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The aim of this study was to validate a molecular classification of colorectal cancer (CRC) based on microsatellite instability (MSI), CpG island methylator phenotype (CIMP) status, BRAF, and KRAS and investigate each subtype's response to chemotherapy. This retrospective observational study included a population-based cohort of 878 CRC patients. We classified tumours into five different subtypes based on BRAF and KRAS mutation, CIMP status, and MSI. Patients with advanced stage II (T4N0M0) and stage III tumours received 5-fluoruracil (5-FU)-based chemotherapy or no adjuvant treatment based on clinical criteria. The main outcome was disease-free survival (DFS). Patients with the combination of microsatellite stable (MSS) tumours, BRAF mutation and CIMP positive exhibited the worst prognosis in univariate (log rank P<0.0001) and multivariate analyses (hazard ratio 1.75, 95% CI 1.05-2.93, P = 0.03) after adjusting for age, sex, chemotherapy, and TNM stage. Treatment with 5-FU-based regimens improved prognosis in patients with the combination of MSS tumours, KRAS mutation and CIMP negative (log rank P = 0.003) as well as in patients with MSS tumours plus BRAF and KRAS wild-type and CIMP negative (log-rank P<0.001). After adjusting for age, sex, and TNM stage in the multivariate analysis, only patients with the latter molecular combination had independently improved prognosis after adjuvant chemotherapy (hazard ratio 2.06, 95% CI 1.24-3.44, P = 0.005). We confirmed the prognostic value of stratifying CRC according to molecular subtypes using MSI, CIMP status, and somatic KRAS and BRAF mutation. Patients with traditional chromosomally unstable tumours obtained the best benefit from adjuvant 5-FU-based chemotherapy.

ObjectiveThe reason cancer pain remains prevalent and hard to classify may be partially explained by the failure to identify neuropathic mechanisms. The objective of this research was to identify the syndromes of cancer pain that may be particularly hard to manage due to their mixed pathophysiology.DesignA series of 384 patients who had cancer of any type, at any stage, and suffered from chronic pain (symptom onset > 3 months) were assessed during a routine return visit in Spain. Medical oncologists indicated the presence and pathophysiology of 33 predefined pain syndromes on a per-patient basis. This information was then measured against clinical, psychosocial, and health care-related data to determine which syndromes pose particular challenges.ResultsThe mean (standard deviation) age of patients was 61.6 (12.6) years, 49.7% were women. Most (82%) had advanced metastatic disease, 68.7% were on second-line or palliative therapies. The worst syndrome was nociceptive, pure neuropathic, and mixed in 34.6, 26.9, and 38.6% of patients, respectively. Any syndrome could be of mixed pathophysiology. Only 10 syndromes were common (≥ 5% of patients). Syndromes related to malignant bone pain and involvement of chest wall structures were the most frequent. Certain syndromes (including tumor-related bone pain, chemotherapy-induced peripheral neuropathies, paraneoplastic pain syndromes, and malignant neuralgias or injury to cranial nerves) can be particularly challenging when they have a mixed pathophysiology, because the neuropathic component is rarely or unevenly considered.ConclusionsVirtually all cancer pain syndromes can present mixed pathophysiology. Certain syndromes can include neuropathic components that are frequently overlooked.

Purpose The prognosis of patients with unresectable M0 gastric cancer remains very poor. We performed a phase II trial to explore the efficacy and toxicity of induction irinotecan-cisplatin (IC) followed by concurrent irinotecan-cisplatin and radiotherapy (IC/RT) in this setting. Methods and materials Patients with unresectable M0 gastric (GC) or oesophageal-gastric junction (EGJC) adenocarcinomas were treated with two courses of IC (irinotecan, 65 mg/m 2 ; cisplatin, 30 mg/m 2 on days 1 and 8 every 21 days) followed by IC/RT (daily radiotherapy—45 Gy—with concurrent IC: irinotecan, 65 mg/m 2 , and cisplatin, 30 mg/m 2 , on days 1, 8, 15, and 22). Resectability was reassessed after this treatment, and surgical resection was performed if feasible. The primary endpoint was the R0 resection rate after induction treatment. Results Seventeen patients were included in the study (EGJC: 6; GC: 11). An R0 resection was achieved in only 5 patients (29%), and according to the design of the trial (Simon’s optimal two-stage) accrual of patients was terminated after the first stage. No patient died during IC, whereas 3 patients (24%) died during IC/RT and one of 5 resected patients (20%) died during the first 30 days after resection. The median survival was 10.5 months, and the actuarial 2-year survival rate was 27%. Conclusions Induction IC followed by IC/RT showed poor efficacy and significant toxicity in patients with unresectable GC/EGJC.

Introduction/BackgroundChemotherapy-induced reactions are mainly immediate hypersensitivity reactions (IHSR), however, non-immediate hypersensitivity reactions (NIHSR) have been described. NIHSRs usually reappear after each re-exposure, but sometimes can lead to the development of IHSRs, which is known as the ‘converter phenotype’. IHSRs can be of different phenotypes: type I (IgE or non-IgE mediated), cytokine release reactions (CRR), mixed (Mx) or indeterminate (Id).NIHSRs are characterized by the onset of symptoms at least 6 hours after drug exposure and are thought to be mediated by T cells.MethodologyBetween January 2018 and June 2023, 18 patients diagnosed with gynecological and breast neoplasms were evaluated because of NIHSR. One patient with ovarian (OC) and 5 with breast cancer (BC) presented NIHSRs; in addition 6 OC, 2 endometrial (EC) and 4 BC with converter phenotype were identified. All patients were sent for evaluation to the Allergy Section of the Dr. Balmis General University Hospital, Alicante-Spain. Patients‘ symptoms, skin biopsies, skin tests, biomarkers, and results of 83 DDs were retrospectively analyzed.ResultsPaclitaxel was the culprit drug in all patients with NIHSRs. Most patients had maculopapular exanthema (MPE) (83%), flushing/warm (83%) and pruritus (50%). On the other hand, the converter phenotype was triggered by paclitaxel in 6 patients, carboplatin in 3, and docetaxel in 3. Clinically, NIHSRs manifested as MPE (58%), flushing/warm (25%) and pain (25%), among others. After switching to an IHSR, patients developed reactions of phenotype 1 (8%), CRR (58%), Mx (17%) and Id (17%).83 DDs were performed, and 13 (16%) breakthrough reactions were observed: 4 IHSRs and 9 NIHSRs.ConclusionDD protocols represent a safe and useful procedure not only for IHSR but also for NIHSR. Reintroduction of the culprit drug through DD may prevent the development of severe NIHSR, as well as prevent progression to IHSR after delayed reactions.DisclosuresNone of the authors have a conflict of interest related to this presentation.

Irinotecan and raltitrexed are active against advanced colorectal cancer, act through different mechanisms, and have non-overlapping toxicity profiles. In vitro studies have shown a schedule-dependent synergism between both drugs. The aim of this multicenter study was to determine the maximum tolerated dose (MTD) of this combination. Patients with 5-fluorouracil-refractory, advanced colorectal cancer were eligible. Dose escalation consisted of irinotecan (250–350 mg/m 2 as a 60-min infusion) in combination with a fixed dose of raltitrexed (3 mg/m 2 as a 15-min infusion, 1 h after irinotecan). Courses were repeated every 21 days. Three to 6 patients were to be included at each dose level. Dose limiting (NCI-CTC grade 3–4) toxicities (DLT) were assessed during the first 2 cycles. Thirteen patients were recruited (4, 3 and 6 in levels I, II and III, respectively). Main toxicity was diarrhea and asthenia, whereas myelotoxicity was mild. At level III, 2/6 patients experienced DLT (grade 4 diarrhea and neutropenia). The MTD was not reached, but further dose escalation was not attempted. Among 12 patients with measurable disease, 2 partial responses were observed for an overall response rate of 17%. The combination of single-agent full doses of irinotecan (350 mg/m 2 ) and raltitrexed (3 mg/m 2 ) in a 3-weekly schedule is feasible, with mild toxicity and a promising clinical activity. Diarrhea is the DLT, but it is not more common or severe than that described with irinotecan alone.

Objetivos: Determinar el efecto del tratamiento con venlafaxina retard en pacientes con trastorno por dependencia de alcohol o de alcohol y cocaína que inician un tratamiento de desintoxicación. Metodología: Estudio observacional, abierto y prospectivo, realizado en España en 2005. Se incluyen 55 pacientes mayores de 18 años con diagnóstico de trastorno por dependencia de alcohol o alcohol y cocaína, ingresados en un centro de Atención Especializada para iniciar tratamiento de desintoxicación. Se administró durante 6 meses venlafaxina retard, a dosis entre 75 y 225 mg/día. Resultados: El tratamiento se asoció a reducciones significativas en las puntuaciones del EuropASI en las siguientes áreas: 3, uso de alcohol, con una puntuación basal y final de 8,2+-0,2 y 6,4+-0,4, respectivamente (P < 0,01); 5, relaciones familiares/sociales, puntuación inicial de 6,9+-0,2 y final de 5,2+-0,5 (P < 0,001); 1, situación médica, con puntuaciones de 3,7+-0,4 y 0,9+-0,3 (visitas basal y final, respectivamente) (P < 0,001); y 6, situación psiquiátrica, con puntuación basal de 7,8+-0,1 y final de 5,4+-0,4 (P < 0,001). La puntuación basal en la Escala Visual Analógica de craving de alcohol fue de 26,7+-4,6, descendiendo a 4,1+-1,5 en la visita final (P < 0,001). Conclusiones: Los resultados de este estudio observacional sugieren que venlafaxina retard podría ser efectiva en el tratamiento coadyuvante de pacientes dependientes de alcohol, que están siguiendo terapia de deshabituación. No obstante, esto debe ser replicado con series más amplias y controladas con placebo.

The aim is to determine the effect of the treatment with venlafaxine extended release in patients with alcohol or cocaine dependence disorder that initiate detoxification treatment. Observational, open, prospective study carried out in Spain in 2005. 55 patients older than 18 years of age with diagnosis of alcohol and/or cocaine dependence disorder, hospitalized in Specialty Care Center to initiate detoxification treatment, were included. Daily doses of 75 to 225 mg of venlafaxine extended release were administered for 6 months. Treatment was associated with significant reductions in EuropASI scores in the following areas: 3, alcohol use, baseline and final score of 8.2 +/- 0.2 and 6.4 +/- 0.4, respectively (P < 0.01); 5, family/social relations, initial score of 6.9 +/- 0.2 and of 5.2 +/- 0.5 at endpoint (P < 0.001); 1, medical status, scores of 3.7 +/- 0.4 and 0.9 +/- 0.3 (baseline and final visits, respectively) (P < 0.001); and 6, psychiatric status, with a baseline score of 7.8 +/- 0.1 and final score of 5.4 +/- 0.4 (P < 0.001). The VAS alcohol craving scores at baseline were 26.7 +/- 4.6, decreasing to 4.1 +/- 1.5 at endpoint (P < 0.001). The results of this observational study suggest that venlafaxine extended release could be effective as a coadyuvant in the treatment of alcohol dependent patients in alcohol detoxification therapy. Nevertheless, this should be confirmed with bigger placebo-controlled samples.

A dramatic evolution of fruit size has accompanied the domestication and improvement of fruit-bearing crop species. In tomato (Solanum lycopersicum), naturally occurring cis-regulatory mutations in the genes of the CLAVATA-WUSCHEL signaling pathway have led to a significant increase in fruit size generating enlarged meristems that lead to flowers with extra organs and bigger fruits. In this work, by combining mapping-by-sequencing and CRISPR/ Cas9 genome editing methods, we isolated EXCESSIVE NUMBER OF FLORAL ORGANS (ENO), an AP2/ERF transcription factor which regulates floral meristem activity. Thus, the ENO gene mutation gives rise to plants that yield larger multilocular fruits due to an increased size of the floral meristem. Genetic analyses indicate that eno exhibits synergistic effects with mutations at the LOCULE NUMBER (encoding SlWUS) and FASCIATED (encoding SlCLV3) loci, two central players in the evolution of fruit size in the domestication of cultivated tomatoes. Our findings reveal that an eno mutation causes a substantial expansion of SlWUS expression domains in a flower-specific manner. In vitro binding results show that ENO is able to interact with the GGC-box cis-regulatory element within the SlWUS promoter region, suggesting that ENO directly regulates SlWUS expression domains to maintain floral stem-cell homeostasis. Furthermore, the study of natural allelic variation of the ENO locus proved that a cis-regulatory mutation in the promoter of ENO had been targeted by positive selection during the domestication process, setting up the background for significant increases in fruit locule number and fruit size in modern tomatoes.

Common bean (Phaseolus vulgaris L.) is an important grain legume domesticated independently in Mexico and Andean South America approximately 8000 years ago. Wild forms are obligate short-day plants, and relaxation of photoperiod sensitivity was important for expansion to higher latitudes and subsequent global spread. To better understand the nature and origin of this key adaptation, we examined its genetic control in progeny of a wide cross between a wild accession and a photoperiod-insensitive cultivar. We found that photoperiod sensitivity is under oligogenic control, and confirm a major effect of the Ppd locus on chromosome 1. The red/far-red photoreceptor gene PHYTOCHROME A3 (PHYA3) was identified as a strong positional candidate for Ppd, and sequencing revealed distinct deleterious PHYA3 mutations in photoperiod-insensitive Andean and Mesoamerican accessions. These results reveal the independent origins of photoperiod insensitivity within the two major common bean gene pools and demonstrate the conserved importance of PHYA genes in photoperiod adaptation of short-day legume species.

omato cell wall-associated kinase 1 (SlWAK1) has only been studied in biotic stress response and hence its function in abiotic stress remains unknown. In a screening under salinity of an insertional mutant collection of tomato (Solanum lycopersicum L.), a mutant exhibiting lower degree of leaf chlorosis than wild type (WT) together with reduced leaf Na+ accumulation was selected. Genetic analysis of the mutation revealed that a single T-DNA insertion in the SlWAK1 gene was responsible of the mutant phenotype. Slwak1 null mutant reduced its shoot growth compared with WT, despite its improved Na+ homeostasis. SlWAK1 disruption affected osmotic homeostasis, as leaf water content was lower in mutant than in WT under salt stress. In addition, Slwak1 altered the source-sink balance under salinity, by increasing sucrose content in roots. Finally, a significant fruit yield reduction was found in Slwak1 vs. WT under long-term salt stress, mainly due to lower fruit weight. Our results show that disruption of SlWAK1 induces a higher sucrose transport from source leaf to sink root, negatively affecting fruit, the main sink at adult stage.