioblastoma (GB) is the most prevalent primary brain cancer and the most aggressive form of glioma because of its poor prognosis and high recurrence. To confirm the importance of epigenetics in glioma, we explored The Cancer Gene Atlas (TCGA) database and we found that several histone/DNA modifications and chromatin remodeling factors were affected at transcriptional and genetic levels in GB compared to lower-grade gliomas. We associated these alterations in our own cohort of study with a significant reduction in the bulk levels of acetylated lysines 9 and 14 of histone H3 in high-grade compared to low-grade tumors. Within GB, we performed an RNA-seq analysis between samples exhibiting the lowest and highest levels of acetylated H3 in the cohort; these results are in general concordance with the transcriptional changes obtained after histone deacetylase (HDAC) inhibition of GB-derived cultures that affected relevant genes in glioma biology and treatment (e.g., A2ML1, CD83 , SLC17A7, TNFSF18 ). Overall, we identified a transcriptional signature linked to histone acetylation that was potentially associated with good prognosis, i.e., high overall survival and low rate of somatic mutations in epigenetically related genes in GB. Our study identifies lysine acetylation as a key defective histone modification in adult high-grade glioma, and offers novel insights regarding the use of HDAC inhibitors in therapy.

Background: Mature teratomas belong to the group of germ line ovarian tumors; they generally have benign behavior. Malignant transformation occurs in 0.2% to 1% of tumors. The objective is to show the results of peritonectomy with HIPEC in the treatment of a mature teratoma with malignant differentiation with signet ring cells., Clinical Case: 43-year-old woman diagnosed with mature malignant teratoma with signet ring cells. It was performed optimal primary cytoreduction surgery, total hysterectomy, bilateral salpingo-oophorectomy, peritonectomy, appendectomy, cholecystectomy and splenectomy adding intraoperative hyperthermic chemotherapy (HIPEC)., Conclusions: Malignant transformation of a mature teratoma of the ovary is a rare event, but not exceptional. HIPEC was used after optimal cytoreduction, with good results, since the patient is in a disease-free period of 36 months. It is necessary to report cases in order to compare different types of treatment to improve oncological results., (© 2023 Revista Médica del Instituto Mexicano del Seguro Social.)

Background: Bone neoplasms require an adequate clinical-radiographic evaluation for their diagnosis. Plain radiographs are the usual method to establish the diagnosis and evaluate differential diagnoses in the study of bone tumor pathology., Objective: To recognize the frequency of radiographic characteristics and associate them with bone tumor pathology., Method: Radiographic data were collected from 132 patients with tumor pathology confirmed by biopsy from bone tumors service of the Traumatology and Orthopedics Hospital Unidades Médicas de Alta Especialidad Dr. Victorio de la Fuente Narváez, Instituto Mexicano del Seguro Social, Ciudad de México, during 2019., Results: 132 patients were registered. The most frequent benign tumor was osteochondroma (27.3%), and malignant was osteosarcoma (9.8%). Active lytic lesions (odds ratio [OR]: 6.9; 95% confidence interval [95% CI]: 2.83-16.85) or aggressive (OR: 26.85; 95% CI: 3.21-224) were associated with giant cells tumors. Poorly differentiated intraosseous blast lesions of bone lineage (OR: 36.15; 95% CI: 4.4-295.5) were associated with osteosarcoma. The periosteal reaction (OR: 36.15; 95% CI: 4.4-295.5), the moth-eaten or permeative pattern (OR: 11.75; 95% CI: 1.26-109) and the central location of the lesion (OR: 3.03; 95% CI: 1.37-6.69) were associated with malignant tumor lesions., Conclusions: Poorly defined intraosseous blast lesions of bone lineage, periosteal reaction, and moth-eaten or permeative pattern of destruction are associated with malignant lesions., (Copyright: © 2023 Permanyer.)

Background: Bone neoplasms are usually misdiagnosed causing a delay in their treatment. Bone neoplasms are usually confused with tendinitis, 31% of the cases corresponds to osteosarcomas and in 21% to Ewing's sarcomas., Objective: To create a clinical-radiographic instrument of high diagnostic suspicion of knee bone neoplasms to prevent a delay in diagnosis., Method: A clinimetric study (sensitivity, consistency and validity) was performed in the bone tumor service, Hospital de Ortopedia de la Unidad Médica de Alta Especialidad Dr. Victorio de la Fuente Narváez, Instituto Mexicano del Seguro Social, in México City., Results: Characteristics of 153 patients were collected. For the sensitivity phase, 3 domains (signs, symptoms, and radiology) and 12 items were included. Consistency was evaluated with ICC (0.944), 95%CI (0.865-0.977), p < 0.001 and a-Cronbach (0.863). Index obtained a sensitivity of 0.80 and a specificity of 0.882 were obtained. The positive predictive value of the test was 66.6% and the negative predictive value was 93.75%. The positive likelihood ratio was 6.8 and the negative likelihood ratio was 0.2. Validity was evaluated using r-Pearson (0.894; p < 0.001)., Conclusions: A high suspicion clinical-radiographic index was designed to detect malignant knee tumors with adequate sensitivity, specificity, appearance, content, criteria, and construct validity., (Copyright: © 2023 Permanyer.)

Background: Truncating pathogenic or likely pathogenic variants of CDH1 cause hereditary diffuse gastric cancer (HDGC), a tumour risk syndrome that predisposes carrier individuals to diffuse gastric and lobular breast cancer. Rare CDH1 missense variants are often classified as variants of unknown significance. We conducted a genotype-phenotype analysis in families carrying rare CDH1 variants, comparing cancer spectrum in carriers of pathogenic or likely pathogenic variants (PV/LPV; analysed jointly) or missense variants of unknown significance, assessing the frequency of families with lobular breast cancer among PV/LPV carrier families, and testing the performance of lobular breast cancer-expanded criteria for CDH1 testing., Methods: This genotype-first study used retrospective diagnostic and clinical data from 854 carriers of 398 rare CDH1 variants and 1021 relatives, irrespective of HDGC clinical criteria, from 29 institutions in ten member-countries of the European Reference Network on Tumour Risk Syndromes (ERN GENTURIS). Data were collected from Oct 1, 2018, to Sept 20, 2022. Variants were classified by molecular type and clinical actionability with the American College of Medical Genetics and Association for Molecular Pathology CDH1 guidelines (version 2). Families were categorised by whether they fulfilled the 2015 and 2020 HDGC clinical criteria. Genotype-phenotype associations were analysed by Student's t test, Kruskal-Wallis, χ 2 , and multivariable logistic regression models. Performance of HDGC clinical criteria sets were assessed with an equivalence test and Youden index, and the areas under the receiver operating characteristic curves were compared by Z test., Findings: From 1971 phenotypes (contributed by 854 probands and 1021 relatives aged 1-93 years), 460 had gastric and breast cancer histology available. CDH1 truncating PV/LPVs occurred in 176 (21%) of 854 families and missense variants of unknown significance in 169 (20%) families. Multivariable logistic regression comparing phenotypes occurring in families carrying PV/LPVs or missense variants of unknown significance showed that lobular breast cancer had the greatest positive association with the presence of PV/LPVs (odds ratio 12·39 [95% CI 2·66-57·74], p=0·0014), followed by diffuse gastric cancer (8·00 [2·18-29·39], p=0·0017) and gastric cancer (7·81 [2·03-29·96], p=0·0027). 136 (77%) of 176 families carrying PV/LPVs fulfilled the 2015 HDGC criteria. Of the remaining 40 (23%) families, who did not fulfil the 2015 criteria, 11 fulfilled the 2020 HDGC criteria, and 18 had lobular breast cancer only or lobular breast cancer and gastric cancer, but did not meet the 2020 criteria. No specific CDH1 variant was found to predispose individuals specifically to lobular breast cancer, although 12 (7%) of 176 PV/LPV carrier families had lobular breast cancer only. Addition of three new lobular breast cancer-centred criteria improved testing sensitivity while retaining high specificity. The probability of finding CDH1 PV/LPVs in patients fulfilling the lobular breast cancer-expanded criteria, compared with the 2020 criteria, increased significantly (AUC 0·92 vs 0·88; Z score 3·54; p=0·0004)., Interpretation: CDH1 PV/LPVs were positively associated with HDGC-related phenotypes (lobular breast cancer, diffuse gastric cancer, and gastric cancer), and no evidence for a positive association with these phenotypes was found for CDH1 missense variants of unknown significance. CDH1 PV/LPVs occurred often in families with lobular breast cancer who did not fulfil the 2020 HDGC criteria, supporting the expansion of lobular breast cancer-centred criteria., Funding: European Reference Network on Genetic Tumour Risk Syndromes, European Regional Development Fund, Fundação para a Ciência e a Tecnologia (Portugal), Cancer Research UK, and European Union's Horizon 2020 research and innovation programme., Competing Interests: Declaration of interests DGE declares fees from Astrazeneca and Recursion. ERW declares grants from International Alliance for Cancer Early Detection, for which they are codirector of the research domain. GNR declares receipt of funding for study materials, medical writing, and article processing charges from Italian Ministry of Education (GNR). MJLL declares consulting fees (via the Radboud University Medical Center) from Merck Sharp & Dohme (MSD), AstraZeneca, Lilly, Janssen-Cilag, Illumina, GlaxoSmithKline. PRB declares fees from AstraZeneca, MSD, and Bristol Myers Squibb; and is a scientific committee member for the Geneticancer patients association. JBa declares fees from AstraZeneca, Lilly, and Pfizer. SA is a member of APC subVCEP of the InSiGHT/ClinGen Hereditary Colorectal Cancer/Polyposis Variant Curation Expert Panel; is an unpaid member of the German Gene Diagnostics Commission and speaker of the Centre for Hereditary Tumour Syndromes of the University of Bonn. RH declares grants from SLA Pharma and Janssen Pharmaceuticals; consulting fees from Janssen and One Two Therapeutics; equipment from Fujifilm; is the head of German Consortium for Familial Gastrointestinal Cancer; and is an unpaid advisory board member of the Lynch Syndrome advocacy Group and the Familial Polyposis Group. ES declares grants from NCT/DKTK Master. ES declares honoraria for presentations from AstraZeneca, Georg Thieme Verlag KG, and payment for expert testimony from Illumina; is a member of the board of directors of Deutsche Gesellschaft für HumanGenetik; an advisor for Dresden-concept Genome Center; and is board of directors president (paid) for LNS laboratoire National de Santé. RdP declares support for presentations (via his institution) from MSD and AstraZeneca. GC declares to receive funding for study materials, medical writing, article processing charges from the Spanish Ministry of Science and Innovation, the Instituto de Salud Carlos III CIBERONC, and the Government of Catalonia.; consulting fees from VCN Biosciences Synthetic Biologics; is the chair of the Council of the International Society of Hereditary Gastrointestinal Tumours and the FUREGA Fundació Recerca en Gastroenterologia; and stock in Synthetic Biologics. CLa declares consulting fees and honoraria from AstraZeneca and MSD, and is a paid advisory board member for Illumina., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Background: Adherence to clinical practice guidelines improves outcomes for patients with breast cancer. However, their implementation may not be feasible in low- and middle-income countries. This study aimed to evaluate physicians' adherence, attitudes, and barriers towards the Colima Consensus, which is the Mexican national breast cancer clinical practice guideline., Methods: A cross-sectional, 31-item survey was e-mailed to Consensus attendees and members of the Mexican Society of Oncology and Mexican Mastology Association. Descriptive statistics, univariate, and multivariate analysis were used to analyze the associations between participants' characteristics, adherence, attitudes, and barriers., Results: Of 439 respondents, 78% percent adhered to Consensus recommendations and 94% believed it was applicable to their clinical practice. Forty percent reported using the Consensus as their sole breast cancer guideline. This was associated with being a surgical oncologist (OR 3.3, 95% CI 2.0-5.3) and practicing at a public hospital (OR 2.1, 95% CI 1.2-3.7). The most common barriers to adherence were lack of resources and logistical problems. Regarding attitudes towards the Consensus, 90% considered it a good educational tool, 89% considered it a reliable source of information, and 90% thought it improved quality of care., Conclusions: We showed high levels of adherence and positive attitudes towards the Colima Consensus, with a significant proportion of physicians using it as their only guideline. Lack of resources and logistical issues were the main barriers to adherence. Our results highlight the relevance of local breast cancer guidelines and suggest a need for the creation of resource-stratified guidelines., (© 2022. The Author(s), under exclusive licence to Federación de Sociedades Españolas de Oncología (FESEO).)

The Breast Cancer Revealed initiative was designed and conducted to know the status of breast cancer at each point of breast cancer care, through i) prevention, ii) detection, iii) diagnosis, iv) treatment, and iv) the capacity of our health systems. The expert panel from 11 Latin American countries identified several strategies and proposed high impact priorities, including implementation of prevention policies, improve primary healthcare capacity for breast cancer screening, have adequate infrastructure to make effective and timely diagnoses, have a multidisciplinary team in the treatment process, access to a variety of treatments for all types of patients, have a coordinated and articulated system from primary care to specialized hospital. In a region with limited resources, prioritization in high-impact strategies for breast cancer control could lead to improved clinical outcomes and quality of life for our patients., Competing Interests: Conflict of Interest Statement JMC received grants from Roche and Genomic Health and payment for lectures from BRP Oncology Updates and Roche Bolivia. The other authors declare they have not potential conflict of interests with this research., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Ewing sarcoma (EwS) is characterized by EWSR1-ETS fusion transcription factors converting polymorphic GGAA microsatellites (mSats) into potent neo-enhancers. Although the paucity of additional mutations makes EwS a genuine model to study principles of cooperation between dominant fusion oncogenes and neo-enhancers, this is impeded by the limited number of well-characterized models. Here we present the Ewing Sarcoma Cell Line Atlas (ESCLA), comprising whole-genome, DNA methylation, transcriptome, proteome, and chromatin immunoprecipitation sequencing (ChIP-seq) data of 18 cell lines with inducible EWSR1-ETS knockdown. The ESCLA shows hundreds of EWSR1-ETS-targets, the nature of EWSR1-ETS-preferred GGAA mSats, and putative indirect modes of EWSR1-ETS-mediated gene regulation, converging in the duality of a specific but plastic EwS signature. We identify heterogeneously regulated EWSR1-ETS-targets as potential prognostic EwS biomarkers. Our freely available ESCLA (http://r2platform.com/escla/) is a rich resource for EwS research and highlights the power of comprehensive datasets to unravel principles of heterogeneous gene regulation by chimeric transcription factors., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: The sodium/iodide symporter (NIS) is a transmembrane protein located on the basolateral membrane of thyrocytes. Despite its physiological and clinical relevance, little is known about the mechanisms that mediate NIS subcellular sorting. In the present study, we examined NIS basolateral trafficking in vitro using non-thyroid and thyroid epithelial cells. Methods: Immunofluorescence and Western blotting were performed to analyze NIS subcellular location and function in cells grown in monolayers under unpolarized and/or polarized conditions. Strategic NIS residues were mutated, and binding of NIS to clathrin adaptor complexes was determined by immunoprecipitation. Results: We show that NIS reaches the plasma membrane (PM) through a thyrotropin-dependent mechanism 24 hours after treatment with the hormone. We demonstrate that NIS basolateral trafficking is a clathrin-mediated mechanism, in which the clathrin adaptor complexes AP-1 (A and B) sort NIS from the trans -Golgi network (TGN) and recycling endosomes (REs). Specifically, we show that the AP-1B μ1 subunit controls NIS basolateral sorting through common REs. In its absence, NIS is apically missorted but remains functional. Additionally, direct NIS basolateral transport from the TGN to the basolateral membrane is mediated by AP-1A through clathrin-coated vesicles that also carry the transferrin receptor. Loss of the μ1 subunit of AP-1A is functionally compensated by AP-1B. Furthermore, loss of both subunits diminishes NIS trafficking to the PM. Finally, we demonstrate that AP-1A binds to the L121 and LL562/563 residues on NIS, whereas AP-1B binds to L583. Conclusions: Our findings highlight the novel involvement of the clathrin-coated machinery in basolateral NIS trafficking. Given that AP-1A expression is reduced in tumors, and its expression correlates with that of NIS, these findings will help uncover new targets in thyroid cancer treatment.

Next-generation sequencing (NGS) has been implemented in clinical oncology for diagnosis, prognosis, and therapeutic guidance. Among the various NGS applications in molecular oncology, we focused on the following topics: laboratory standards for targeted gene panels (somatic mutations) and therapeutic guidance based on NGS of lung cancer and rare cancers, namely sarcomas and cancers of unknown primary. Multiple quality control checkpoints should be addressed in the pre-analytical phase for good quality and interpretation of the NGS results. It includes tumor size and cellularity, tissue processing and decalcification, tumor fraction, tumor viability, fixatives, and staining. Communication between clinicians and laboratory support is also essential. In lung cancer, all patients with non-squamous non-small cell lung cancer should be tested with a NGS panel, and it should include not only genes with approved targeted therapies (ALK, BRAF, EGFR, MET, NTRK, RET, and ROS1) but also genes with potentially actionable genomic alterations (HER2 and KRAS). Since there is a lack of extensive knowledge regarding the use of NGS in rare tumors performing comprehensive genomic profiling, NGS panels to better manage the disease are recommended. Moreover, other patients with other incurable solid tumors may benefit from being included in biomarker-driven clinical trials. Multidisciplinary tumor boards with the participation of experts with the ability to integrate genomic profiling data are essential to tailor the best strategy for each patient. Considering that there are no national guidelines, this article aims to guide laboratory and clinical practice for the use of NGS in the context of lung cancer, rare tumors, and cancer of unknown primary in Portugal.

Endoglin (ENG) is a mesenchymal stem cell (MSC) marker typically expressed by active endothelium. This transmembrane glycoprotein is shed by matrix metalloproteinase 14 (MMP14). Our previous work demonstrated potent preclinical activity of first-in-class anti-ENG antibody-drug conjugates as a nascent strategy to eradicate Ewing sarcoma (ES), a devastating rare bone/soft tissue cancer with a putative MSC origin. We also defined a correlation between ENG and MMP14 expression in ES. Herein, we show that ENG expression is significantly associated with a dismal prognosis in a large cohort of ES patients. Moreover, both ENG/MMP14 are frequently expressed in primary ES tumors and metastasis. To deepen in their functional relevance in ES, we conducted transcriptomic and proteomic profiling of in vitro ES models that unveiled a key role of ENG and MMP14 in cell mechano-transduction. Migration and adhesion assays confirmed that loss of ENG disrupts actin filament assembly and filopodia formation, with a concomitant effect on cell spreading. Furthermore, we observed that ENG regulates cell-matrix interaction through activation of focal adhesion signaling and protein kinase C expression. In turn, loss of MMP14 contributed to a more adhesive phenotype of ES cells by modulating the transcriptional extracellular matrix dynamics. Overall, these results suggest that ENG and MMP14 exert a significant role in mediating correct spreading machinery of ES cells, impacting the aggressiveness of the disease.

Background: One of the main difficulties of adoptive cell therapies with chimeric antigen receptor (CAR)-T cells in solid tumors is the identification of specific target antigens. The tumor microenvironment can present suitable antigens for CAR design, even though they are not expressed by the tumor cells. We have generated a CAR specific for the splice variant extra domain A (EDA) of fibronectin, which is highly expressed in the tumor stroma of many types of tumors but not in healthy tissues., Methods: EDA expression was explored in RNA-seq data from different human tumor types and by immunohistochemistry in paraffin-embedded tumor biopsies. Murine and human anti-EDA CAR-T cells were prepared using recombinant retro/lentiviruses, respectively. The functionality of EDA CAR-T cells was measured in vitro in response to antigen stimulation. The antitumor activity of EDA CAR-T cells was measured in vivo in C57BL/6 mice challenged with PM299L-EDA hepatocarcinoma cell line, in 129Sv mice-bearing F9 teratocarcinoma and in NSG mice injected with the human hepatocarcinoma cell line PLC., Results: EDA CAR-T cells recognized and killed EDA-expressing tumor cell lines in vitro and rejected EDA-expressing tumors in immunocompetent mice. Notably, EDA CAR-T cells showed an antitumor effect in mice injected with EDA-negative tumor cells lines when the tumor stroma or the basement membrane of tumor endothelial cells express EDA. Thus, EDA CAR-T administration delayed tumor growth in immunocompetent 129Sv mice challenged with teratocarcinoma cell line F9. EDA CAR-T treatment exerted an antiangiogenic effect and significantly reduced gene signatures associated with epithelial-mesenchymal transition, collagen synthesis, extracellular matrix organization as well as IL-6-STAT5 and KRAS pathways. Importantly, the human version of EDA CAR, that includes the human 41BB and CD3ζ endodomains, exerted strong antitumor activity in NSG mice challenged with the human hepatocarcinoma cell line PLC, which expresses EDA in the tumor stroma and the endothelial vasculature. EDA CAR-T cells exhibited a tropism for EDA-expressing tumor tissue and no toxicity was observed in tumor bearing or in healthy mice., Conclusions: These results suggest that targeting the tumor-specific fibronectin splice variant EDA with CAR-T cells is feasible and offers a therapeutic option that is applicable to different types of cancer., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

The aim of this study was to verify the presence of glyphosate in breast milk and to characterize maternal environmental exposure. Sixty-seven milk samples were collected from lactating women in the city of Francisco Beltrão, Paraná, living in urban (n=26) and rural (n=41) areas, at the peak of glyphosate application in corn and soy crops in the region (April and May 2018). To characterize the study population, socio-epidemiological data of the women were collected. To determine glyphosate levels, a commercial enzyme immunosorbent assay kit was used. Glyphosate was detected in all breast milk samples analyzed with a mean value of 1.45 µg/L. Despite some descriptive differences, there were no statistically significant differences (P<0.05) between the categories of the variables tested. Also, glyphosate was detected in drinking water samples from the urban area and in artesian well water from the rural area of the region where the studied population lived. The estimation of the total amount of glyphosate ingested by breastfeeding babies in a period of 6 months was significant. These results suggest that the studied lactating population was contaminated with glyphosate, possibly through continued environmental exposure.

The GNAQ and GNA11 genes are mutated in almost 80-90% of uveal melanomas in a mutually exclusive pattern. These genes encode the alpha subunits of the heterotrimeric G proteins, Gq and G 11 ; thus, mutations of these genes result in the activation of several important signaling pathways, including phospholipase C, and activation of the transcription factor YAP. It is well known that both of them act as driver genes in the oncogenic process and it has been assumed that they do not play a role in the prognosis of these tumours. However, it has been hypothesised that mutations in these genes could give rise to molecularly and clinically distinct types of uveal melanomas. It has also been questioned whether the type and location of mutation in the GNAQ and GNA11 genes may affect the progression of these tumours. All of these questions, except for their implications in carcinogenesis, remain controversial. Uveal melanoma has a distinctive genetic profile, and specific recurrent mutations, which make it a potential candidate for treatment with targeted therapy. Given that the most frequent mutations are those observed in the GNAQ and GNA11 genes, and that both genes are involved in oncogenesis, these molecules, as well as the downstream signalling pathways in which they are involved, have been proposed as promising potential therapeutic targets. Therefore, in this review, special attention is paid to the current data related to the possible prognostic implications of both genes from different perspectives, as well as the therapeutic options targeting them.

Constitutional genomic imbalances are known to cause malformations, disabilities, neurodevelopmental delay, and dysmorphia and can lead to dysfunctions in the cell cycle. In extremely rare genetic conditions such as small supernumerary marker chromosomes (sSMC), it is important to understand the cellular consequences of this extra marker, as well the factors that contribute to their maintenance or elimination through successive cell cycles and phenotypic impact. The study of chromosomal mosaicism provides a natural model to characterize the effect of aneuploidy on genome stability and compare cells with the same genetic background and environment exposure, but differing in the presence of sSMC. Here, we report the functional characterization of different cell lines from two familial patients with mosaic sSMC derived from chromosome 12. We performed studies of proliferation dynamics, stability, and variability of these cells using fluorescent in situ hybridization (FISH), sister chromatid exchanges (SCE), and conventional staining. We also quantified the telomere-related genomic instability of sSMC cells using 3D telomeric profile analysis by quantitative-FISH. sSMC cells exhibited differences in the cell cycle dynamics compared to normal cells. First, the sSMC cells exhibited lower proliferation index and higher frequency of SCE than normal cells, associated with a higher level of chromosomal instability. Second, sSMC cells exhibited more telomeric-related genomic instability. Lastly, the differences of sSMC cells distribution among tissues could explain different phenotypic repercussions observed in patients. These results will help in our understanding of the sSMC stability, maintenance during cell cycle, and the cell cycle variables involved in the different phenotypic manifestations.

It is widely accepted that the tumor microenvironment, particularly the extracellular matrix, plays an essential role in the development of tumors through the interaction with specific protein-membrane receptors. One of the most relevant proteins in this context is the transmembrane protein CD44. The role of CD44 in tumor progression, invasion, and metastasis has been well established in many cancers, although a comprehensive review concerning its role in sarcomas has not been published. CD44 is overexpressed in most sarcomas and several in vitro and in vivo experiments have shown a direct effect on tumor progression, dissemination, and drug resistance. Moreover, CD44 has been revealed as a useful marker for prognostic and diagnostic (CD44v6 isoform) in osteosarcoma. Besides, some innovative treatments such as HA-functionalized liposomes therapy have become an excellent CD44-mediated intracellular delivery system for osteosarcoma. Unfortunately, the reduced number of studies deciphering the prognostic/diagnostic value of CD44 in other sarcoma subgroups, neither than osteosarcoma, in addition to the low number of patients involved in those studies, have produced inconclusive results. In this review, we have gone through the information available on the role of CD44 in the development, maintenance, and progression of sarcomas, analyzing their implications at the prognostic, therapeutic, and mechanistic levels. Moreover, we illustrate how research involving the specific role of CD44 in the different sarcoma subgroups could suppose a chance to advance towards a more innovative perspective for novel therapies and future clinical trials., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Fernández-Tabanera, Melero-Fernández de Mera and Alonso.)