Estudio Farmacogenético En Pacientes Con Carcinoma Rectal Tratados Con Quimorradioterapia Neoadyuvante Basada En Capecitabina

Estudio de los polimorfismos del gen de la timidilato sintasa y los genes reparadores del ADN ERCC1 y XRCC1 y su relación con la rdespuesta al tratamiento neoadyvante con qumiorradioterapia basada en capecitabin, en pacientes afecto de carcinoma colorrectal de localmente avanzado.Estudi dels polimorfismes del gen de la timidilato sintasa i els gens reparadors del ADN ERCC1 i XRCC1 i la seva relació amb la reposta al tractament neoadjuvant amb quimiorradioterapia basada en capacitabina, en pacients afectes de carcinoma colorrectal localmente avançat

A Novel NFIX-STAT6 Gene Fusion in Solitary Fibrous Tumor: A Case Report

Solitary fibrous tumor is a rare subtype of soft-tissue sarcoma with a wide spectrum of histopathological features and clinical behaviors, ranging from mildly to highly aggressive tumors. The defining genetic driver alteration is the gene fusion NAB2–STAT6, resulting from a paracentric inversion within chromosome 12q, and involving several different exons in each gene. STAT6 (signal transducer and activator of transcription 6) nuclear immunostaining and/or the identification of NAB2–STAT6 gene fusion is required for the diagnostic confirmation of solitary fibrous tumor. In the present study, a new gene fusion consisting of Nuclear Factor I X (NFIX), mapping to 19p13.2 and STAT6, mapping to 12q13.3 was identified by targeted RNA-Seq in a 74-year-old female patient diagnosed with a deep-seated solitary fibrous tumor in the pelvis. Histopathologically, the neoplasm did not display nuclear pleomorphism or tumor necrosis and had a low proliferative index. A total of 378 unique reads spanning the NFIXexon8–STAT6exon2 breakpoint with 55 different start sites were detected in the bioinformatic analysis, which represented 59.5% of the reads intersecting the genomic location on either side of the breakpoint. Targeted RNA-Seq results were validated by RT-PCR/ Sanger sequencing. The identification of a new gene fusion partner for STAT6 in solitary fibrous tumor opens intriguing new hypotheses to refine the role of STAT6 in the sarcomatogenesis of this entity

Preoperative exercise training prevents functional decline after lung resection surgery: a randomized, single-blind controlled trial

[Abstract] Objectives: To investigate the effects of a preoperative pulmonary rehabilitation programme in patients with lung cancer undergoing video-assisted thoracic surgery. Design: Randomized, single-blind controlled trial. Setting: Teaching hospital. Subjects: Patients with suspected or confirmed lung cancer undergoing video-assisted thoracic surgery. Intervention: Participants were randomized to either a prehabilitation group or a control group. Participants in the prehabilitation group underwent a combination of moderate endurance and resistance training plus breathing exercises three to five times per week. Main measures: The primary outcome of the study was exercise capacity. Secondary outcomes were muscle strength (Senior Fitness Test), health-related quality of life (Short-Form 36) and the postoperative outcomes. Patients were evaluated at baseline (before randomization), presurgery (only the prehabilitation group), after surgery and three months post-operatively. Results: A total of 40 patients were randomized and 22 finished the study (10 in the prehabilitation group and 12 in the control group). Three patients were lost to follow-up at three months. After the training, there was a statistically significant improvement in exercise tolerance (+397 seconds, p = 0.0001), the physical summary component of the SF-36 (+4.4 points, p = 0.008) and muscle strength (p < 0.01). There were no significant differences between groups after surgery. However, three months postoperatively, significant differences were found in the mean change of exercise capacity (p = 0.005), physical summary component (p = 0.001) and upper and lower body strength (p = 0.045 and p = 0.002). Conclusions: A pulmonary rehabilitation programme before video-assisted thoracic surgery seems to improve patients’ preoperative condition and may prevent functional decline after surger

ABCB1 Genetic Variants as Predictors of Irinotecan-Induced Severe Gastrointestinal Toxicity in Metastatic Colorectal Cancer Patients

Irinotecan is widely used in the treatment of metastatic colorectal cancer (mCRC) despite its severe toxicities. Toxicity is often associated with the UGT1A1*28/*28 genotype. An explanation for idiopathic toxicity beyond the UGT1A1 biomarker, however, remains a major concern for clinicians. One of the main irinotecan transporters is P-glycoprotein (P-gp), which is a hepatic efflux pump encoded by ABCB1. P-gp is involved in the biliary excretion of irinotecan and its active metabolite SN-38. We aimed to assess whether functional variants in ABCB1 also contribute to identifying patients at risk of toxicity. A cohort of 308 mCRC patients treated with irinotecan-based regimens were genotyped for polymorphisms in ABCB1 (rs1128503, rs2032582, and rs1045642). The effect of these variants and their haplotypes on irinotecan-induced severe toxicity (diarrhea, neutropenia, asthenia, nausea, and mucositis) was assessed. After adjusting for the relevant clinical and pathological parameters in the multivariate analysis, we found rs1128503 was significantly associated with severe diarrhea and mucositis (P=0.014 and P=0.002, respectively). Additionally, rs2032582 was associated with severe mucositis (P<0.001). Our results show that rs1128503 genotyping could help to predict severe gastrointestinal toxicity induced by irinotecan

Epigenetic inactivation of the putative DNA/RNA helicase SLFN11 in human cancer confers resistance to platinum drugs

Platinum-derived drugs such as cisplatin and carboplatin are among the most commonly used cancer chemotherapy drugs, but very few specific molecular and cellular markers predicting differential sensitivity to these agents in a given tumor type have been clearly identified. Epigenetic gene silencing is increasingly being recognized as a factor conferring distinct tumoral drug sensitivity, so we have used a comprehensive DNA methylation microarray platform to interrogate the widely characterized NCI60 panel of human cancer cell lines with respect to CpG methylation status and cisplatin/carboplatin sensitivity. Using this approach, we have found promoter CpG island hypermethylation-associated silencing of the putative DNA/RNA helicase Schlafen-11 (SLFN11) to be associated with increased resistance to platinum compounds. We have also experimentally validated these findings in vitro. In this setting, we also identified the BRCA1 interacting DHX9 RNA helicase (also known as RHA) as a protein partner for SLFN11, suggesting a mechanistic pathway for the observed chemoresistance effect. Most importantly, we have been able to extend these findings clinically, following the observation that those patients with ovarian and non-small cell lung cancer carrying SLFN11 hypermethylation had a poor response to both cisplatin and carboplatin treatments. Overall, these results identify SLFN11 epigenetic inactivation as a predictor of resistance to platinum drugs in human cancer

Pharmacogenetic clinical randomised phase II trial to evaluate the efficacy and safety of FOLFIRI with high-dose irinotecan (HD-FOLFIRI) in metastatic colorectal cancer patients according to their UGT1A 1 genotype

Patients harbouring the UGT1A1 *28/*28 genotype are at risk of severe toxicity with the standard irinotecan dose. However, this dose is considerably lower than the dose that can be tolerated by UGT1A1 *1/*1 and *1/*28 patients. This randomised phase II trial evaluated the efficacy and safety of the FOLFIRI regimen with high-dose irinotecan (HD-FOLFIRI) in metastatic colorectal cancer patients. Eighty-two patients with the UGT1A1 *1/*1 or the *1/*28 genotype were randomised to receive HD-FOLFIRI versus FOLFIRI. Patients with the UGT1A1 *28/*28 genotype were excluded. In the experimental group, the irinotecan dose was 300 mg/m 2 for UGT1A1 *1/*1 and 260 mg/m 2 for *1/*28 patients. In the control group, the dose was 180 mg/m 2. We analysed the overall response rate (ORR), toxicity, and survival. The ORR was significantly higher in the HD-FOLFIRI group (67.5 versus 43.6%; p = 0.001 OR: 1.73 [95% CI:1.03-2.93]). Neutropenia (17.7%), diarrhoea (5.1%), and asthenia (5.1%) were the most common grade 3-4 toxicity. No differences were observed in severe toxicity (22.5% versus 20.5%), dose reduction (22.5% versus 28.2%), or prophylactic G-CSF (17.5% versus 12.8%). No difference in survival was found. Patients with the UGT1A1 *1/*1 and *1/*28 genotypes can receive high doses of irinotecan to achieve a more favourable ORR without significant adverse events

A Novel NFIX-STAT6 Gene Fusion in Solitary Fibrous Tumor: A Case Report

Solitary fibrous tumor is a rare subtype of soft-tissue sarcoma with a wide spectrum of histopathological features and clinical behaviors, ranging from mildly to highly aggressive tumors. The defining genetic driver alteration is the gene fusion NAB2–STAT6, resulting from a paracentric inversion within chromosome 12q, and involving several different exons in each gene. STAT6 (signal transducer and activator of transcription 6) nuclear immunostaining and/or the identification of NAB2–STAT6 gene fusion is required for the diagnostic confirmation of solitary fibrous tumor. In the present study, a new gene fusion consisting of Nuclear Factor I X (NFIX), mapping to 19p13.2 and STAT6, mapping to 12q13.3 was identified by targeted RNA-Seq in a 74-year-old female patient diagnosed with a deep-seated solitary fibrous tumor in the pelvis. Histopathologically, the neoplasm did not display nuclear pleomorphism or tumor necrosis and had a low proliferative index. A total of 378 unique reads spanning the NFIXexon8–STAT6exon2 breakpoint with 55 different start sites were detected in the bioinformatic analysis, which represented 59.5% of the reads intersecting the genomic location on either side of the breakpoint. Targeted RNA-Seq results were validated by RT-PCR/ Sanger sequencing. The identification of a new gene fusion partner for STAT6 in solitary fibrous tumor opens intriguing new hypotheses to refine the role of STAT6 in the sarcomatogenesis of this entity

Novel Somatic Genetic Variants as Predictors of Resistance to EGFR-Targeted Therapies in Metastatic Colorectal Cancer Patients

Background: About 40% of RAS/BRAF wild-type metastatic colorectal cancer (mCRC) patients undergoing anti-EGFR-based therapy have poor outcomes. Treatment failure is not only associated with poorer prognosis but higher healthcare costs. Our aim was to identify novel somatic genetic variants in the primary tumor and assess their effect on anti-EGFR response. Patients and Methods: Tumor (somatic) and blood (germline) DNA samples were obtained from two well-defined cohorts of mCRC patients, those sensitive and those resistant to EGFR blockade. Genetic variant screening of 43 EGFR-related genes was performed using targeted next-generation sequencing (NGS). Relevant clinical data were collected through chart review to assess genetic results. Results: Among 61 patients, 38 were sensitive and 23 were resistant to treatment. We identified eight somatic variants that predicted non-response. Three were located in insulin-related genes (I668N and E1218K in IGF1R, T1156M in IRS2) and three in genes belonging to the LRIG family (T152T in LRIG1, S697L in LRIG2 and V812M in LRIG3). The remaining two variants were found in NRAS (G115Efs*46) and PDGFRA (T301T). We did not identify any somatic variants related to good response. Conclusions: This study provides evidence that novel somatic genetic variants along the EGFR-triggered pathway could modulate the response to anti-EGFR drugs in mCRC patients. It also highlights the influence of insulin-related genes and LRIG genes on anti-EGFR efficacy. Our findings could help characterize patients who are resistant to anti-EGFR blockade despite harboring RAS/BRAF wild-type tumors

Uterine sarcomas : clinical practice guidelines for diagnosis, treatment, and follow-up, by Spanish group for research on sarcomas (GEIS)

Uterine sarcomas are very infrequent and heterogeneous entities. Due to its rarity, pathological diagnosis, surgical management, and systemic treatment are challenging. Treatment decision process in these tumors should be taken in a multidisciplinary tumor board. Available evidence is low and, in many cases, based on case series or clinical trials in which these tumors have been included with other soft tissue sarcoma. In these guidelines, we have tried to summarize the most relevant evidence in the diagnosis, staging, pathological disparities, surgical management, systemic treatment, and follow-up of uterine sarcomas

Respiratory Physiotherapy in Post-COVID-19: A Decision-Making Algorithm for Clinical Practice

[Resumen] La pandemia causada por la enfermedad de la COVID-19 ha supuesto un gran reto para los profesionales del sistema sociosanitario, intensificándose con el manejo y atención de las manifestaciones clínicas que potencialmente pueden presentarse de manera persistente en las personas que han superado la enfermedad. Para ello, la fisioterapia respiratoria se presenta como piedra angular dentro del modelo de abordaje interdisciplinar que requiere esta población. Dado que la implementación de esta opción terapéutica continúa siendo limitada en España, es imprescindible realizar una evaluación integral y exhaustiva de la persona que nos permita establecer criterios de selección a fin de optimizar el uso de los recursos humanos y materiales existentes. Para ello, se propone un algoritmo de decisión terapéutica basado en pruebas de evaluación validadas y objetivas de las posibles manifestaciones clínicas del paciente. La aplicación de este algoritmo, en cualquier nivel asistencial (atención especializada y atención primaria/comunitaria) junto con la atención centrada en la persona, el impulso del uso de los espacios comunitarios verdes y azules de las ciudades y un adecuado uso de las tecnologías de la comunicación y la información, nos permitirá optimizar el modelo de atención de fisioterapia respiratoria en el contexto actual, marcado por la COVID-19.[Abstract] The outbreak of COVID-19 has posed a great challenge for the healthcare system which has been later aggravated by the need of managing clinical manifestations and potential sequelae in COVID-19 survivors. In this context, respiratory Physiotherapy emerges as a cornerstone in the interdisciplinary management warranted in this population. Given that the implementation and resources available for the interdisciplinary therapeutic interventions in Spain is scarce, it is essential to perform a comprehensive, exhaustive and personalised assessment. This will allow us to establish more accurate selection criteria in order to optimise the use of existing human and material resources. To this end, we propose here a decision-making algorithm for clinical practice to assess the clinical manifestations in people recovered from COVID-19 based on well-established, validated tests and assessment tools. This algorithm can be used at any clinical practice environment (primary care/community or hospital-based), combined with a patient-centered model and the use of community and e-Health resources and its application to improve the Physiotherapy care of these patients in the COVID-19 era