Guselkumab effectiveness, and posology in patients with moderate to severe hidradenitis suppurativa: A retrospective bicentric experience.

Hidradenitis suppurativa (HS) is a chronic, inflammatory, and recalcitrant skin disease of the terminal hair follicle. Therapeutic alternatives in HS are limited nowadays. Adalimumab, is the only approved biological treatment for patients with moderate to severe HS, and some patients do not reach an optimal response, or experience a progressive response loss, needing therapeutic alternatives. IL-23 pathway is also involved in HS pathogenesis, so its blockade could contribute to reach disease control. Guselkumab is a monoclonal antibody targeting the p19 subunit of extracellular IL-23, currently approved for psoriasis in adults, and recently some authors have reported its effectiveness in patients with moderate to severe HS refractory to other systemic treatments, becoming a hope for some patients. However adequate dosing and intervals have not been determined yet, so in most published series, doses approved for psoriasis are commonly used. On this topic a retrospective bicentric study including HS patients treated with guselkumab in the dermatologic departments of university hospitals Puerta de Hierro of Majadahonda (Madrid, Spain) and Doctor Peset of Valencia (Valencia, Spain) was conducted. We reported effectiveness, dosage and frequency of administration in the cohort, in order to establish the most effective dosage regimen and to clarify the potential role of guselkumab for this disease.

Early Tracheostomy for Managing ICU Capacity During the COVID-19 Outbreak: A Propensity-Matched Cohort Study.

BACKGROUND: During the first wave of the COVID-19 pandemic, shortages of ventilators and ICU beds overwhelmed health care systems. Whether early tracheostomy reduces the duration of mechanical ventilation and ICU stay is controversial. RESEARCH QUESTION: Can failure-free day outcomes focused on ICU resources help to decide the optimal timing of tracheostomy in overburdened health care systems during viral epidemics? STUDY DESIGN AND METHODS: This retrospective cohort study included consecutive patients with COVID-19 pneumonia who had undergone tracheostomy in 15 Spanish ICUs during the surge, when ICU occupancy modified clinician criteria to perform tracheostomy in Patients with COVID-19. We compared ventilator-free days at 28 and 60 days and ICU- and hospital bed-free days at 28 and 60 days in propensity score-matched cohorts who underwent tracheostomy at different timings (≤ 7 days, 8-10 days, and 11-14 days after intubation). RESULTS: Of 1,939 patients admitted with COVID-19 pneumonia, 682 (35.2%) underwent tracheostomy, 382 (56%) within 14 days. Earlier tracheostomy was associated with more ventilator-free days at 28 days (≤ 7 days vs > 7 days [116 patients included in the analysis]: median, 9 days [interquartile range (IQR), 0-15 days] vs 3 days [IQR, 0-7 days]; difference between groups, 4.5 days; 95% CI, 2.3-6.7 days; 8-10 days vs > 10 days [222 patients analyzed]: 6 days [IQR, 0-10 days] vs 0 days [IQR, 0-6 days]; difference, 3.1 days; 95% CI, 1.7-4.5 days; 11-14 days vs > 14 days [318 patients analyzed]: 4 days [IQR, 0-9 days] vs 0 days [IQR, 0-2 days]; difference, 3 days; 95% CI, 2.1-3.9 days). Except hospital bed-free days at 28 days, all other end points were better with early tracheostomy. INTERPRETATION: Optimal timing of tracheostomy may improve patient outcomes and may alleviate ICU capacity strain during the COVID-19 pandemic without increasing mortality. Tracheostomy within the first work on a ventilator in particular may improve ICU availability.

Methodology for the regulation of boom sprayers operating in circular trajectories.

A methodology for the regulation of boom sprayers working in circular trajectories has been developed. In this type of trajectory, the areas of the plots of land treated by the outer nozzles of the boom are treated at reduced rates, and those treated by the inner nozzles are treated in excess. The goal of this study was to establish the methodology to determine the flow of the individual nozzles on the boom to guarantee that the dose of the product applied per surface unit is similar across the plot. This flow is a function of the position of the equipment (circular trajectory radius) and of the displacement velocity such that the treatment applied per surface unit is uniform. GPS technology was proposed as a basis to establish the position and displacement velocity of the tractor. The viability of this methodology was simulated considering two circular plots with radii of 160 m and 310 m, using three sets of equipment with boom widths of 14.5, 24.5 and 29.5 m. Data showed as increasing boom widths produce bigger errors in the surface dose applied (L/m(2)). Error also increases with decreasing plot surface. As an example, considering the three boom widths of 14.5, 24.5 and 29.5 m working on a circular plot with a radius of 160 m, the percentage of surface with errors in the applied surface dose greater than 5% was 30%, 58% and 65% respectively. Considering a circular plot with radius of 310 m the same errors were 8%, 22% and 31%. To obtain a uniform superficial dose two sprayer regulation alternatives have been simulated considering a 14.5 m boom: the regulation of the pressure of each nozzle and the regulation of the pressure of each boom section. The viability of implementing the proposed methodology on commercial boom sprayers using GPS antennas to establish the position and displacement velocity of the tractor was justified with a field trial in which a self-guiding commercial GPS system was used along with three precision GPS systems located in the sprayer boom. The use of an unique central GPS unit should allow the estimation of the work parameters of the boom nozzles (including those located at the boom ends) with great accuracy.

Pleth variability index may predict preload responsiveness in patients treated with nasal high flow: a physiological study.

The purpose of this study was to determine whether the plethysmographic variability index ("PVi") can predict preload responsiveness in patients with nasal high flow (NHF) (≥30 L/min) with any sign of hypoperfusion. "Preload responsiveness" was defined as a ≥10% increase in stroke volume (SV), measured by transthoracic echocardiography, after passive leg raising. SV and PVi were reassessed in preload responders after receiving a 250-mL fluid challenge. Twenty patients were included and 12 patients (60%) were preload responders. Responders showed higher baseline mean PVi (24% vs. 13%; P = 0.001) and higher mean PVi variation (ΔPVi) after passive leg raising (6.8% vs. -1.7%; P < 0.001). No differences between mean ΔPVi after passive leg raising and mean ΔPVi after fluid challenge were observed (6.8% vs. 7.4%; P = 0.24); and both values were strongly correlated (r = 0.84; P < 0.001). Baseline PVi and ΔPVi after passive leg raising showed excellent diagnostic accuracy identifying preload responders (AUROC 0.92 and 1.00, respectively). Baseline PVi ≥ 16% had a sensitivity of 91.7% and a specificity of 87.5% for detecting preload responders. Similarly, ΔPVi after passive leg raising ≥2% had a 100% of both sensitivity and specificity. Thus, PVi might predict "preload responsiveness" in patients treated with NHF, suggesting that it may guide fluid administration in these patients.NEW & NOTEWORTHY This is the first study that analyzes the use of noninvasive plethysmographic variability index (PVi) for preload assessment in patients treated with nasal high flow (NHF). Its results showed that PVi might identify preload responders. Therefore, PVi may be used in the day-to-day clinical decision-making process in critically ill patients treated with NHF, helping to provide adequate resuscitation volume.

The Effects of Biochar on Indigenous Arbuscular Mycorrhizae Fungi from Agroenvironments.

The effects of biochar on soil-plant-microorganisms systems are currently being extensively investigated. Considering that arbuscular mycorrhizal fungi (AMF) play an essential role in nutrient dynamics, the present study aims at understanding vine shoot-derived biochar effects on AMF activity and the impact of their multiplication in soils on water-stress resistance of plants. Three agronomic tests were performed in greenhouse pots. The first experiment evaluated the effects of three factors: final pyrolysis temperature for biochar production (400 °C and 600 °C), application rate (0 weight-wt.- % as a control, 1.5 wt. %, and 3.0 wt. %) and texture of the growing media (sandy-loam and clay-loam origin) on AMF, microbial communities and phosphatase activity. In the second experiment, an indigenous consortium of AMF was multiplied through the solid substrate method and sorghum as a trap plant with biochar addition. This process was compared to a control treatment without biochar. Obtained inocula were tested in a third experiment with lettuce plants under different water irrigation conditions. Results from the first experiment showed a general increase in AMF activity with the addition of the biochar produced at 400 °C in the sandy-loam texture substrate. Results of the second experiment showed that the biochar addition increased AMF root colonization, the number of AMF spores and AMF infective potential. Results of the third experiment showed that biochar-derived AMF inoculum increased AMF root colonization, AMF spores, dry biomass and the SPAD index in a lettuce crop under low-water irrigation conditions.

Development of new drug strategies in infrequent digestive tumors: esophageal, biliary tract, and anal cancers.

PURPOSE OF REVIEW: In the last years, interesting advances have been reported in the treatment of infrequent digestive tumors. The increasing development of new targeted therapies in human cancer has also impacted in these rare gastrointestinal malignancies providing a wide range of possibilities in the design of future clinical trials. RECENT FINDINGS: The inhibition of angiogenesis and the blockage of the epidermal growth factor receptor pathway have provided the most interesting activity in recently reported studies for esophageal and biliary tract carcinomas. Additionally, several targeted therapies have been developed to target the main kinase proteins of the most important pathways of these malignancies. The results of the biggest phase III trial in locally advanced anal carcinoma have been recently published. Finally, the inhibition of epidermal growth factor receptor has also showed promising activity in anal carcinomas. SUMMARY: Recent advances in the knowledge of molecular mechanism of carcinogenesis have led to meaningful changes in the management of gastrointestinal cancers. Although the major advances in targeted therapy have been introduced in the treatment of colorectal cancer, new interesting approaches have been reported in less frequent gastrointestinal tumors such as esophageal, biliary tract, and anal canal carcinoma opening a new hope in the treatment of these rare tumors in the molecular targeted therapy era.

Understanding the predictive role of K-ras for epidermal growth factor receptor-targeted therapies in colorectal cancer.

The prognosis of metastatic colorectal cancer (mCRC) remains poor regardless of the advances obtained in recent years with new therapeutic agents, surgical procedures, and diagnostic methods. New treatments directed to molecular targets have emerged and are being developed to improve these results, but there is a need to optimize and define the best use of these new approaches. Current use of irinotecan, oxaliplatin, and bevacizumab combined with the long-time standards 5-fluorouracil and leucovorin as first- or second-line treatment for patients with mCRC has resulted in median overall survival figures of > 20 months. Additional improvements in treatment are likely to be facilitated by the use of rationally selected therapeutic agents that target functionally important proteins in tumor cells, such as the epidermal growth factor receptor (EGFR). The activation of EGFR leads to the activation of intracellular effectors involved in intracellular signaling pathways such as the G protein K-Ras. The K-Ras oncoprotein controls transduction of signals required for proliferation, differentiation, and survival, mainly acting as guanosine diphosphate/guanosine triphosphate-regulated binary switches located at the inner surface of the plasma membrane. Monoclonal antibodies (MoAbs) designed to bind to the ectodomain of the EGFR have shown activity in chemorefractory mCRC and in the first-line setting. Cetuximab and panitumumab are MoAbs that bind to the EGFR and thereby inhibit cell proliferation, metastasis, and angiogenesis. Recent clinical data confirm that the efficacy of cetuximab and panitumumab is confined to patients bearing tumors with wild-type K-ras. K-ras mutation analysis may now be considered a new standard of care in the selection of patients for EGFR-targeted therapy.

Update on novel strategies to optimize cetuximab therapy in patients with metastatic colorectal cancer.

The prognosis of metastatic colorectal cancer (mCRC) remains poor despite the advances made in recent years with new therapeutic agents, surgical procedures, and diagnostic methods. New treatments directed toward molecular targets have emerged and are being developed to improve these results, but there is a need to optimize and define the best use of these new approaches. Cetuximab is a chimeric monoclonal antibody that binds to the epidermal growth factor receptor and thereby inhibits cell proliferation, metastasis, and angiogenesis. Preclinical studies indicate that cetuximab induces synergistic antitumor activity when combined with chemotherapy or radiation. In pretreated patients with mCRC, cetuximab might restore sensitivity toward irinotecan and has therefore been registered for the treatment of patients with mCRC refractory to irinotecan. Moreover, cetuximab seems to add substantial benefit to standard oxaliplatin- and irinotecan-based combinations, resulting in high response rates in the first-line setting. Recent preclinical and clinical data have optimized cetuximab therapy. New targeted therapy combinations and the identification of biomarkers associated with disease control in patients treated with cetuximab are changing the current management of mCRC. Also, preliminary data suggest that cetuximab can be administered in a more convenient 2-week schedule in combination with standard chemotherapy.

A phase II Study Evaluating Combined Neoadjuvant Cetuximab and Chemotherapy Followed by Chemoradiotherapy and Concomitant Cetuximab in Locoregional Oesophageal Cancer Patients.

BACKGROUND: Pre-operative chemoradiotherapy using a 5-fluorouracil (5-FU)/cisplatin backbone is widely used to improve surgical outcomes in locoregional oesophageal cancer patients, despite a non-negligible failure rate. OBJECTIVE: We evaluated intensification of this approach to improve patient outcomes by adding cetuximab to induction 5-FU/cisplatin/docetaxel (TPF) and to chemoradiotherapy in a phase II study. PATIENTS AND METHODS: Between November 2006 and April 2009, 50 patients with stage II-IVa squamous cell carcinoma (SCC) or adenocarcinoma of the oesophagus or gastro-oesophageal junction initiated three TPF/cetuximab cycles. Six weeks later, patients with response or stabilisation initiated 6 weeks of cisplatin/cetuximab/radiotherapy, followed by surgery. The primary objective was the clinical complete response (cCR) rate after induction therapy plus chemoradiotherapy in intent-to-treat patients. RESULTS: Thirty-eight patients were evaluable after chemoradiotherapy, 84% of whom showed disease control. Six patients (12%) achieved a cCR, with a 54% overall response rate. Twenty-seven patients underwent surgery, 11 of whom (22%; nine SCC, two adenocarcinoma) had a pathological CR (41%). Fifteen patients were alive after a median follow-up of 23.2 months. Median progression-free survival was 12.2 months (95% confidence interval [CI] 1.7-22.8). Median overall survival was 23.4 months (95% CI 12.2-36.6) and was significantly longer among the 22 patients with complete resection than in the five patients without (42.1 vs. 24.9 months; p = 0.02, hazard ratio: 3.6, 95% CI 1.1-11.6). The toxicity profile was acceptable. CONCLUSIONS: Neoadjuvant cetuximab/TPF followed by chemoradiotherapy in locoregional oesophageal carcinoma patients is feasible and offers a modest response rate in this trial. The results of combining trimodality neoadjuvant treatment with cetuximab are consistent with the literature. Registration: The study is registered at ClinicalTrials.gov (NCT00733889).

Correction to: A Phase II Study Evaluating Combined Neoadjuvant Cetuximab and Chemotherapy Followed by Chemoradiotherapy and Concomitant Cetuximab in Locoregional Oesophageal Cancer Patients.

Errors were subsequently identified in the article and the following corrections should be noted.

Long term results of a phase II trial of induction chemotherapy with uracil-ftegafur (UFT), vinorelbine and cisplatin (UFTVP) followed by radiotherapy concomitant with UFT and carboplatin (RT/UFTJ) in non-resectable locally advanced (stage IV-B) squamous cell head and neck carcinoma and peripheral blood stem cell support (PBSCS) with febrile neutropenia.

PURPOSE: To evaluate the response of advanced squamous cell head and neck carcinoma to a combination of induction chemotherapy and radiotherapy. METHODS: We present long-term results of a phase II trial of Induction Chemotherapy with UFT 200 mg/m(2) p.o. days 1 to 21, Vinorelbine 25 mg/m(2) i.v. days 1 and 8 and Cisplatin 100 mg/m(2) i.v. day 1 (UFTVP) each 21 days for 4 courses, followed by Radiotherapy concomitant with UFT 100 mg/m(2) p.o. daily and Carboplatin AUC = 0.5 i.v. weekly (RT/UFTJ) in patients (pts) with Non-Resectable Locally Advanced (Stage IV-B) Squamous Cell Head and Neck Carcinoma (IV-B-SCHNC). Primary endpoint was Complete Response to induction UFTVP and secondary endpoints were Disease Free Status Rate after locoregional treatment and long-term Overall Survival. Between 1994 and 1997, 32 pts were included. RESULTS: Complete Response to Induction UFTVP was 59% (95% CI: 48%-70%). Main toxicity of UFTVP was G 3,4 neutropenia (94% of pts; 25% developed febrile neutropenia and 1 of this pts dead). After Induction Chemotherapy with UFTVP, 30 pts received radiotherapy and 25 of them received concomitant Carboplatin and UFT (RT/UFTJ): main toxicity was mucositis (G3-4: 72%) and one patient died during RT/UFTJ because pneumonia. Twenty-five pts (78%) were alive and disease free at the end of the whole treatment. Actuarial 5 year Overall survival is 32%. CONCLUSION: Although toxicity is important, this approach has interesting activity and deserves further investigation.