A Signal-finding Study of Abemaciclib in Heavily Pretreated Patients with Metastatic Castration-Resistant Prostate Cancer: Results from CYCLONE 1.

BACKGROUND: Cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors radically changed the treatment paradigm for breast cancer. Similar to estrogen receptor in breast cancer, androgen receptor signaling activates cyclin D-CDK4/6, driving proliferation and resistance to hormonal manipulation in prostate cancer. This study was designed to detect signals of clinical activity for abemaciclib in treatment-refractory metastatic castration-resistant prostate cancer (mCRPC). METHODS: Eligible patients had progressive mCRPC, measurable disease, and previously received ≥1 novel hormonal agent(s) and 2 lines of taxane chemotherapy. Abemaciclib 200 mg BID was administered on a continuous dosing schedule. Primary endpoint was objective response rate (ORR) without concurrent bone progression. This study was designed to detect a minimum ORR of 12.5%. RESULTS: At trial entry, forty (90.9%) of 44 patients had objective radiographic disease progression, four (9.1%) had prostate-specific antigen (PSA)-only progression, and 20 (46.5%) had visceral metastases (of these, 60% had liver metastases). Efficacy analyses are as follows: ORR without concurrent bone progression: 6.8%; disease control rate: 45.5%; median time to PSA progression: 6.5 months (95% CI: 3.2, NA); median radiographic PFS; 2.7 months (95% CI: 1.9, 3.7); and median OS: 8.4 months (95% CI: 5.6, 12.7). Most frequent grade ≥3 TEAEs were neutropenia (25.0%), anemia, and fatigue (11.4% each). No grade 4 or 5 AEs were related to abemaciclib. CONCLUSION: Abemaciclib monotherapy was well tolerated and showed clinical activity in this heavily pretreated population, nearly half with visceral metastases. This study is considered preliminary proof-of-concept and designates CDK4/6 as a valid therapeutic target in prostate cancer.

Improvement of thrombosis management in patients with cancer: a practical consensus document of recommendations for cancer-associated thrombosis patients' healthcare in Spain.

Cancer patients are at risk of venous thromboembolism (VTE), its recurrence, but also at risk of bleeding while anticoagulated. In addition, cancer therapies have been associated to increased VTE risk. Guidelines for VTE treatment in cancer patients recommend low molecular weight heparins (LMWH) or direct oral anticoagulants (DOAC) for the initial treatment, DOAC for VTE short-term treatment, and LMWH or DOAC for VTE long-term treatment. This consensus article arises from a collaboration between different Spanish experts on cancer-associated thrombosis. It aims to reach an agreement on a practical document of recommendations for action allowing the healthcare homogenization of cancer-associated thrombosis (CAT) patients in Spain considering not only what is known about VTE management in cancer patients but also what is done in Spanish hospitals in the clinical practice. The text summarizes the current knowledge and available evidence on the subject in Spain and provides a series of practical recommendations for CAT management and treatment algorithms to help clinicians to manage CAT over time.

Cost-effectiveness of apixaban and rivaroxaban in thromboprophylaxis of cancer patients treated with chemotherapy in Spain.

BACKGROUND: Apixaban and rivaroxaban are two direct-acting oral anticoagulants (DOACs) recommended for thromboprophylaxis in cancer patients treated with chemotherapy in an ambulatory setting. We aimed to assess the cost-utility of thromboprophylaxis with apixaban and rivaroxaban vs no thromboprophylaxis in ambulatory cancer patients starting chemotherapy with an intermediate-to-high risk of venous thromboembolism (VTE), Khorana score ≥ 2 points. METHODS: A cost-effectiveness analysis was performed from the perspective of Spain's National Health System (NHS) using an analytical decision model in the short-term (180 days) and a Markov model in the long-term (5 years). Transition probabilities were obtained from randomized, double-blind, placebo-controlled clinical trials of apixaban and rivaroxaban in adult ambulatory patients with cancer at risk for VTE, treated with chemotherapy (AVERT and CASSINI trials). The costs (€2,021) were taken from Spanish sources. The utilities of the model were obtained through the EQ-5D questionnaire. Deterministic (base case) and probabilistic (second-order Monte Carlo simulation) analyses were conducted. RESULTS: In the probabilistic sensitivity analysis, apixaban generated a cost per patient of €1,082 ± 187, with a 95% confidence interval (CI) of €713-1,442, while no prophylaxis produced a cost per patient of €1,146 ± 218, with a 95% CI of €700-1,491, with a saving of €64 per patient and a gain of 0.008 QALYs. Likewise, rivaroxaban provided a cost per patient of €993 ± 133, with a 95% CI of €748-1,310, while no prophylaxis produced a cost per patient of €872 ± 152, with a 95% CI of €602-1,250, with an additional expense of €121 per patient and a gain of 0.008 QALYs. CONCLUSIONS: In thromboprophylaxis of cancer patients, the use of apixaban and rivaroxaban generated similar costs compared to non-prophylaxis, without the difference found being statistically significant, with a clinically insignificant QALY gain.

Nitrogen sources differentially affect respiration, growth, and carbon allocation in Andean and Lowland ecotypes of Chenopodium quinoa Willd.

Chenopodium quinoa Willd. is a native species that originated in the High Andes plateau (Altiplano) and its cultivation spread out to the south of Chile. Because of the different edaphoclimatic characteristics of both regions, soils from Altiplano accumulated higher levels of nitrate (NO3-) than in the south of Chile, where soils favor ammonium (NH4 +) accumulation. To elucidate whether C. quinoa ecotypes differ in several physiological and biochemical parameters related to their capacity to assimilate NO3- and NH4 +, juvenile plants of Socaire (from Altiplano) and Faro (from Lowland/South of Chile) were grown under different sources of N (NO3- or NH4 +). Measurements of photosynthesis and foliar oxygen-isotope fractionation were carried out, together with biochemical analyses, as proxies for the analysis of plant performance or sensitivity to NH4 +. Overall, while NH4 + reduced the growth of Socaire, it induced higher biomass productivity and increased protein synthesis, oxygen consumption, and cytochrome oxidase activity in Faro. We discussed that ATP yield from respiration in Faro could promote protein production from assimilated NH4 + to benefit its growth. The characterization of this differential sensitivity of both quinoa ecotypes for NH4 + contributes to a better understanding of nutritional aspects driving plant primary productivity.

Outcome after conservative or surgical treatment for new-onset epilepsy in children with cerebral cavernous malformation.

OBJECTIVE: This study aimed to investigate and compare the outcome of conservatively or surgically treated children with cerebral cavernous malformation (CCM) and new-onset CCM-related epilepsy (CRE) during a 5-year period. METHODS: In this observational monocentric cohort study, data were collected ambispectivley. Our database was screened for CCM patients treated between 2003 and 2020. Patients ≤18 years of age with complete magnetic resonance imaging dataset, clinical baseline characteristics, and diagnosis of new-onset CRE were included. Definite seizure control was classified as International League Against Epilepsy class <2. Functional outcome was assessed using the modified Rankin Scale score. CRE patients were separated into two groups according to their treatment modality. Seizure control, intake of antiseizure medication, and functional outcomes were assessed. Systematic literature research was performed to identify other cases of new-onset CRE in children and to compare the collected data with published data. RESULTS: Thirty-nine pediatric CRE patients were analyzed. A total of 18 (46.1%) patients were conservatively treated, while 21 (53.8%) underwent surgical CCM removal. While the functional outcome was similar in both groups at the last follow-up, definite seizure control was better in the surgical group (77.8%) than in the conservative group (25.0%) both after 5-years of follow-up (p = 0.038), and at last follow-up with 85.7% versus 50% respectively (p = 0.035). We found substantially higher rates of discontinuation of antiseizure medication at the last available follow-up in patients undergoing surgical resection (p = 0.009). The systematic literature review identified 4 studies with a total of 30 additional children with early onset CRE. CONCLUSION: Surgical treatment of pediatric patients with new-onset CRE had higher rates of complete seizure control and early discontinuation of antiseizure medication than conservative treatment. Neurological outcomes of patients managed surgically or conservatively were comparable. These results encourage early surgical management of children with CRE even in the absence of pharmacoresistant epilepsy, but randomized control trials are urgently needed for further decision-making.

Two Congeneric Shrubs from the Atacama Desert Show Different Physiological Strategies That Improve Water Use Efficiency under a Simulated Heat Wave.

Desert shrubs are keystone species for plant diversity and ecosystem function. Atriplex clivicola and Atriplex deserticola (Amaranthaceae) are native shrubs from the Atacama Desert that show contrasting altitudinal distribution (A. clivicola: 0-700 m.a.s.l.; A. deserticola: 1500-3000 m.a.s.l.). Both species possess a C4 photosynthetic pathway and Kranz anatomy, traits adaptive to high temperatures. Historical records and projections for the near future show trends in increasing air temperature and frequency of heat wave events in these species' habitats. Besides sharing a C4 pathway, it is not clear how their leaf-level physiological traits associated with photosynthesis and water relations respond to heat stress. We studied their physiological traits (gas exchange, chlorophyll fluorescence, water status) before and after a simulated heat wave (HW). Both species enhanced their intrinsic water use efficiency after HW but via different mechanisms. A. clivicola, which has a higher LMA than A. deserticola, enhances water saving by closing stomata and maintaining RWC (%) and leaf Ψmd potential at similar values to those measured before HW. After HW, A. deserticola showed an increase of Amax without concurrent changes in gs and a significant reduction of RWC and Ψmd. A. deserticola showed higher values of Chla fluorescence after HW. Thus, under heat stress, A. clivicola maximizes water saving, whilst A. deserticola enhances its photosynthetic performance. These contrasting (eco)physiological strategies are consistent with the adaptation of each species to their local environmental conditions at different altitudes.

Giant Cavernous Malformation Mimicking an Infiltrative Intracranial Neoplasm in Children-Case Report and Systematic Review of the Literature.

BACKGROUND: Giant cavernous malformations (GCMs) are rare and poorly characterized neurovascular lesions in adults or children and often misclassified. In this study, we provide a review of pediatric GCM cases to highlight this rare entity as an important differential diagnosis in preoperative assessment. METHODS: We report a pediatric case of GCM that presented as an intracerebral, periventricular, and infiltrative mass lesion. We performed a systematic review of published literature describing cases of GCM in children using the PubMed, Embase, and Cochrane Library databases. Studies describing cerebral or spinal cavernous malformation >4 cm were included. Demographic, clinical, radiographic, and outcome data were extracted. RESULTS: Thirty-eight studies accounting for 61 patients were reviewed. most patients were 1-10 years old and 55.73% were male. Average lesion sizes ranged between 4 and 6 cm (40.98% >6 cm; 8.19% >10 cm). Supratentorial localization was most common (75.40%), with frontal and parieto-occipital regions being frequent localizations. Infratentorial lesions (24.60%) were located within the cerebellum (16.39%) and brainstem (8.19%). One case of spinal cavernoma was found. The main clinical manifestations were seizures (44.26%), focal neurologic deficit (36.06%), and headache (22.95%). Imaging showed contrast enhancement (36.06%), cystic features (27.86%), and infiltrative growth pattern (4.91%). CONCLUSIONS: GCMs show variable clinical and radiologic features, representing a diagnostic challenge for treating surgeons. Imaging may show various tumorlike features such as cystic or infiltrative patterns with contrast enhancement. The existence of GCM should be considered preoperatively. Gross total resection should be attempted whenever possible, because it correlates with a good recovery and long-term outcomes. Also, a clear definition criteria of when a cerebral cavernous malformation is termed giant should be established.

The role of immunotherapy in non-clear cell renal cell carcinoma.

The category of non-clear cell renal cell carcinoma (nccRCC) includes several clinically, histologically, and molecularly diverse entities. Traditionally, they comprise type 1 and type 2 papillary, chromophobe, unclassified, and other histologies (medullary, collecting duct carcinoma, and translocation-associated). Molecular knowledge has allowed the identification of some other specific subtypes, such as fumarate hydratase-deficient renal cell carcinoma (RCC) or succinate dehydrogenase-associated RCC. In addition, it has recognized some alterations with a possible predictive role, e.g., MET proto-oncogene receptor tyrosine kinase (MET) alterations in papillary tumors. Standard therapies for the management of advanced clear cell RCC (ccRCC), i.e., vascular endothelial growth factor receptor (VEGFR) pathway inhibitors and mammalian target of rapamycin inhibitors, have shown poorer results in nccRCC patients. Therefore, there is a need to improve the efficacy of the treatment for advanced nccRCC. Immunotherapy, especially immune checkpoint inhibitors (ICIs) targeting programmed death 1/programmed death ligand 1 and cytotoxic T-lymphocyte associated protein 4 (CTLA-4), has demonstrated a significant survival benefit in several malignant neoplasias, including ccRCC, with a proportion of patients achieving long survival. The combinations of ICI or ICI + VEGFR tyrosine kinase inhibitors (TKIs) are the standard of care in advanced ccRCC. Unfortunately, major pivotal trials did not include specific nccRCC populations. In recent years, several studies have retrospectively or prospectively evaluated ICIs alone or in combination with another ICI or with TKIs in nccRCC patients. In this article, we review data from available trials in order to elucidate clinical and molecular profiles that could benefit from immunotherapy approaches.

Long-term Clinical Outcomes of a Spanish Cohort of Metastatic Renal Cell Carcinoma Patients with a Complete Response to Sunitinib.

INTRODUCTION: The long-term clinical outcomes of patients with metastatic renal cell carcinoma (mRCC) and a complete response (CR) to the tyrosine kinase inhibitor (TKI) sunitinib are poorly known. The characteristics of these patients could reveal previously undetected associations with clinical variables. PATIENTS AND METHODS: This observational, retrospective study (ATILA) used data from a registry of patients with mRCC who had received first-line sunitinib and had achieved CR from 2007 to 2018 in Spain. RESULTS: Sixty-two patients with CR were included; 48 patients (77.4%) received sunitinib in monotherapy and 14 (22.6%) combined with or followed by local treatment. Median age was 58.5 years (range, 32-81). Most patients (79.0%) had clear cell histology and had undergone previous nephrectomy (90.3%). The majority (70.2%) had an intermediate IMDC prognosis, 23% favorable and 7.0% poor. The median time on treatment with sunitinib was 28.2 months (IQR, 16.7-41.0) and the median time to CR was 10.9 months (IQR, 7.2-19.3). After a median follow-up of 8 years (range, 3-13 years), the median PFS was not reached. The overall median duration of complete response was 64.1 months (IQR, 32.2-99.4). The tolerance and safety profile of sunitinib was consistent with previous reports. CONCLUSION: Durable CR to sunitinib was observed in patients regardless the prognosis group, metastasis site or histology type, with 75% of patients remaining in CR after 10 years. CLINICALTRIALS: gov: NCT03916458.

A correlative biomarker study and integrative prognostic model in chemotherapy-naïve metastatic castration-resistant prostate cancer treated with enzalutamide.

BACKGROUND: There is a considerable need to incorporate biomarkers of resistance to new antiandrogen agents in the management of castration-resistant prostate cancer (CRPC). METHODS: We conducted a phase II trial of enzalutamide in first-line chemo-naïve asymptomatic or minimally symptomatic mCRPC and analyzed the prognostic value of TMPRSS2-ERG and other biomarkers, including circulating tumor cells (CTCs), androgen receptor splice variant (AR-V7) in CTCs and plasma Androgen Receptor copy number gain (AR-gain). These biomarkers were correlated with treatment response and survival outcomes and developed a clinical-molecular prognostic model using penalized cox-proportional hazard model. This model was validated in an independent cohort. RESULTS: Ninety-eight patients were included. TMPRSS2-ERG fusion gene was detected in 32 patients with no differences observed in efficacy outcomes. CTC detection was associated with worse outcome and AR-V7 in CTCs was associated with increased rate of progression as best response. Plasma AR gain was strongly associated with an adverse outcome, with worse median prostate specific antigen (PSA)-PFS (4.2 vs. 14.7 m; p < 0.0001), rad-PFS (4.5 vs. 27.6 m; p < 0.0001), and OS (12.7 vs. 38.1 m; p < 0.0001). The clinical prognostic model developed in PREVAIL was validated (C-Index 0.70) and the addition of plasma AR (C-Index 0.79; p < 0.001) increased its prognostic ability. We generated a parsimonious model including alkaline phosphatase (ALP); PSA and AR gain (C-index 0.78) that was validated in an independent cohort. CONCLUSIONS: TMPRSS2-ERG detection did not correlate with differential activity of enzalutamide in first-line mCRPC. However, we observed that CTCs and plasma AR gain were the most relevant biomarkers.

Teleoncology: A Solution for Everyone? A Single-Center Experience with Telemedicine during the Coronavirus Disease 2019 (COVID-19) Pandemic.

Since the beginning of the COVID-19 pandemic, the use of telehealth was rapidly implemented without previous evidence. The ONCOTELEMD study aimed to evaluate the opinion of patients attended via telemedicine during this period and to study factors that condition patient preferences on its use. Included patients had a confirmed cancer diagnosis and were contacted by telephone between 13 March and 30 April 2020, in the Medical Oncology Service of Hospital Parc Taulí, Sabadell. A 12-question survey was presented to them between 4 February and 19 April 2021. Statistical analysis was carried out using chi-square and multivariable logistic regression tests. Six hundred forty-six patients were included; 487 responded to the survey. The median age was 68 years (27-90), 55.2% were female. Most patients had a surveillance visit (65.3%) and were diagnosed with colorectal or breast cancer (43% and 26.5%, respectively); 91.8% of patients were satisfied, and 60% would accept the use of telemedicine beyond the pandemic. Patients aged more than 50 years (OR 0.40; 95% CI, 0.19-0.81; p = 0.01) and diagnosed with breast cancer (OR 0.45; 95% CI, 0.26-0.69; p < 0.001) were less predisposed to adopt telehealth in the future. Patients agreed to be informed via telehealth of scan or lab results (62% and 84%, respectively) but not of new oral or endovenous treatments (52% and 33.5%, respectively). Additionally, 75% of patients had a medium or low-null technologic ability, and 51.3% would only use the telephone or video call to contact health professionals. However, differences were found according to age groups (p < 0.0001). In total, patients surveyed were satisfied with telemedicine and believed telehealth could have a role following the COVID-19 pandemic. Moreover, our results remark on the importance of individualizing the use of telehealth, showing relevant data on patient preferences and digital literacy.

Radium-223 for patients with metastatic castration-resistant prostate cancer with asymptomatic bone metastases progressing on first-line abiraterone acetate or enzalutamide: A single-arm phase II trial.

PURPOSE: The paper aims to evaluate the efficacy and safety of 223Ra in patients who progressed after first-line androgen deprivation therapy. PATIENTS AND METHODS: EXCAAPE (NCT03002220) was a multicentre, single-arm, open-label, non-controlled phase IIa trial in 52 patients with metastatic castration-resistant prostate cancer and asymptomatic bone metastases who have progressed on abiraterone acetate or enzalutamide, up to six doses of 223Ra (55 kBq/kg of body weight per month). The primary end-point was radiographic progression-free survival (rPFS). Secondary end-points included rPFS based on androgen receptor splice variant 7 (AR-V7) expression in circulating tumour cells (CTCs), overall survival, and safety. RESULTS: Median rPFS was 5.5 months (95% CI 5.3-5.5). Median rPFS of patients with AR-V7(-) CTCs was longer than that of patients with AR-V7(+) CTCs (5.5 versus 2.2 months, respectively; P = 0.056). Median overall survival was 14.8 months (95% CI 11.2-not reached) and was significantly greater for AR-V7(-) patients than for AR-V7(+) patients (14.8 months versus 3.5 months, respectively; P < 0.01). 223Ra was well tolerated; anaemia and thrombocytopenia were the most common grade 3/4 adverse events (5.8% and 11.5%, respectively). CONCLUSIONS: 223Ra seems to be a reasonable treatment for patients with metastatic castration-resistant prostate cancer and asymptomatic bone metastases progressing on novel hormonal therapy and had an acceptable safety profile.

New Insights into Bacillus-Primed Plant Responses to a Necrotrophic Pathogen Derived from the Tomato-Botrytis Pathosystem.

Induced systemic resistance (ISR) is one of the most studied mechanisms of plant−microbe interaction and is considered a very promising alternative for integrated pest management programs. In our study, we explored the plant defense response induced by Bacillus velezensis BBC047 in relation to its application before or after Botrytis cinerea infection of tomato plants. The inoculation of BBC047 did not considerably alter the gene expression of the tomato tissues, whereas infection with B. cinerea in BBC047-primed plants induced expression of LRR and NBS-LRR receptors, which are highly related to the ISR response. As expected, B. cinerea infection generated molecular patterns typical of a defense response to pathogen infection as the overexpression of pathogenesis-related proteins (PRs) in leaflets distant to the point of infection. The curative treatment (P + F + B) allowed us to gain insights into plant response to an inverted priming. In this treatment, B. cinerea caused the m tissue damage, extending nearly entirely across the entire infected leaves. Additionally, genes generally associated with early SAR response (<16 h) were overexpressed, and apparently, the beneficial strain was not perceived as such. Therefore, we infer that the plant defense to the curative treatment represents a higher degree of biological stress triggered by the incorporation of strain BBC047 as second arriving microorganism. We highlight the importance the phytosanitary status of plants prior to inoculation of beneficial microorganism for the biocontrol of pathogens.

Signal Perceptron: On the Identifiability of Boolean Function Spaces and Beyond.

In a seminal book, Minsky and Papert define the perceptron as a limited implementation of what they called "parallel machines." They showed that some binary Boolean functions including XOR are not definable in a single layer perceptron due to its limited capacity to learn only linearly separable functions. In this work, we propose a new more powerful implementation of such parallel machines. This new mathematical tool is defined using analytic sinusoids-instead of linear combinations-to form an analytic signal representation of the function that we want to learn. We show that this re-formulated parallel mechanism can learn, with a single layer, any non-linear k-ary Boolean function. Finally, to provide an example of its practical applications, we show that it outperforms the single hidden layer multilayer perceptron in both Boolean function learning and image classification tasks, while also being faster and requiring fewer parameters.

Cost-effectiveness of direct oral anticoagulants compared to low-molecular-weight-heparins for treatment of cancer associated venous thromboembolism in Spain.

AIM: Recent studies have compared the efficacy and safety of direct-acting oral anticoagulants (DOAC) and low-molecular-weight heparin (LMWH) for cancer-associated venous thromboembolism (VTE). However, there is no available cost-effectiveness analysis comparing DOAC and LMWH. The study aimed to conduct a cost-effectiveness analysis of DOAC (apixaban, edoxaban, and rivaroxaban) vs. LMWH for the treatment of cancer-associated VTE in Spain from the Spanish healthcare system perspective. METHODS: We developed a Markov model with a 12-month time horizon. The states included pulmonary embolism, deep vein thrombosis, major and non-major bleeding, chronic thromboembolic pulmonary hypertension, post-thrombotic syndrome, and death. The use of medical resources and drug costs were obtained from the 2021 Spanish Ministry of Health database, and the main references for obtaining the outcomes were derived from Caravaggio, Hokusai VTE Cancer, ADAM VTE, and SELECT-D trials. We performed a deterministic and probabilistic sensitivity analysis to validate the robustness. The Incremental Cost-Effectiveness Ratio (ICER) scores cost per life-year (€/LY) gained and cost per quality-adjusted life-year (€/QALY) gained. RESULTS: The 12-month cost of DOAC was 1,994€ (apixaban 1,944€, edoxaban 1,968€, rivaroxaban 2,122€) and 2,152€ for LMWH. The amount of QALY for DOAC was 0.54 (apixaban 0.55, rivaroxaban 0.53, and edoxaban 0.52) and 0.53 for LMWH. We observed similar results for LYs. ICER scores in terms both of €/LY and €/QALY show that DOAC is dominant over LMWH and apixaban showed the best profile. LIMITATIONS: Our research is based on an indirect comparison of a short-term clinical trial. CONCLUSION: Our results suggest that DOAC is cost-effective and cost-saving compared to LMWH in treating VTE.

Preconditioning to Water Deficit Helps Aloe vera to Overcome Long-Term Drought during the Driest Season of Atacama Desert.

Throughout evolution, plants have developed different strategies of responses and adaptations that allow them to survive in different conditions of abiotic stress. Aloe vera (L.) Burm.f. is a succulent CAM plant that can grow in warm, semi-arid, and arid regions. Here, we tested the effects of preconditioning treatments of water availability (100, 50, and 25% of soil field capacity, FC) on the response of A. vera to prolonged drought growing in the hyper-arid core of the Atacama Desert. We studied leaf biomass, biochemical traits, and photosynthetic traits to assess, at different intervals of time, the effects of the preconditioning treatments on the response of A. vera to seven months of water deprivation. As expected, prolonged drought has deleterious effects on plant growth (a decrease of 55-65% in leaf thickness) and photosynthesis (a decrease of 54-62% in Emax). There were differences in the morphophysiological responses to drought depending on the preconditioning treatment, the 50% FC pretreatment being the threshold to better withstand prolonged drought. A diurnal increase in the concentration of malic acid (20-30 mg mg-1) in the points where the dark respiration increased was observed, from which it can be inferred that A. vera switches its C3-CAM metabolism to a CAM idling mode. Strikingly, all A. vera plants stayed alive after seven months without irrigation. Possible mechanisms under an environmental context are discussed. Overall, because of a combination of morphophysiological traits, A. vera has the remarkable capacity to survive under severe and long-term drought, and further holistic research on this plant may serve to produce biotechnological solutions for crop production under the current scenario of climatic emergency.

Ilixadencel, a Cell-based Immune Primer, plus Sunitinib Versus Sunitinib Alone in Metastatic Renal Cell Carcinoma: A Randomized Phase 2 Study.

Background: The prognosis of patients with synchronous metastatic renal cell carcinoma (mRCC) is poor. Whereas single-agent tyrosine kinase inhibition (TKI) is clearly insufficient, the effects can be enhanced by combinations with immune checkpoint inhibitors. Innovative treatment options combining TKI and other immune-stimulating agents could prove beneficial. Objective: To evaluate the clinical effects on metastatic disease when two doses of allogeneic monocyte-derived dendritic cells (ilixadencel) are administrated intratumorally followed by nephrectomy and treatment with sunitinib compared with nephrectomy and sunitinib monotherapy, in patients with synchronous mRCC. Design setting and participants: A randomized (2:1) phase 2 multicenter trial enrolled 88 patients with newly diagnosed mRCC to treatment with the combination ilixadencel/sunitinib (ILIXA/SUN; 58 patients) or sunitinib alone (SUN; 30 patients). Outcome measurements and statistical analysis: The primary endpoints were 18-mo survival rate and overall survival (OS). A secondary endpoint was objective response rate (ORR) assessed up to 18 mo after enrollment. Statistic evaluations included Kaplan-Meier estimates, log-rank tests, Cox regression, and stratified Cochran-Mantel-Haenszel tests. Results and limitations: The median OS was 35.6 mo in the ILIXA/SUN arm versus 25.3 mo in the SUN arm (hazard ratio 0.73, 95% confidence interval 0.42-1.27; p = 0.25), while the 18-mo OS rates were 63% and 66% in the ILIXA/SUN and SUN arms, respectively. The confirmed ORR in the ILIXA/SUN arm were 42.2% (19/45), including three patients with complete response, versus 24.0% (six/25) in the SUN arm (p = 0.13) without complete responses. The study was not adequately powered to detect modest differences in survival. Conclusions: The study failed to meet its primary endpoints. However, ilixadencel in combination with sunitinib was associated with a numerically higher, nonsignificant, confirmed response rate, including complete responses, compared with sunitinib monotherapy. Patient summary: We studied the effects of intratumoral vaccination with ilixadencel followed by sunitinib versus sunitinib only in a randomized phase 2 study. The combination treatment showed numerically higher numbers of confirmed responses, suggesting an immunologic effect.

Consensus on prevention and treatment of cancer-associated thrombosis (CAT) in controversial clinical situations with low levels of evidence.

BACKGROUND: Cancer patients suffer high risk of venous thromboembolism (VTE). Cancer-associated VTE (CAT) causes hospitalization, morbidity, delayed cancer treatment, and mortality; therefore, exceptional CAT prevention and management are imperative. METHODS: This review offers practical recommendations and treatment algorithms for eight complex, clinically relevant situations posing great uncertainty regarding management and requiring an urgent decision: VTE prophylaxis in ambulatory cancer patients with pancreatic pancreas (1) or lung cancer with molecular alterations (2); optimal management of VTE during antineoplastic treatment with antiangiogenics (3) or chemotherapy (4); protracted VTE treatment, determinants; (5) drugs used (6), and optimal VTE management in situations of high bleeding risk (7) or recurrent VTE (8). RESULTS: With the evidence available, primary thromboprophylaxis in patients with lung cancer harbouring ALK/ROS1 translocations or pancreatic cancer receiving ambulatory chemotherapy must be appraised. If antiangiogenic therapy can yield a clear benefit and the patient recovers from a grade 3 thrombotic event, it can be cautiously re-introduced in selected cases, provided that the person agrees to assume the risk after being duly informed. Anticoagulation maintenance beyond 6 months is recommended in individuals with metastatic tumours, on active treatment, or at high risk for recurrent VTE without bleeding risk. In such cases, LMWH and DOACs are safe, being mindful that the latter could entail a higher risk of bleeding; consequently, they should be used judiciously in more haemorrhagic tumours, such as gastrointestinal cancers. In cases of recurrent VTE, the presence of active cancer, infra-therapeutic dose, and anticoagulant treatment failure must be ruled out. In individuals with platelet counts of 25,000-50,000 and VTE liable to recur who need anticoagulation, full-dose LMWH and transfusion support can be contemplated to reach values of > 50,000. In CAT unlikely to recur, decreasing the LMWH dose by 25-50% is recommended. Renal impairment associated with thrombosis must be treated with LMWHs; there is no need to adjust the dose in patients with CrCl > 30; with CrCl = 15-30, dose adjustment is advised, and suspended when CrCl is < 15. CONCLUSION: We provide useful advice for complex, clinically relevant situations that clinicians treating CAT must face devoid of any unequivocal, strong, evidence-based recommendations.

Measures to evaluate quality of care in renal cancer: results of a Delphi study in Spain

PurposeTo review current measures for renal cancer care and develop a comprehensive and updated list of measures for their practical use in Spain.MethodsThe study was developed by Fundación ECO, a Spanish foundation aiming to improve oncology quality of care. A systematic literature review was carried out to identify measures and knowledge gaps. A scientific committee composed of nine experts reviewed the literature findings and added measures. A preliminary list of 42 measures was evaluated with the Delphi method to gather feedback from 47 medical oncology experts in Spain. Experts scored the appropriateness of the measures and ranked their priority in two consecutive online surveys. The scientific committee reviewed the Delphi results and developed the measures. A technical group from Universidad Francisco de Vitoria conducted and oversaw the Delphi method.ResultsThe Delphi method led to consensus on all 42 measures. The scientific committee used a prioritisation matrix to select 25 of these measures for evaluating quality of care in renal cancer. These measures regarded structure, process, and outcome and covered general management, diagnosis, treatment, follow-up, and evaluation of health outcomes. Easy-to-use index cards were developed for all 25 measures, including their definition, formula, acceptable level of attainment, and rationale.ConclusionsThis manuscript aims to provide healthcare professionals with expert- and evidence-based measures that are useful for evaluating quality of care in renal cancer in Spain and cover all aspects and stages.

Measures to evaluate quality of care in renal cancer: results of a Delphi study in Spain.

PURPOSE: To review current measures for renal cancer care and develop a comprehensive and updated list of measures for their practical use in Spain. METHODS: The study was developed by Fundación ECO, a Spanish foundation aiming to improve oncology quality of care. A systematic literature review was carried out to identify measures and knowledge gaps. A scientific committee composed of nine experts reviewed the literature findings and added measures. A preliminary list of 42 measures was evaluated with the Delphi method to gather feedback from 47 medical oncology experts in Spain. Experts scored the appropriateness of the measures and ranked their priority in two consecutive online surveys. The scientific committee reviewed the Delphi results and developed the measures. A technical group from Universidad Francisco de Vitoria conducted and oversaw the Delphi method. RESULTS: The Delphi method led to consensus on all 42 measures. The scientific committee used a prioritisation matrix to select 25 of these measures for evaluating quality of care in renal cancer. These measures regarded structure, process, and outcome and covered general management, diagnosis, treatment, follow-up, and evaluation of health outcomes. Easy-to-use index cards were developed for all 25 measures, including their definition, formula, acceptable level of attainment, and rationale. CONCLUSIONS: This manuscript aims to provide healthcare professionals with expert- and evidence-based measures that are useful for evaluating quality of care in renal cancer in Spain and cover all aspects and stages.