Association between PD1 mRNA and response to anti-PD1 monotherapy across multiple cancer types.

Background: We hypothesized that the abundance of PD1 mRNA in tumor samples might explain the differences in overall response rates (ORR) observed following anti-PD1 monotherapy across cancer types. Patients and methods: RNASeqv2 data from 10 078 tumor samples representing 34 different cancer types was analyzed from TCGA. Eighteen immune-related gene signatures and 547 immune-related genes, including PD1, were explored. Correlations between each gene/signature and ORRs reported in the literature following anti-PD1 monotherapy were calculated. To translate the in silico findings to the clinical setting, we analyzed the expression of PD1 mRNA using the nCounter platform in 773 formalin-fixed paraffin embedded (FFPE) tumor samples across 17 cancer types. To test the direct relationship between PD1 mRNA, PDL1 immunohistochemistry (IHC), stromal tumor-infiltrating lymphocytes (sTILs) and ORR, we evaluated an independent FFPE-based dataset of 117 patients with advanced disease treated with anti-PD1 monotherapy. Results: In pan-cancer TCGA, PD1 mRNA expression was found strongly correlated (r > 0.80) with CD8 T-cell genes and signatures and the proportion of PD1 mRNA-high tumors (80th percentile) within a given cancer type was variable (0%-84%). Strikingly, the PD1-high proportions across cancer types were found strongly correlated (r = 0.91) with the ORR following anti-PD1 monotherapy reported in the literature. Lower correlations were found with other immune-related genes/signatures, including PDL1. Using the same population-based cutoff (80th percentile), similar proportions of PD1-high disease in a given cancer type were identified in our in-house 773 tumor dataset as compared with TCGA. Finally, the pre-established PD1 mRNA FFPE-based cutoff was found significantly associated with anti-PD1 response in 117 patients with advanced disease (PD1-high 51.5%, PD1-intermediate 26.6% and PD1-low 15.0%; odds ratio between PD1-high and PD1-intermediate/low = 8.31; P < 0.001). In this same dataset, PDL1 tumor expression by IHC or percentage of sTILs was not found associated with response. Conclusions: Our study provides a clinically applicable assay that links PD1 mRNA abundance, activated CD8 T-cells and anti-PD1 efficacy.

[Follow-up of patients treated by VKA: Interest of a pharmaceutical link between the hospital and the retail pharmacies]. / Suivi des patients traités par AVK : intérêt d'un relais pharmaceutique entre l'hôpital et la ville.

Vitamin K antagonists (VKA) are used by 1,7% of the French population. Patient education and monitoring can decrease the number of iatrogenic hospitalizations due to VKA. We assessed the impact of a communication between hospital and retail pharmacists about patient's knowledge on VKA. The aim of our study has been to evaluate the value added by the link between the hospital pharmacist and the community pharmacist on the follow-up of patients treated by vitamin K antagonist. Patient information about VKA treatment is offered to inpatients in our hospital. An information form is filled for each patient treated by VKA. Patient's knowledge is assessed on the document (Name of VKA, cause of treatment, monitoring, risks of overdose, compliance…). This form is sent to the community pharmacist after the training when the patient leaves the hospital (by fax or by email). The form is sent back by the community pharmacist after the second training. Sixty-eight patients received the training, 48 forms have been sent to the retail pharmacists and 43 forms have been sent back to the hospital. Seven retail pharmacists replied spontaneously. Twenty-eight patients increased their knowledge (in average+21%) and 12 patients stabilized their knowledge. The best-known concepts were the INR target, the time of drug intake, the risks of overdose and the information of the family. The improvement of knowledge is significant for the name of VKA, the cause of treatment, efficacy assessment and signs of overdose. The implementation of a communication between the hospital and the retail pharmacies is time-consuming but the follow-up of those patients seems essential to keep a good knowledge.

Gender trends at the annual Spanish Urologic Association (AEU) meeting: A review of AEU programmes over a 10-year period (2012-2022).

INTRODUCTION: Gender equity in urological meetings is pivotal for fostering diversity and inclusivity in the field. This study aims to evaluate the representation of Spanish urologist and regional disparities, and to assess its alignment with the demographic composition of the urological community. MATERIALS AND METHODS: All urology meetings organized by the AEU between January 2012 and December 2022 were reviewed, including meeting information and details of the faculty. Additionally, we analysed geographic distribution of speakers across 17 different regions. Gender demographics were obtained disaggregating data by sex and year from the Organización Médica Colegial de España (OMC) and from those urologists affiliated to the AEU. RESULTS: Analysing 52 AEU congresses held from 2012 to 2022, encompassing 3,407 speakers, the study found that 95.25% of speakers were from Spain and 89.6% were male speakers. Over the years, there was a positive trend in female speaker representation, increasing by 1.1% annually, slightly lagging the 1.8% annual rise in the number of female urologists in Spain. In specific subfields like functional, transplantation, and oncology sessions, the study revealed a higher representation of women, indicating focused efforts in these areas. Geographically, Madrid, Catalonia and Andalusia exhibited the highest representation. CONCLUSIONS: Although there was a positive trend towards an increased participation of female urologists in Spanish urological meetings, it fails to accurately reflect the proportional increase in the number of women entering the urology profession in recent years. This study underscores the importance of ongoing efforts to ensure diverse and balanced representation in urological forum.

Unraveling the clinicopathological and molecular changes induced by neoadjuvant chemotherapy and endocrine therapy in hormone receptor-positive/HER2-low and HER2-0 breast cancer.

BACKGROUND: The characterization and comparison of gene expression and intrinsic subtype (IS) changes induced by neoadjuvant chemotherapy (NACT) and endocrine therapy in hormone receptor-positive (HR+)/human epidermal growth factor receptor 2 (HER2)-low versus HR+/HER2-0 breast cancer (BC) has not been conducted so far. Most evidence on the association of HER2 status with pathologic responses and prognosis in HR+/HER2-negative BC is controversial and restricted to NACT-treated disease. Similarly, a temporal heterogeneity in HER2 status has been described only with NACT. METHODS: We retrospectively recruited a consecutive cohort of 186 patients with stage I-IIIB HR+/HER2-negative BC treated with neoadjuvant therapy (NAT). Available diagnostic biopsies and surgical samples were characterized for main pathological features, PAM50 IS and ROR-P score, and gene expression. Associations with pathologic complete response, residual cancer burden-0/I, event-free survival (EFS) and overall survival (OS) based on HER2 status were assessed. Pre/post pathologic/molecular changes were analyzed in matched samples. RESULTS: The HER2-low (62.9%) and HER2-0 (37.1%) cohorts did not differ significantly in main baseline features, treatments administered, breast-conserving surgery, pathologic complete response and residual cancer burden-0/I rates, EFS, and OS. NAT induced, regardless of HER2 status, a significant reduction of estrogen receptor/progesterone receptor and Ki67 levels, a down-regulation of PAM50 proliferation- and luminal-related genes/signatures, an up-regulation of selected immune genes, and a shift towards less aggressive IS and lower ROR-P. Moreover, 25% of HER2-0 changed to HER2-low and 34% HER2-low became HER2-0. HER2 shifts were significant after NACT (P < 0.001), not neoadjuvant endocrine therapy (P = 0.063), with consistent ERBB2 mRNA level dynamics. HER2 changes were not associated with EFS/OS. CONCLUSIONS: HER2-low and HER2-0 status change after NAT in ∼30% of cases, mostly after NACT. Targeted adjuvant strategies should be investigated accordingly. Molecular downstaging with current chemo/endocrine agents and immunotherapy should not rely on HER2 immunohistochemical levels in HR+/HER2-negative BC. Instead, HER2-low-targeted approaches should be explored to pursue more effective and/or less toxic dimensional downstaging.

Prognostic value of intrinsic subtypes in hormone-receptor-positive metastatic breast cancer: systematic review and meta-analysis.

BACKGROUND: In hormone receptor-positive (HoR+) breast cancer (BC), gene expression analysis identifies luminal A (LumA), luminal B (LumB), human epidermal growth factor receptor 2 (HER2)-enriched (HER2-E), basal-like (BL) intrinsic subtypes and a normal-like group. This classification has an established prognostic value in early-stage HoR+ BC. Here, we carried out a trial-level meta-analysis to determine the prognostic ability of subtypes in metastatic BC (MBC). MATERIALS AND METHODS: We systematically reviewed all the available prospective phase II/III trials in HoR+ MBC where subtype was assessed. The primary endpoint was progression-free survival (PFS)/time to progression (TTP) of the LumA subtype compared to non-LumA. Secondary endpoints were PFS/TTP of each individual subtype, according to treatment, menopausal and HER2 status and overall survival (OS). The random-effect model was applied, and heterogeneity assessed through Cochran's Q and I2. Threshold for significance was set at P < 0.05. The study was registered in PROSPERO (ID: CRD42021255769). RESULTS: Seven studies were included (2536 patients). Non-LumA represented 55.2% and was associated with worse PFS/TTP than LumA [hazard ratio (HR) 1.77, P < 0.001, I2 = 61%], independently of clinical HER2 status [Psubgroup difference (Psub) = 0.16], systemic treatment (Psub = 0.96) and menopausal status (Psub = 0.12). Non-LumA tumors also showed worse OS (HR 2.00, P < 0.001, I2 = 65%), with significantly different outcomes for LumB (PFS/TTP HR 1.46; OS HR 1.41), HER2-E (PFS/TTP HR 2.39; OS HR 2.08) and BL (PFS/TTP HR 2.67; OS HR 3.26), separately (PFS/TTP Psub = 0.01; OS Psub = 0.005). Sensitivity analyses supported the main result. No publication bias was observed. CONCLUSIONS: In HoR+ MBC, non-LumA disease is associated with poorer PFS/TTP and OS than LumA, independently of HER2, treatment and menopausal status. Future trials in HoR+ MBC should consider this clinically relevant biological classification.

Rationale, design and methodology of TESEO study: a registry of thrombosis and neoplasia of SEOM (Spanish Society of Medical Oncology).

BACKGROUND AND RATIONALE: Thromboembolic complications are a serious, preventable and common event in cancer patients that contributes to increasing morbidity and mortality. Despite increasing knowledge on cancer-associated thrombosis (CAT), there are still several aspects of diagnosis, clinical management, treatment and prognosis with uncertainties that are under-represented in randomized clinical trials. For this reason, the Spanish Society of Medical Oncology (SEOM) launched in June 2018 a registry of CAT. METHODS/DESIGN: TESEO is an ongoing prospective, non-interventional, multicentric study in consecutive cancer patients with newly diagnosed of thromboembolic event (TEE). Eligibility criteria include being > 18 years with a histologically confirmed diagnosis of cancer and a symptomatic or incidental TEE confirmed with an imaging technique in the previous month or any time after the cancer diagnosis and signing of informed consent. The study consists of two types of integrated but independent prospective registries. Regular CAT sub-registry includes information on patient's cancer´s characteristics, anticoagulant treatment provided and outcome data. Special CAT sub-registry includes variables related to special situations of CAT that comprise patients with severe kidney failure, thrombocytopenia, high risk of bleeding related to the cancer or with coexistence of bleeding and patients who receive new treatments such a targeted therapy, antiangiogenics agents and immunotherapy. The registry considers the status of the cancer and the time to assess how the prognosis is changed based on when the thrombus occurs. Some outcomes such as rethrombosis, major bleeding, tumor progression and survival will be valued in various time intervals including 1, 3, 6 and 12 months after the even in the first year; and then every 6 months until the patient's death. RESULTS: After 18 months and with 35 centers and researchers, the registry has 1128 patients. CONCLUSION: TESEO registry will provide clinical real-world evidence for prevention, treatment and complications of CAT in different scenarios that are under-represented in randomized clinical trials.

[Postpartum hemolytic uremic syndrome: a rare entity and a treatment challenge]. / Síndrome hemolítico-urémico post-parto: entidad rara de manejo complejo.

Hemolytic uremic syndrome (HUS) is a rare entity that in 7% of cases has been related to oral contraceptives, pregnancy and puerperium, In this clinical setting prognosis is worse and renal replacement therapy is usually needed. Different authors agree that plamapheresis is the treatment of choice, and has improved patient survival to 80-90%. We describe a case of a young woman that 10 days postpartum developed thrombocytopenia, microangiopathic hemolytic anemia and acute renal failure with nephrotic range proteinuria. With the suspicion of HUS she was started on plasmapheresis initially stopped due to an anaphylactic reaction to plasma and finally due to hyperhidratation with acute pulmonary edema needing mechanical ventilation. Renal biopsy confirmed the diagnosis. Clinical course was complicated with refractory hypertension and infectious complications In conclusion postpartum HUS is a rare clinical entity , that forces a differential diagnosis with hypertensive complications of pregnancy. It is associated to multiple complications difficult to handle during follow-up. Plasmapheresis treatment adds complexity to clinical care but is the only treatment of proven efficacy in order to improve survival and renal prognosis.

[Nodular lymphoid hyperplasia of the small bowel with IgA deficiency and hemolytic anemia (author's transl)]. / Hiperplasia nodular linfoide del intestino delgado con déficit de IgA y anemia hemolítica.

The syndrome of nodular lymphoid hyperplasia of the small bowel with hypogammaglobulinemia is one of the hypogammaglobulinemic enteropathies. Chronic diarrhea and malabsorption are the most characteristic features of this disease, and they are frequently associated to hypogammaglobulinemia of various types (acquired, congenital non sex-linked) and to selective IgA deficiency. The immunological deficiency gives rise to the more characteristic features of the disease, namely: a) hypogammaglobulinemia; b) respiratory infections and dental caries; c) Giardia lamblia infestation of the small bowel; d) the characteristic radiological features; and, e) the histological aspect of the intestinal mucosa with absence of plasma cells. Periodical follow-up is needed because of the increased incidence of tumors in immunological deficiency states. A new case of nodular lymphoid hyperplasia associated to hemolytic anemia and granulomatous hepatitis is reported, and its possible pathogenesis is discussed.

Síndrome de la arteria mesentérica superior en edad pediátrica: ¿infrecuente o infradiagnosticado? / Superior mesenteric artery syndrome in pediatric age: is it rare of underdiagnosed?

Objetivo. Reconocer el síndrome de la arteria mesentérica superior (SAMS) como causa de dolor abdominal recurrente en edad pediátrica y los problemas clínicos relacionados que pueden enmascararlo, siendo el tránsito esófago-gastroduodenal (TEGD) suficiente para su diagnóstico. Pacientes y métodos. Se recogen 12 pacientes afectos de SAMS, entre los años 2006 y 2013, la mayoría remitidos por dolor abdominal, en general con sospecha de reflujo gastroesofágico (RGE) y/o patología intestinal malabsortiva. Las técnicas de imagen empleadas para su estudio son el TEGD y la ecografía abdominal. Se lleva a cabo Tomografía Computarizada (TC) abdominal con contraste únicamente en 2 pacientes. Resultados. El TEGD fue diagnóstico en el 100% de los casos. Ni las ecografías ni los TC abdominales aportaron datos concluyentes ni hallazgos adicionales determinantes para el diagnóstico y tratamiento. Conclusiones. Enfatizamos la contribución del SAMS en el dolor abdominal recurrente en niños, así como los factores predisponentes y desencadenantes de esta entidad, siendo el TEGD la prueba diagnóstica de elección (AU)

Introduction. To recognize the superior mesenteric artery síndrome (SMAS) as a cause of recurrent abdominal pain in childhood and related clinical problems that can mimic it, being the upper gastrointestinal (UGIT) enough to diagnosis. Patients and method. 12 patients with SAMS were collected between 2006 and 2013, most of them presented with abdominal pain and usually suspected of gastroesophageal reflux (GER) and/or malabsorptive intestinal disorders. The imaging techniques used were UGIT and abdominal ultrasound. Abdominal contrast-enhanced Computed Tomography (CDCT) was performed in only 2 patients. Results. UGIT allowed accurate diagnosis in all patients. Neither abdominal ultrasound nor CECT provide conclusive or determining additional findings for diagnostic or therapeutic approach. Conclusions. We emphasize the contribution of SAMS to recurrent abdominal pain in children, as well as predisposing factors and triggers of this entity, being the UGIT the diagnostic test of choice (AU)

Síndrome hemolítico-urémicopost-parto: entidad rara de manejo complejo / No disponible

El síndrome hemolítico urémico (SHU) es una entidad de escasa incidencia, donde un 7% de casos se asocia a la toma de anticonceptivos orales, al embarazo y al puerperio, siendo tales casos de peor pronóstico, pues frecuentemente necesitan tratamiento renal sustitutivo1. Distintos autores coinciden en que la plasmaféresis es la terapia de elección, que ha mejorado la supervivencia a 80-90%2,3. Describimos el caso de una joven que en el décimo día del puerperio presenta plaquetopenia, anemia hemolíticamicroangiopática (AHM), e insuficiencia renal con proteinuria nefrótica. Con la orientación de SHU se pauta plasmaféresis, que se suspende inicialmente por alergia al plasma infundido, y definitivamente por hiperhidratación con edema agudo de pulmón (EAP) que precisa ventilación mecánica. La biopsia renal confirma el diagnóstico de presunción. La evolución resulta tórpida, marcada por la hipertensión arterial (HTA) refractaria y complicaciones infecciosas. En conclusión, el SHU post-parto es una patología poco frecuente, que asocia muchas complicaciones de difícil manejo a lo largo de su evolución y que obliga al diagnóstico diferencial con los estados hipertensivos del embarazo4. A su vez, el tratamiento con plasmaféresis añade complejidad al cuadro, pero es el único procedimiento que ha demostrado mejorar la supervivencia y el pronóstico renal (AU)

Hemolytic uremic syndrome (HUS) is a rare entity that in 7% of cases has been related to oral contraceptives, pregnancy and puerperium, In this clinical setting prognosis is worse and renal replacement therapy is usually needed. Different authors agree that plamapheresis is the treatment of choice, and has improved patient survival to 80-90%. We describe a case of a young woman that 10 days postpartum developed thrombocytopenia, microangiopathic hemolytic anemia and acute renal failure with nephritic range proteinuria. With the suspiction of HUS she was started on plasmapheresis initially stopped due to an anaphylactic reaction to plasma and finally due to hyperhidratation with acute pulmonary edema needing mechanical ventilation. Renal biopsy confirmed the diagnosis. Clinical course was complicated with refractory hypertension and infectious complications In conclusion postpartum HUS is a rare clinical entity , that forces a differential diagnosis with hypertensive complications of pregnancy. It is associated to multiple complications difficult to handle during follow-up. Plasmapheresis treatment adds complexity to clinical care but is the only treatment of proven efficacy in order to improve survival and renal prognosis (AU)