Cyclic fasting bolsters cholesterol biosynthesis inhibitors' anticancer activity.

Identifying oncological applications for drugs that are already approved for other medical indications is considered a possible solution for the increasing costs of cancer treatment. Under the hypothesis that nutritional stress through fasting might enhance the antitumour properties of at least some non-oncological agents, by screening drug libraries, we find that cholesterol biosynthesis inhibitors (CBIs), including simvastatin, have increased activity against cancers of different histology under fasting conditions. We show fasting's ability to increase CBIs' antitumour effects to depend on the reduction in circulating insulin, insulin-like growth factor-1 and leptin, which blunts the expression of enzymes from the cholesterol biosynthesis pathway and enhances cholesterol efflux from cancer cells. Ultimately, low cholesterol levels through combined fasting and CBIs reduce AKT and STAT3 activity, oxidative phosphorylation and energy stores in the tumour. Our results support further studies of CBIs in combination with fasting-based dietary regimens in cancer treatment and highlight the value of fasting for drug repurposing in oncology.

Potential Biomarkers Associated with Prognosis and Trastuzumab Response in HER2+ Breast Cancer.

Breast cancer (BC) is the most common malignancy among women worldwide. Around 15-25% of BC overexpress the human epidermal growth factor receptor 2 (HER2), which is associated with a worse prognosis and shortened disease-free survival. Therefore, anti-HER2 therapies have been developed, such as monoclonal antibodies (trastuzumab, Tz), antibody-drug conjugates (ado-trastuzumab emtansine, T-DM1), and pharmacological inhibitors of tyrosine kinase activity (lapatinib, Lp). Although Tz, the standard treatment, has significantly improved the prognosis of patients, resistance still affects a significant population of women and is currently a major challenge in clinical oncology. Therefore, this study aims to identify potential biomarkers to predict disease progression (prognostic markers) and the efficacy of Tz treatment (predictive markers) in patients with HER2+ BC. We hypothesize that proteins involved in cell motility are implicated in Tz-resistance. We aim to identify alterations in Tz-resistant cells to guide more efficient oncologic decisions. By bioinformatics, we selected candidate proteins and determined how their expression, localization, and the process they modulate were affected by anti-HER2 treatments. Next, using HER2+ BC patients' data, we assessed these proteins as prognostic and predictive biomarkers. Finally, using Tz-resistant cells, we evaluated their roles in Tz response. We identified deregulated genes associated with cell motility in Tz/T-DM1-resistant vs. -sensitive cells. We showed that Tz, T-DM1, and Lp decrease cell viability, and their effect is enhanced in combinations. We determined synergism between Tz/T-DM1 and Lp, making possible a dose reduction of each drug to achieve the same therapeutic effect. We found that combinations (Tz/T-DM1 + Lp) efficiently inhibit cell adhesion and migration. Furthermore, we demonstrated the induction of FAK nuclear and cortactin peri-nuclear localization after T-DM1, Lp, and Tz/T-DM1 + Lp treatments. In parallel, we observed that combined treatments downregulate proteins essential for metastatic dissemination, such as SRC, FAK, and paxillin. We found that low vinculin (VCL) and cortactin (CTTN) mRNA expression predicts favorable survival rates and has diagnostic value to discriminate between Tz-sensible and Tz-resistant HER2+ BC patients. Finally, we confirmed that vinculin and cortactin are overexpressed in Tz-resistance cells, SKBR3-RTz. Moreover, we found that Tz plus FAK/paxillin/cortactin-silencing reduced cell adhesion/migration capacity in Tz-sensitive and -resistant cells. In conclusion, we demonstrate that combined therapies are encouraging since low doses of Tz/T-DM1 + Lp inhibit metastatic processes by downregulating critical protein expression and affecting its subcellular localization. We propose that vinculin and cortactin might contribute to Tz-sensibility/resistance in BC cells. Finally, we identify potential prognostic and predictive biomarkers that are promising for personalized BC management that would allow efficient patient selection in order to mitigate resistance and maximize the safety and efficacy of anti-HER2 therapies.

Survival Differences in High-Risk Prostate Cancer by Age.

PURPOSE: Age is an established determining factor in survival in low-risk prostate cancer (PC), being this evidence weaker in high-risk tumors. Our aim is to evaluate the survival of patients with high-risk PC treated with curative intent and to identify differences across ages at diagnosis. METHODS: We did a retrospective analysis of patients with high-risk PC treated with surgery (RP) or radiotherapy (RDT) excluding N+ patients. We divided patients by age groups: < 60, 60-70, and > 70 years. We performed a comparative survival analysis. A multivariate analysis adjusted for clinically relevant variables and initial treatment received was performed. RESULTS: Of a total of 2383 patients, 378 met the selection criteria with a median follow-up of 8.9 years: 38 (10.1%) < 60 years, 175 (46.3%) between 60-70 years, and 165 (43.6%) >70 years. Initial treatment with surgery was predominant in the younger group (RP:63.2%, RDT:36.8%), and with radiotherapy in the older group (RP:17%, RDT:83%) (p = 0.001). In the survival analysis, significant differences were observed in overall survival, with better results for the younger group. However, these results were reversed in biochemical recurrence-free survival, with patients < 60 years presenting a higher rate of biochemical recurrence at 10 years. In the multivariate analysis, age behaved as an independent risk variable only for overall survival, with a HR of 2.8 in the group >70 years (95%CI: 1.22-6.5; p = 0.015). CONCLUSION: In our series, age appeared to be an independent prognostic factor for overall survival, with no differences in the rest of the survival rates.

Evaluation of lead exposition length on the liver and intestinal histoarchitecture of eared dove (Zenaida auriculata).

Lead (Pb) is a metal that can produces irreversible damage in living organisms. Some studies had reported that Pb produces histophysiological alterations in the digestive system (mainly liver) of birds; however, the effect of this metal on small intestine has not been fully examined. Additionally, little information is available on Pb disturbances in native birds of South America. The present study aimed to evaluate the effect of different Pb exposure times on blood δ-aminolevulinic acid dehydratase (δ-ALAD) activity and on the histological and morphometric characteristics of the digestive system (liver and proximal intestine) of eared doves (Zenaida auriculata). A decrease of the blood δ-ALAD activity, dilatation of blood vessels and leukocyte infiltrates in intestinal submucosa and muscular layers, and reduction of the enterocyte nuclear diameter and Lieberkühn crypts area were observed. In liver were noted steatosis, proliferation of bile ducts, dilated sinusoids, leukocyte infiltrates, and melanomacrophage centers. The portal tract area and the thickness of the portal vein wall were increased. In conclusion, the results showed that Pb produces histological and morphometric alterations on the liver and small intestine according to the exposure time, which should be considered when the dangerousness of environmental pollutants is evaluated in wild animals.

Combination Treatment of Retinoic Acid Plus Focal Adhesion Kinase Inhibitor Prevents Tumor Growth and Breast Cancer Cell Metastasis.

All-trans retinoic acid (RA), the primary metabolite of vitamin A, controls the development and homeostasis of organisms and tissues. RA and its natural and synthetic derivatives, both known as retinoids, are promising agents in treating and chemopreventing different neoplasias, including breast cancer (BC). Focal adhesion kinase (FAK) is a crucial regulator of cell migration, and its overexpression is associated with tumor metastatic behavior. Thus, pharmaceutical FAK inhibitors (FAKi) have been developed to counter its action. In this work, we hypothesize that the RA plus FAKi (RA + FAKi) approach could improve the inhibition of tumor progression. By in silico analysis and its subsequent validation by qPCR, we confirmed RARA, SRC, and PTK2 (encoding RARα, Src, and FAK, respectively) overexpression in all breast cells tested. We also showed a different pattern of genes up/down-regulated between RA-resistant and RA-sensitive BC cells. In addition, we demonstrated that both RA-resistant BC cells (MDA-MB-231 and MDA-MB-468) display the same behavior after RA treatment, modulating the expression of genes involved in Src-FAK signaling. Furthermore, we demonstrated that although RA and FAKi administered separately decrease viability, adhesion, and migration in mammary adenocarcinoma LM3 cells, their combination exerts a higher effect. Additionally, we show that both drugs individually, as well as in combination, induce the expression of apoptosis markers such as active-caspase-3 and cleaved-PARP1. We also provided evidence that RA effects are extrapolated to other cancer cells, including T-47D BC and the human cervical carcinoma HeLa cells. In an orthotopic assay of LM3 tumor growth, whereas RA and FAKi administered separately reduced tumor growth, the combined treatment induced a more potent inhibition increasing mice survival. Moreover, in an experimental metastatic assay, RA significantly reduced metastatic lung dissemination of LM3 cells. Overall, these results indicate that RA resistance could reflect deregulation of most RA-target genes, including genes encoding components of the Src-FAK pathway. Our study demonstrates that RA plays an essential role in disrupting BC tumor growth and metastatic dissemination in vitro and in vivo by controlling FAK expression and localization. RA plus FAKi exacerbate these effects, thus suggesting that the sensitivity to RA therapies could be increased with FAKi coadministration in BC tumors.

Atezolizumab, vemurafenib, and cobimetinib in patients with melanoma with CNS metastases (TRICOTEL): a multicentre, open-label, single-arm, phase 2 study.

BACKGROUND: Targeted therapy and immunotherapy have shown intracranial activity in melanoma with CNS metastases, but there remains an unmet need, particularly for patients with symptomatic CNS metastases. We aimed to evaluate atezolizumab in combination with cobimetinib or vemurafenib plus cobimetinib in patients with melanoma with CNS metastases. METHODS: TRICOTEL was a multicentre, open-label, single-arm, phase 2 study done in two cohorts: a BRAFV600 wild-type cohort and a BRAFV600 mutation-positive cohort, recruited at 21 hospitals and oncology centres in Brazil, France, Germany, Hungary, Italy, Spain, and Switzerland. Eligible patients were aged 18 years or older with previously untreated metastatic melanoma, CNS metastases of 5 mm or larger in at least one dimension, and an Eastern Cooperative Oncology Group performance status of 2 or less. Patients in the BRAFV600 wild-type cohort received intravenous atezolizumab (840 mg, days 1 and 15 of each 28-day cycle) plus oral cobimetinib (60 mg once daily, days 1-21). Patients in the BRAFV600 mutation-positive cohort received intravenous atezolizumab (840 mg, days 1 and 15 of each 28-day cycle) plus oral vemurafenib (720 mg twice daily) plus oral cobimetinib (60 mg once daily, days 1-21); atezolizumab was withheld in cycle 1. Treatment was continued until progression, toxicity, or death. The primary outcome was intracranial objective response rate confirmed by assessments at least 4 weeks apart, as assessed by independent review committee (IRC) using modified Response Evaluation Criteria in Solid Tumours version 1.1. Because of early closure of the BRAFV600 wild-type cohort, the primary endpoint of intracranial objective response rate by IRC assessment was not done in this cohort; intracranial objective response rate by investigator assessment was reported instead. Efficacy and safety were analysed in all patients who received at least one dose of study medication. This trial is closed to enrolment and is registered with ClinicalTrials.gov, NCT03625141. FINDINGS: Between Dec 13, 2018, and Dec 7, 2020, 65 patients were enrolled in the BRAFV600 mutation-positive cohort; the BRAFV600 wild-type cohort was closed early after enrolment of 15 patients. Median follow-up was 9·7 months (IQR 6·3-15·0) for the BRAFV600 mutation-positive cohort and 6·2 months (3·5-23·0) for the BRAFV600 wild-type cohort. Intracranial objective response rate was 42% (95% CI 29-54) by IRC assessment in the BRAFV600 mutation-positive cohort and 27% (95% CI 8-55) by investigator assessment in the BRAFV600 wild-type cohort. Treatment-related grade 3 or worse adverse events occurred in 41 (68%) of 60 patients who received atezolizumab plus vemurafenib plus cobimetinib in the BRAFV600 mutation-positive cohort, the most common of which were lipase increased (15 [25%] of 60 patients) and blood creatine phosphokinase increased (ten [17%]). Eight (53%) of 15 patients treated with atezolizumab plus cobimetinib in the BRAFV600 wild-type cohort had treatment-related grade 3 or worse adverse events, most commonly anaemia (two [13%]) and dermatitis acneiform (two [13%]). Treatment-related serious adverse events occurred in 14 (23%) of 60 patients in the BRAFV600 mutation-positive cohort and two (13%) of 15 in the BRAFV600 wild-type cohort. One death in the BRAFV600 mutation-positive cohort (limbic encephalitis) was considered to be related to atezolizumab treatment. INTERPRETATION: Adding atezolizumab to vemurafenib plus cobimetinib provided promising intracranial activity in patients with BRAFV600-mutated melanoma with CNS metastases. FUNDING: F Hoffmann-La Roche.

Real-world treatment patterns and overall survival in BRAF-mutant melanoma patients treated with immunotherapy or targeted therapy.

Aim: To assess overall survival (OS) in patients with advanced BRAF-mutant melanoma by first-line (1L) targeted therapy (TT) or checkpoint inhibitor (CPI) use, second-line (2L) TT or CPI use, and treatment sequence. Patients & methods: Advanced BRAF-mutant melanoma patients treated with 1L CPI or TT were selected from a real-world, electronic health record-derived database. Results: CPI was associated with improved survival after adjustment for potential confounders (hazard ratio, 0.75 [95% CI, 0.66-0.87]). Median OS was similar between 2L therapies and among likely treatment sequences. Conclusion: This real-world study demonstrated a survival benefit with 1L CPI versus TT. Analyses of 2L and treatment sequences were unable to detect or rule out clinically relevant differences in OS.

Immune checkpoint inhibitors and targeted therapies are the preferred treatment options for patients with advanced BRAF-mutant melanoma, with more patients starting first-line treatment with checkpoint inhibitors in the real world. Our study suggests that starting treatment with checkpoint inhibitors instead of targeted therapies may improve survival; however, we were unable to determine the optimal sequence of treatments that patients should be given. The findings of this study highlight the need for further investigation into the optimal treatment sequence with checkpoint inhibitors and targeted therapies in advanced BRAF-mutant melanoma.

Influence of androgen deprivation therapy on the severity of COVID-19 in prostate cancer patients.

BACKGROUND: The TMPRSS2 protein has been involved in severe acute respiratory syndrome caused by coronavirus 2 (SARS-CoV-2). The production is regulated by the androgen receptor (AR). It is speculated that androgen deprivation therapy (ADT) may protect patients affected by prostate cancer (PC) from SARS-CoV-2 infection. METHODS: This is a retrospective study of patients treated for COVID-19 in our institution who had a previous diagnosis of PC. We analyzed the influence of exposure of ADT on the presence of severe course of COVID-19. RESULTS: A total of 2280 patients were treated in our center for COVID-19 with a worse course of disease in males (higher rates of hospitalization, intense care unit [ICU] admission, and death). Out of 1349 subjects registered in our PC database, 156 were on ADT and 1193 were not. Out of those, 61 (4.52%) PC patients suffered from COVID-19, 11 (18.0%) belonged to the ADT group, and 50 (82.0%) to the non-ADT group. Regarding the influence of ADT on the course of the disease, statistically significant differences were found neither in the death rate (27.3% vs. 34%; p = 0.481), nor in the presence of severe COVID-19: need for intubation or ICU admission (0% vs. 6.3%; p = 0.561) and need for corticoid treatment, interferon beta, or tocilizumab (60% vs. 34.7%; p = 0.128). Multivariate analysis adjusted for clinically relevant comorbidities did not find that ADT was a protective factor for worse clinical evolution (risk ratio [RR] 1.08; 95% confidence interval [CI], 0.64-1.83; p = 0.77) or death (RR, 0.67; 95% CI, 0.26-1.74; p = 0.41). CONCLUSIONS: Our study confirms that COVID-19 is more severe in men. However, the use of ADT in patients with PC was not shown to prevent the risk of severe COVID-19.

Safety and Feasibility of Fasting-Mimicking Diet and Effects on Nutritional Status and Circulating Metabolic and Inflammatory Factors in Cancer Patients Undergoing Active Treatment.

In preclinical studies, fasting was found to potentiate the effects of several anticancer treatments, and early clinical studies indicated that patients may benefit from regimes of modified fasting. However, concerns remain over possible negative impact on the patients' nutritional status. We assessed the feasibility and safety of a 5-day "Fasting-Mimicking Diet" (FMD) as well as its effects on body composition and circulating growth factors, adipokines and cyto/chemokines in cancer patients. In this single-arm, phase I/II clinical trial, patients with solid or hematologic malignancy, low nutritional risk and undergoing active medical treatment received periodic FMD cycles. The body weight, handgrip strength and body composition were monitored throughout the study. Growth factors, adipokines and cyto/chemokines were assessed by ELISA. Ninety patients were enrolled, and FMD was administered every three weeks/once a month with an average of 6.3 FMD cycles/patient. FMD was largely safe with only mild side effects. The patients' weight and handgrip remained stable, the phase angle and fat-free mass increased, while the fat mass decreased. FMD reduced the serum c-peptide, IGF1, IGFBP3 and leptin levels, while increasing IGFBP1, and these modifications persisted for weeks beyond the FMD period. Thus, periodic FMD cycles are feasible and can be safely combined with standard antineoplastic treatments in cancer patients at low nutritional risk. The FMD resulted in reduced fat mass, insulin production and circulating IGF1 and leptin. This trial was registered on Clinicaltrials.gov in July 2018 with the identifier NCT03595540.

Heregulin-induced cell migration is prevented by trastuzumab and trastuzumab-emtansine in HER2+ breast cancer.

PURPOSE: Heregulin (HRG) signaling has been implicated in the development of an aggressive phenotype in breast cancer (BC) cells, and HER2 overexpression has been associated with a worse prognosis in BC patients. Nevertheless, the molecular mechanisms through which HRG affects the efficiency of anti-HER2 therapies such as trastuzumab (Tz) and trastuzumab-emtansine (T-DM1) are currently unknown. METHODS: In the present study, we evaluate the molecular action of HRG toward fundamental scaffold proteins and several kinases in the signal transduction pathways triggered via HER2/HER3, which integrate precise and sequential steps to promote changes in cell morphology to impulse BC cell migration. In addition, we evaluate the effectiveness of Tz and T-DM1 on the control of key proteins involved in BC cell motility, since the acquisition of a migratory phenotype is essential to promote invasion and metastasis. RESULTS: We show that HRG induces actin cytoskeleton reorganization and focal adhesion complex formation, and promotes actin nucleation in BT-474 BC cells. This signaling is triggered by HER2/HER3 to c-Src, FAK and paxillin. When paxillin is phosphorylated, it recruits PAK1, which then phosphorylates cortactin. In parallel, paxillin signals to N-WASP, and both signalings regulate Arp2/3 complex, leading to the local reorganization of actin fibers. CONCLUSIONS: Our findings reveal an original mechanism by which HRG increases HER2+ BC cell motility, and show that the latter can be abolished by Tz and T-DM1 treatments. These results provide evidence for the molecular mechanisms involved in cell motility and drug resistance. They will be useful to develop new and more specific therapeutic schemes that interfere with the progression and metastasis of HER2+ BC.

SIRT6 enhances oxidative phosphorylation in breast cancer and promotes mammary tumorigenesis in mice.

BACKGROUND: Sirtuin 6 (SIRT6) is a NAD+-dependent deacetylase with key roles in cell metabolism. High SIRT6 expression is associated with adverse prognosis in breast cancer (BC) patients. However, the mechanisms through which SIRT6 exerts its pro-oncogenic effects in BC remain unclear. Here, we sought to define the role of SIRT6 in BC cell metabolism and in mouse polyoma middle T antigen (PyMT)-driven mammary tumors. METHODS: We evaluated the effect of a heterozygous deletion of Sirt6 on tumor latency and survival of mouse mammary tumor virus (MMTV)-PyMT mice. The effect of SIRT6 silencing on human BC cell growth was assessed in MDA-MB-231 xenografts. We also analyzed the effect of Sirt6 heterozygous deletion, of SIRT6 silencing, and of the overexpression of either wild-type (WT) or catalytically inactive (H133Y) SIRT6 on BC cell pyruvate dehydrogenase (PDH) expression and activity and oxidative phosphorylation (OXPHOS), including respiratory complex activity, ATP/AMP ratio, AMPK activation, and intracellular calcium concentration. RESULTS: The heterozygous Sirt6 deletion extended tumor latency and mouse survival in the MMTV-PyMT mouse BC model, while SIRT6 silencing slowed the growth of MDA-MB-231 BC cell xenografts. WT, but not catalytically inactive, SIRT6 enhanced PDH expression and activity, OXPHOS, and ATP/AMP ratio in MDA-MB-231 and MCF7 BC cells. Opposite effects were obtained by SIRT6 silencing, which also blunted the expression of genes encoding for respiratory chain proteins, such as UQCRFS1, COX5B, NDUFB8, and UQCRC2, and increased AMPK activation in BC cells. In addition, SIRT6 overexpression increased, while SIRT6 silencing reduced, intracellular calcium concentration in MDA-MB-231 cells. Consistent with these findings, the heterozygous Sirt6 deletion reduced the expression of OXPHOS-related genes, the activity of respiratory complexes, and the ATP/AMP ratio in tumors isolated from MMTV-PyMT mice. CONCLUSIONS: Via its enzymatic activity, SIRT6 enhances PDH expression and activity, OXPHOS, ATP/AMP ratio, and intracellular calcium concentration, while reducing AMPK activation, in BC cells. Thus, overall, SIRT6 inhibition appears as a viable strategy for preventing or treating BC.

Compassionate use of tocilizumab in severe SARS-CoV2 pneumonia.

INTRODUCTION: Tocilizumab (TCZ) is an interleukin-6 receptor antagonist, which has been used for the treatment of severe SARS-CoV-2 pneumonia (SSP), which aims to ameliorate the cytokine release syndrome (CRS) induced acute respiratory distress syndrome (ARDS). However, there are no consistent data about who might benefit most from it. METHODS: We administered TCZ on a compassionate-use basis to patients with SSP who were hospitalized (excluding intensive care and intubated cases) and who required oxygen support to have a saturation >93%. The primary endpoint was intubation or death after 24 h of its administration. Patients received at least one dose of 400 mg intravenous TCZ from March 8, 2020 to April 20, 2020. RESULTS: A total of 207 patients were studied and 186 analyzed. The mean age was 65 years and 68% were male patients. A coexisting condition was present in 68% of cases. Prognostic factors of death were older age, higher IL-6, d-dimer and high-sensitivity C-reactive protein (HSCRP), lower total lymphocytes, and severe disease that requires additional oxygen support. The primary endpoint (intubation or death) was significantly worst (37% vs 13%, p < 0·001) in those receiving the drug when the oxygen support was high (FiO2 >0.5%). CONCLUSIONS: TCZ is well tolerated in patients with SSP, but it has a limited effect on the evolution of cases with high oxygen support needs.

[Recommendations on bladder cancer Management during COVID-19 pandemia: lessons learned and future plans.] / Recomendaciones sobre el manejo del carcinoma de vejiga en situación de pandemia por Covid-19. Experiencia aprendida y preparación para el futuro.

OBJECTIVES: The guidelines and recommendation sof good clinical practice have been disrupted by new and urgent policies, marked by the COVID-19 pandemic. Urothelial carcinoma has a significant prevalence in Spain, whose population has been greatly affected by COVID-19, directly by the disease and indirectly by the confinement. The objective of this work is to offer recommendations on protocols and guidelines adjusted to different phases of the pandemic. MATERIAL AND METHODS: This document on the management of bladder carcinoma is based on few evidence on urological oncological practice during the first months of the pandemic and on the authors' experience in this pathology during the crisis of COVID-19. Hospital experts in infectious disseases and radiology have participated to design a common strategy to reorganize the activity. RESULTS: Different proposals for treatment and follow-up of patients diagnosed with bladder cancer adjusted for oncological risk and the different phases of the pandemic are presented. CONCLUSIONS: The pandemic's spread was unimaginable just a few months ago. Health systems have been shaken by the disease in the most critical phases. It is necessary, at this time, to make an additional effort to develop tools that can facilitate the care of bladder carcinoma and minimize the impact and risks for patients and health professionals in the future.

 OBJETIVOS: Las directrices y recomendaciones de la buena práctica clínica se han visto trastocadas por las nuevas y urgentes prioridades, marcadas po rla pandemia COVID-19. El carcinoma urotelial es una enfermedad de prevalencia significativa en España, cuya población se ha visto muy afectada por la COVID-19, directamente por la enfermedad e indirectamente por el confinamiento. El objetivo de este trabajo es ofrecer recomendaciones sobre protocolos y circuitos asistenciales ajustados a diferentes fases de la pandemia. MATERIAL Y MÉTODOS: El presente documento sobre el manejo del carcinoma vesical, se basa en la escasa evidencia sobre la práctica oncológica urológica durante los primeros meses de la pandemia y en la experiencia de los autores en esta patología durante la crisis del COVID-19. En ella, han participado expertos hospitalarios en patología infecciosa y radiodiagnóstico para diseñar una estrategia común y reorganizar así la actividad. RESULTADOS: Se presentan distintas propuestas de tratamiento y seguimiento de los pacientes diagnosticados de cáncer vesical ajustados al riesgo oncológico en las diferentes fases de la pandemia. CONCLUSIONES: La velocidad de expansión de la pandemia era inimaginable hace solo unos meses. Los sistemas sanitarios se han visto sacudidos por la enfermedad en las fases más críticas. Es necesario, en estos momentos, realizar un esfuerzo más para desarrollar herramientas que puedan facilitar la asistencia del carcinoma vesical y minimizar el impacto y los riesgos para los pacientes y los profesionales de la salud en el futuro.

MYC-Associated Factor MAX is a Regulator of the Circadian Clock.

The circadian transcriptional network is based on a competition between transcriptional activator and repressor complexes regulating the rhythmic expression of clock-controlled genes. We show here that the MYC-associated factor X, MAX, plays a repressive role in this network and operates through a MYC-independent binding to E-box-containing regulatory regions within the promoters of circadian BMAL1 targets. We further show that this "clock" function of MAX is required for maintaining a proper circadian rhythm and that MAX and BMAL1 contribute to two temporally alternating transcriptional complexes on clock-regulated promoters. We also identified MAX network transcriptional repressor, MNT, as a fundamental partner of MAX-mediated circadian regulation. Collectively, our data indicate that MAX regulates clock gene expression and contributes to keeping the balance between positive and negative elements of the molecular clock machinery.

The value of tumour weight as a predictive factor for recurrence and progression in non-muscle invasive bladder cancer.

Objective: To further assess the influence of the weight after TURBT as a predictive factor for recurrence and progression in NMIBC.Materials and methods: A cohort of patients with a first episode of NMIBC between 1999 and 2016 was analysed retrospectively. We studied the correlation between the tumour's size and weight, the time-dependent ROC curves for the optimal weight value for the prediction of recurrence and progression and their association with the risk of recurrence and progression at one and five years.Results: We analysed 470 patients who met inclusion criteria. Median (IQR) follow-up time was four years (2.2-6.7), 227 (48.3%) patients had a recurrence and 46 (9.8%) progressed. Median (IQR) weight after resection was 2 g (0.8-6) and its correlation with size was 0.56. The optimal value for the prediction of recurrence was 4 g. The RFS at one and five years with a weight <4 g was 77.7% and 53.5%, respectively, compared to 57.8% and 34.7% with higher weight (p < .001). PFS at one and five years was 98% and 92.7% for a weight <4 g compared to 91.4% and 83.1% for tumours >4 g, respectively (p = .02). On multivariate analysis, a higher weight was associated with an increased risk of recurrence: HR [95%:CI] = 1.52[1.05-1.86], and progression: HR[95%:CI] = 1.87[1.01-3.47] (p < .05).Conclusion: The weight of the specimen obtained after TURBT is a predictive factor of both recurrence and progression in NMIBC that may be more accurate than tumour size and easily and objectively measured. An increase of 52% and 87% in the risk of recurrence and progression, respectively, was found in tumours weighing more than 4 g.

Molecular Basis of LH Action on Breast Cancer Cell Migration and Invasion via Kinase and Scaffold Proteins.

Breast cancer (BC) is a major public health problem affecting women worldwide. Approximately 80% of diagnosed cases are hormone-dependent breast cancers. These hormones are known to stimulate tumor development and progression. In this setting, tentative evidence suggests that luteinizing hormone (LH) may also play a role in tumors. In BC cells that express functional LH receptors (LHR), this hormone regulates cell migration and invasion by controlling several kinases that activate actin cytoskeletal proteins. In this article, we show that LH induces phosphorylation of paxillin and its translocation toward the plasmatic membrane, where focal adhesion complexes are assembled. This process is triggered via a rapid extra-gonadal LHR signaling to Src/FAK/paxillin, which results in the phosphorylation/activation of the nucleation promoter factors cortactin and N-WASP. As a consequence, Arp2/3 complexes induce actin polymerization, essential to promote cell adhesion, migration, and invasion, thus enhancing metastatic spread of tumoral cells. Our findings provide relevant information about how gonadotrophins exert their action in BC. This information helps us understand the extragonadal effects of LH on BC metastasis. It may provide new perspectives for therapeutic treatment, especially for women with high serum levels of gonadotrophins.

Effect of hospital volume on 90-day mortality after radical cystectomy for bladder cancer in Spain.

OBJECTIVE: To investigate 90-day mortality rate of RC for bladder cancer in a nationwide population-based study. DESIGN, SETTING, AND PARTICIPANTS: We used mandatory hospital discharge forms of all patients submitted to RC due to bladder cancer in Spain during 2011-2015 (n = 12,154 in 196 hospitals). At present, a centralization policy for RC has not been issued by the health authorities. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: We calculated in-hospital, 30-, 60- and 90-day mortality. Average annual RC volume was used as a continuous variable (log-transformed) and also grouped into deciles to identify any potential non-linear relationships. Logistic regression model with mixed effect was performed adjusting for year of surgery, comorbidity, surgical approach, type of admission, age, sex, and hospital size. RESULTS AND LIMITATION: Overall 90-day mortality rate was 6.5%. Lowest mortality rates (3.3% at 90 days) are achieved in hospitals doing more than 38 cases per year. The 90-day adjusted mortality rate is associated with annual average RC volume with a 20.6% decrease per 10 extra RCs/year (95% CI 12.3-28.1% p < 0.001). High Charlson comorbidity index, advanced age, and open surgical approach were the clinical variables associated with higher mortality. CONCLUSIONS: Our study identifies an inverse association between 90-day mortality and hospital volume. High-volume hospitals achieve lower mortality rate within 90 days.

Prostate cancer adverse pathology reclassification in patients undergoing active surveillance in a long-term follow-up series.

BACKGROUND: Active surveillance (AS) has become a valid option for patients with a very low risk of prostate cancer (PC) with a widespread application. There are still a few series, with a medium follow-up longer than 5 years, reporting data on pathological upgrading. The objective is to evaluate the changes in surveillance biopsies of patients with low-risk PC in a long-term follow-up and determine if a longer stay in AS could involve worse pathological findings. MATERIALS AND METHODS: A retrospective analysis of our institutional database of patients with PC undergoing AS during 2004 to 2018 was performed. The inclusion criteria were prostate-specific antigen (PSA) ≤ 10 ng/mL, Gleason grade 1 and T1c/T2a. Patients were assessed by serum PSA level and digital rectal examination at 6-month intervals. Transrectal ultrasound-guided prostate biopsies were performed during the first year of follow-up, and every 2 or 3 years thereafter. The pathology details of biopsies were analyzed and compared with the current series on AS. RESULTS: Three-hundred nineteen patients undergoing AS were evaluated with a median follow-up of 5.3 years and a mean age of 67.4 years. Sixty-three patients did not meet all the criteria to be considered low-risk PC but were included in the analysis. Overall, 128 patients (40.1%) underwent active treatment (84.7% of them due to pathological progression in surveillance biopsies). The proportion of patients with a reported upgrading ranged between 19.4% and 35.3%, although only the fourth biopsy showed an upgrading proportion of over 30%. Limitations include the retrospective design of the study and the existence of different protocols between other cohorts that make it difficult to compare their results. CONCLUSIONS: For patients who remained in surveillance the percentage of upgrading increased slightly with the time, being more frequent after the third-surveillance biopsy. These findings support the importance of extending surveillance biopsies for patients who remain candidates for curative treatment.