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Hydrological drought is a pervasive and reoccurring challenge in managing water resources. Reservoirs are critical for lessening the impacts of drought on water available for many uses. We use a novel and generalized approach to identify periods of unusually low reservoir storage—via comparisons to operational rule curves and historical patterns—to investigate how droughts affect storage in 250 reservoirs across the conterminous U.S. (CONUS). We find that the maximum amount of water stored in reservoirs is decreasing, and that periods of unusually low storage are becoming longer, more severe, and more variable in (a) western and central CONUS reservoirs, and (b) reservoirs with primarily over‐year storage. Results suggest that reservoir storage has become less reliable and more vulnerable to larger deviations from desired storage patterns. These changes have coincided with ongoing shifts to the hydroclimate of CONUS, and with sedimentation further reducing available reservoir storage. Plain Language Summary Drought in water systems is a major challenge in managing water resources. Reservoirs are important as they can lessen the impacts of drought on water availability for many users. However, they are impacted by drought as well. We use a novel and generally applicable method to identify when reservoir storage is unusually low, potentially from drought, at 250 reservoirs across the conterminous U.S. We find that the maximum amount of water stored in reservoirs is decreasing across the U.S. We also find that periods of unusually low storage are becoming longer and more severe in western and central U.S. regions as well as for certain types of reservoirs. This suggests that reservoir storage may be less reliable and more vulnerable to extreme conditions and may be further impacted by changing climate and hydrology across the U.S. and by sediment building up behind reservoirs. Key Points Low‐storage periods are longer, more severe, and more variable in over‐year storage reservoirs and in the western and central CONUS Longer periods of low storage for some regions in recent years suggests decreased reservoir reliability in a changing hydroclimate Maximum annual storage is also declining across CONUS, furthered by storage losses from sedimentation

The aim of the study was to assess the toxicity and the clinical activity of biweekly oxaliplatin in combination with infusional 5-fluorouracil (5-FU) and folinic acid (FA) administered every 2 weeks (FOLFOX-4 regimen) in patients with advanced gastric cancer (AGC). A total of 61 previously untreated AGC patients were treated with oxaliplatin 85 mg m −2 on day 1, FA 200 mg m −2 as a 2 h infusion followed by bolus 5-FU 400 mg m −2 and a 22 h infusion of 5-FU 600 mg m −2 , repeated for 2 consecutive days every 2 weeks. All patients were assessable for toxicity and response to treatment. Four (7%) complete responses and 19 partial responses were observed (overall response rate, 38%). Stable disease was observed in 22 (36%) patients, with progressive disease in the other six (10%) patients. Median time to progression (TTP) and median overall survival (OS) were 7.1 and 11.2 months, respectively. National Cancer Institute Common Toxicity Criteria grade 3 and 4 haematologic toxicities were neutropenia, anaemia and thrombocytopenia in 36, 10 and 5% of the patients, respectively. Grade 3 peripheral neuropathy was recorded in three (5%) patients. FOLFOX-4 is an active and well-tolerated chemotherapy. Response rate (RR), TTP and OS were comparable with those of other oxaliplatin-based regimens, suggesting a role for this combination in gastric cancer.

Background: Retreatment with ipilimumab has been shown to re-establish disease control in some patients with disease progression. Here, we report the efficacy and safety of retreatment with ipilimumab 3 mg kg −1 among patients participating in an expanded access programme in Italy. Methods: Patients who achieved disease control during induction therapy were retreated with ipilimumab upon progression (3 mg kg −1 every 3 weeks for up to four doses), providing they had not experienced toxicity that precluded further dosing. Tumour assessments were conducted after retreatment, and patients were monitored throughout for adverse events. Results: Of 855 patients treated with ipilimumab, 51 were retreated upon disease progression. Of these, 28 (55%) regained disease control upon retreatment and 42% were alive 2 years after the first induction dose of ipilimumab; median overall survival was 21 months. Eleven patients (22%) had a treatment-related adverse event of any grade during retreatment. These were generally mild-to-moderate and resolved within a median of 4 days. No new types of toxicity were reported. Conclusions: For patients who meet predefined criteria, retreatment with ipilimumab is generally well tolerated and can translate into clinical benefit. This strategy should be compared with other therapeutic options in randomised controlled trials.

Neuroendocrine Neoplasms (NEN) are a group of heterogeneous malignancies derived from neuroendocrine cell compartment, with different roles in both endocrine and nervous system. Most NETs have gastroentero-pancreatic (GEP) origin, arising in the foregut, midgut, or hindgut. The 2010 WHO classification divides GEP-NETs into two main subgroups, neuroendocrine tumors (NET) and neuroendocrine carcinomas (NEC), according with Ki-67 levels. NET are tumors with low (<20 %) Ki-67 value, and NECs, including small cell lung carcinomas and Merkel Cell carcinomas, are all NETs with high Ki-67 levels (>20 %–G3). Poorly differentiated neuroendocrine carcinomas (NEC) are usually treated with cisplatin-based chemotherapy regimens. Here we present a case of a patient with pancreatic NEC progressing after cisplatin and etoposide, treated with temozolomide as palliative, second line treatment. According with the poor Performance Status (PS = 2) and to reduce the toxicity of the treatment was chosen an intermittent dosing regimen of metronomic temozolomide (75 mg/m 2 /day—one-week-on/on-week-off). MGMT resulted methylated. On July 2014 the patient started the treatment. On August 2014 the patient obtained a significant clinical benefit (PS = 0) and the total body CT scan performed on October 2014 showed a RECIST partial response on all the sites of disease. No drug-related side effects were reported by the patient. After 18 months of therapy the treatment continues without significant toxicity, and with further remission of the metastases. Treatment with metronomic “one-week-on/on-week-off” Temozolomide can be considered a good treatment option in patients with poor performance status, affected by pNEC with MGMT methylation.

Genetic heterogeneity in drug-metabolizing enzyme/transporter (DMET) genes affects specific drug-related cancer phenotypes. To investigate the relationships between genetic variation and response to treatment in acute myeloid leukemia (AML), we genotyped 1931 variants on DMET genes in 94 CD33-positive AML patients enrolled in a phase III multicenter clinical trial combining Gemtuzumab-Ozogamicin (GO) with Fludarabine–Cytarabine–Idarubicin (FLAI) regimen, with the DMET Plus platform. Two ADH1A variants showed statistically significant differences (odds ratio (OR)=5.68, P =0.0006; OR=5.35, P =0.0009) in allele frequencies between patients in complete/partial remission and patients without response, two substitutions on CYP2E1 (OR=0.13, P =0.001; OR=0.09, P =0.003) and one on SLCO1B1 (OR=4.68, P =0.002) were found to differently influence liver toxicity, and two nucleotide changes on SULTB1 and SLC22A12 genes correlated with response to GO (OR=0.24, P =0.0009; OR=2.75, P =0.0029). Genetic variants were thus found for the first time to be potentially associated with differential response and toxicity in AML patients treated with a combination of GO–FLAI regimen.

The study compared, by a prospective, randomized method, 6 treatment options: A: Sclero therapy ; B: High-dose sclerotherapy; C: Multiple ligations; D: Stab avulsion; E: Foam-sclero therapy ; F: Surgery (ligation) followed by sclerotherapy. Results were analyzed 10 years after inclusion and initial treatment. Endpoints of the study were variations in ambulatory venous pressure (AVP), refilling time (RT), presence of duplex-reflux, and number of recurrent or new incompetent venous sites. The number of patients, limbs, and treated venous segments were comparable in the 6 treatment groups, also comparable for age and sex distribution. The occur rence of new varicose veins at 5 years varied from 34% for group F (surgery + sclero) and ligation (C) to 44% for the foam + sclero group (E) and 48% for group A (dose 1 sclero). At 10 years the occurrence of new veins varied from 37% in F to 56% in A. At inclusion AVP was comparable in the different groups. At 10 years the decrease in AVP and the increase in RT (indicating decrease in reflux), was generally comparable in the different groups. Also at 10 years the number of new points of major incompetence was comparable in all treatment groups. These results indicate that, when correctly performed, all treatments may be similarly effective. \"Standard,\" low-dose sclerotherapy appears to be less effective than high-dose sclero and foam-sclerotherapy which may obtain, in selected subjects, results comparable to surgery.

This study assessed levels of agreement in knowledge and opinions about salmon fisheries and ecology of the Copper River, Alaska, in three user groups: the Ahtna, an Alaska Native people indigenous to the upper river; commercial fishers who fish at the mouth of the river; and fishery managers and biologists with jurisdiction over the entire watershed. We anticipated that cultural background, academic training, long-term experience on the water, and spatial focus would be reflected in each group's knowledge and opinions. Cultural consensus analysis showed agreement within each group, similar opinions between commercial fishers and managers and biologists, and distinct Ahtna opinions. Managers and biologists were the most cohesive group; they related to the entire watershed and relied on quantitative information as the basis for fisheries management. Ahtna focused on the upper river and incorporated observed long-term sociocultural, economic, and environmental changes into their opinions about the fisheries. Commercial fishers focused on the lower river and had strong familiarity with scientific principles of fisheries management. The similar views of commercial fishers and managers and biologists may result from the fact that commercial fishers' economic success also depends on their understanding of fisheries management. To respond to socioeconomic and ecological sustainability issues, fisheries management would benefit from recognizing these perspectives and promoting participation of all stakeholder groups and effective communication among them. Cette étude a permis d'évaluer les degrés d'accord en matière de connaissances et d'opinions sur l'écologie et la pêche au saumon de la rivière Copper, en Alaska, chez trois groupes d'utilisateurs : les Ahtna, peuple autochtone de l'Alaska natif du haut de la rivière; les pêcheurs commerciaux qui pèchent à l'embouchure de la rivière; et les gestionnaires et biologistes des pêches qui ont compétence sur l'ensemble du bassin versant. Nous nous attendions à ce que les connaissances et les opinions de chaque groupe soient rattachées aux antécédents culturels, à l'expérience académique, à l'expérience à long terme de la pêche et l'orientation spatiale. L'analyse du consensus culturel a permis de démontrer un accord au sein de chaque groupe, des opinions similaires entre les pêcheurs commerciaux et les biologistes-gestionnaires, et des opinions distinctes chez les Ahtna. Les biologistes-gestionnaires ont constitué le groupe le plus cohérent. Ils comprenaient l'ensemble du bassin versant et s'appuyaient sur des données quantitatives pour gérer les pêches. Pour leur part, les Ahtna se concentraient sur le haut de la rivière et tenaient compte, dans leurs opinions au sujet des pêches, des changements socioculturels, économiques et environnementaux observés à long terme. Les pêcheurs commerciaux se concentraient sur le bas de la rivière et connaissaient bien les principes scientifiques de la gestion des pêches. Les points de vue similaires des pêcheurs commerciaux et des biologistes-gestionnaires peuvent découler du fait que la réussite financière des pêcheurs commerciaux dépend aussi de leur compréhension de la gestion des pêches. Pour répondre aux questions de durabilité écologique et socioéconomique, la gestion des pêches pourrait bénéficier de la reconnaissance de ces perspectives, puis promouvoir la participation de tous les groupes d'intervenants de même que des communications efficaces entre eux.

Objective and methods: Combined hematopoietic stem cell transplants (HSCT) plus solid organ transplants (SOT) have been rarely reported. The majority of patients with a previous history of liver transplants were children that underwent HSCT for aplastic anemia after viral hepatitis. Here we report an adult patient who received a cord blood HSCT after a preceding liver transplantation. Results: In 1993 a 42 year old man required orthotopic liver transplantation for cirrhosis after B viral hepatitis. In April 2006 acute myeloid leukaemia M1 citotype , normal karyotype, FLTITD positive was diagnosed and a first complete remission was reached after 2 induction and consolidation cycles. At that time the patient was not considered eligible for a transplant program due the previous history of SOT. In February 2008 the patient relapsed and came to our Centre: he was treated with high-dose Cytosine-arabinoside chemotherapy, that was complicated by a pulmonary aspergillosis , but reached a second complete remission. We decided to start a cord blood donor search, since siblings were not available and he could not wait for an unrelated donor search. A cord blood with HLA locus A allelic mismatch and locus C antigenic mismatch was identified. Patient's comorbidity index according Sorror at transplant was 5. In May 2008 a preparative regimen containing Treosulfan, Fludarabine and ATG Fresenius was administered and 1,2 x 105/Kg CD 34+ cells were reinfused. Grade I mucositis and grade II hepatoxicity were observed. A bacterial pneumonia and CMV reactivation occurred at day 6 and at day 34 respectively and both rapidly resolved. A neutrophil count > 1 x 109/L was reached at day 19 and platelet counts > 20 and > 50 x 109/L platelet count were reached at day 36 and day 43 respectively. No acute and chronic GVHD were observed. A 100% donor chimerism has been reached in whole peripheral blood and in CD3+ cells since 28 days onwards. No minimal residual disease has been detected by marrow immunophenotyping and by WT-1 gene expression until last follow-up, at day 171. Conclusion: To our knowledge this is the first report of a successful cord blood allogeneic HSCT in an adult patient with a history of liver transplantation. This case might encourage physicians to propose allogeneic HSCT by any stem cell source to patients with high-risk haematological diseases, who had previous liver or other SOT's.