Ruxolitinib Adherence in Myelofibrosis and Polycythemia Vera: the "RAMP" Italian multicenter prospective study.

Ruxolitinib is beneficial in patients with myelofibrosis (MF) and polycythemia vera (PV). Information on ruxolitinib adherence is scant. The Ruxolitinib Adherence in Myelofibrosis and Polycythemia Vera (RAMP) prospective multicenter study (NCT06078319) included 189 ruxolitinib-treated patients. Patients completed the Adherence to Refills and Medications Scale (ARMS) and Distress Thermometer and Problem List (DTPL) at the earliest convenience, after registration in the study, and at later timepoints. At week-0, low adherence (ARMS > 14) and high distress (DT ≥ 4) were declared by 49.7% and 40.2% of patients, respectively. The main reason for low adherence was difficult ruxolitinib supply (49%), intentional (4.3%) and unintentional (46.7%) non-take. In multivariable regression analysis, low adherence was associated to male sex (p = 0.001), high distress (p < 0.001), and treatment duration ≥ 1 year (p = 0.03). Over time, rates of low adherence and high distress remained stable, but unintentional non-take decreased from 47.9% to 26.0% at week-48. MF patients with stable high adherence/low distress were more likely to obtain/maintain the spleen response at week-24. Low adherence to ruxolitinib represents an unmet clinical need that require a multifaceted approach, based on reason behind it (patients characteristics and treatment duration). Its recognition may help distinguishing patients who are truly refractory and those in need of therapy optimization.

Idiopathic erythrocytosis: a germline disease?

Polycythemia Vera (PV) is typically caused by V617F or exon 12 JAK2 mutations. Little is known about Polycythemia cases where no JAK2 variants can be detected, and no other causes identified. This condition is defined as idiopathic erythrocytosis (IE). We evaluated clinical-laboratory parameters of a cohort of 56 IE patients and we determined their molecular profile at diagnosis with paired blood/buccal-DNA exome-sequencing coupled with a high-depth targeted OncoPanel to identify a possible underling germline or somatic cause. We demonstrated that most of our cohort (40/56: 71.4%) showed no evidence of clonal hematopoiesis, suggesting that IE is, in large part, a germline disorder. We identified 20 low mutation burden somatic variants (Variant allelic fraction, VAF, < 10%) in only 14 (25%) patients, principally involving DNMT3A and TET2. Only 2 patients presented high mutation burden somatic variants, involving DNMT3A, TET2, ASXL1 and WT1. We identified recurrent germline variants in 42 (75%) patients occurring mainly in JAK/STAT, Hypoxia and Iron metabolism pathways, among them: JAK3-V722I and HIF1A-P582S; a high fraction of patients (48.2%) resulted also mutated in homeostatic iron regulatory gene HFE-H63D or C282Y. By generating cellular models, we showed that JAK3-V722I causes activation of the JAK-STAT5 axis and upregulation of EPAS1/HIF2A, while HIF1A-P582S causes suppression of hepcidin mRNA synthesis, suggesting a major role for these variants in the onset of IE.

Splanchnic vein thrombosis in myeloproliferative neoplasms: risk factors for recurrences in a cohort of 181 patients.

We retrospectively studied 181 patients with polycythaemia vera (n=67), essential thrombocythaemia (n=67) or primary myelofibrosis (n=47), who presented a first episode of splanchnic vein thrombosis (SVT). Budd-Chiari syndrome (BCS) and portal vein thrombosis were diagnosed in 31 (17.1%) and 109 (60.3%) patients, respectively; isolated thrombosis of the mesenteric or splenic veins was detected in 18 and 23 cases, respectively. After this index event, the patients were followed for 735 patient years (pt-years) and experienced 31 recurrences corresponding to an incidence rate of 4.2 per 100 pt-years. Factors associated with a significantly higher risk of recurrence were BCS (hazard ratio (HR): 3.03), history of previous thrombosis (HR: 3.62), splenomegaly (HR: 2.66) and leukocytosis (HR: 2.8). Vitamin K-antagonists (VKA) were prescribed in 85% of patients and the recurrence rate was 3.9 per 100 pt-years, whereas in the small fraction (15%) not receiving VKA more recurrences (7.2 per 100 pt-years) were reported. Intracranial and extracranial major bleeding was recorded mainly in patients on VKA and the corresponding rate was 2.0 per 100 pt-years. In conclusion, despite anticoagulation treatment, the recurrence rate after SVT in myeloproliferative neoplasms is high and suggests the exploration of new avenues of secondary prophylaxis with new antithrombotic drugs and JAK-2 inhibitors.

High rate of recurrent venous thromboembolism in patients with myeloproliferative neoplasms and effect of prophylaxis with vitamin K antagonists.

The optimal duration of treatment with vitamin K antagonists (VKA) after venous thromboembolism (VTE) in patients with Philadelphia-negative myeloproliferative neoplasms (MPNs) is uncertain. To tackle this issue, we retrospectively studied 206 patients with MPN-related VTE (deep venous thrombosis of the legs and/or pulmonary embolism). After this index event, we recorded over 695 pt-years 45 recurrences, venous in 36 cases, with an incidence rate (IR) of 6.5 per 100 pt-years (95% confidence interval (CI): 4.9-8.6). One hundred fifty-five patients received VKA; the IR of recurrent thrombosis per 100 pt-years was 4.7 (95% CI: 2.8-7.3) on VKA and 8.9 (95% CI: 5.7-13.2) off VKA (P=0.03). In patients receiving VKA, the IR of recurrent thrombosis per 100 pt-years was 5.3 (95% CI: 3.2-8.4) among 108 patients on long-term VKA and 12.8 (95% CI: 7.3-20.7) after discontinuation among the 47 who ceased treatment (P=0.008), with a doubled risk of recurrence after stopping VKA (hazard ratio: 2.21, 95% CI: 1.19-5.30). The IR of major bleeding per 100 pt-years was 2.4 (95%: CI: 1.1-4.5) on VKA and 0.7 (95% CI: 0.08-2.5) off VKA (P=0.08). In conclusion, in MPN patients with VTE recurrent thrombosis is significantly reduced by VKA and caution should be adopted in discontinuation; however, the incidence of recurrence on treatment remains high, calling for clinical trials aimed to improve prophylaxis in this setting.

De novo gastric adenocarcinoma 1 year after sleeve gastrectomy in a transplant patient.

INTRODUCTION: It has been reported in the literature that upper gastrointestinal malignancies after bariatric surgery are mostly gastro-esophageal, although it is not clear whether bariatric surgery represents a risk factor for the development of esophageal and/or gastric cancer. We report a case of a de novo gastric adenocarcinoma occurring in a transplant patient 1 year after a laparoscopic sleeve gastrectomy. PRESENTATION OF CASE: A 44 year-old woman with a BMI of 38kg/m(2), hypertension, type 1 diabetes mellitus, multiple malignancies and a pancreas transplant underwent laparoscopic sleeve gastrectomy. The patient presented with intense dysphagias during the follow up. Studies were performed and the diagnoses of grade 2/3 adenocarcinoma were made. The patient underwent a robotic assisted total gastrectomy with a roux-en-y intracorporeal esophagojejunostomy. The procedure resulted in multiple metastasic lymph nodes, focal and transmural invasions to multiple organs with a tumor free margin resection. The patient presented with a postoperative pleural effusion, with no further complications. DISCUSSION: The diagnosis of gastroesophageal cancer after bariatric surgery is usually late since these patients have common upper gastrointestinal symptoms related to the procedure that could delay the diagnosis. De novo gastric cancer after sleeve gastrectomy has only been reported in one instance, in contrast with other bariatric surgery procedures. CONCLUSIONS: No direct relation has been established between sleeve gastrectomy and the development of gastric cancer. Robotic procedures allow for complex multiorgan resections, while preserving the benefits of minimally invasive surgery.

Biomassa e teor de óleo essencial em Aloysia triphylla (l'hérit) Britton submetida a diferentes níveis de reposição hídrica e à variação sazonal das condições ambientais / Biomass and essential oil content in Aloysia triphylla (L'Herit) Britton subjected to different levels of water reposition and season alchanges of environmental conditions

RESUMOA variação nos elementos meteorológicos ao longo do ano, configurando as quatro estações, proporciona diferentes condições de crescimento e desenvolvimento das plantas, alterando o metabolismo e a constituição dos tecidos vegetais. Assim, o presente trabalho teve o objetivo de determinar a influência da sazonalidade em parâmetros fenométricos e na produção de óleo essencial em Aloysia triphylla (L'Hérit) Britton, submetida a diferentes níveis de reposição hídrica cultivada em ambiente protegido. As avaliações foram realizadas no dia que marcou a metade de cada estação do ano (verão, outono, inverno e primavera), sendo coletado todo o material vegetativo 20 cm acima do solo. A reposição hídrica foi baseada na evapotranspiração de referência (ETo) para o ambiente externo em função dos dados de entrada da equação de Penman-Monteith a qual apresenta parametrizações para dados obtidos em estações meteorológicas em padrões oficiais, sendo assim aplicados 125, 100, 75 e 50% da ETo em turno de rega de dois dias. A produção de massa fresca, seca e de parte aérea, bem como a área foliar, apresentaram maiores valores na estação primavera, sendo o inverno e o verão responsáveis pelos menores valores. O maior teor de óleo essencial foi observado nas estações de menor produção de biomassa, ou seja, verão e inverno. A reposição hídrica que proporcionou maior produção de material vegetativo foi a de 125% da ETo; no entanto, o maior teor de óleo foi observado nas menores reposições hídricas (75 e 50 % da ETo, respectivamente). A produção de óleo foi maior na primavera, a qual não sofreu influência da reposição hídrica ao longo do ano.

ABSTRACTThe variation in weather elements throughout the year, setting the four seasons, provides different conditions for growth and development of plants, altering the metabolism and the structure of plants` tissues. This study aimed to determine the influence of seasonality on fenometrics parameters and on the oil production in Aloysia triphylla (L'Herit) Britton, subjected to different levels of water availability cultivated in greenhouse conditions. The evaluations were made on the day that marked the middle of each season (summer, autumn, winter and spring), and all plant material were collected 20 cm above ground. The water reposition was based on the evapotranspiration reference (ETo) to the external environment being applied 125, 100, 75 and 50% of ETo in an irrigation interval of two days. The production of fresh, dry and aerial part mass, as well as leaf areamass, showed higher values in the spring season, while winter and summer were responsible for lower values. The highest content of essential oil was observed at seasons with lower biomass production. The water availability that provided higher production of plant material was the one with 125% of ETo, however, the highest oil content was observed at lower water availability (75% and 50% of ETo, respectively). The oil production was higher in the spring and was not affected throughout the year by the water availability.

Effectiveness of gastric neurostimulation in patients with gastroparesis.

BACKGROUND: Patients with gastroparesis have significantly delayed gastric emptying because of impaired nerve function. Gastric neurostimulation from Enterra Therapy provides electrical pulses to the stomach tissue that promotes stimulation of stomach smooth muscle, thereby enhancing gastric emptying. This study evaluates the effectiveness of Enterra Therapy (Medtronic, Minneapolis, Minnesota) in reducing symptoms and improving the quality of life of patients with drug-refractory gastroparesis. MATERIAL AND METHODS: In this study 25 patients underwent minimally invasive, laparoscopic placement of the Enterra Therapy device. Patients were asked to rank their severity of symptoms and quality of life retrospectively by completing the Gastrointestinal Symptoms Rating Scale and Short Form 36 Health Survey with respect to their condition before and 6 months after initiation of Enterra Therapy. RESULTS: Eighteen patients completed the surveys. Patients showed statistically significant improvement in their overall Gastrointestinal Symptoms Rating Scale scores and the mental health component of the Short Form 36 Health Survey. DISCUSSION: Currently, Enterra Therapy has Humanitarian Use Device status, which means that more clinical evidence is needed to prove its effectiveness in gastroparesis. By showing that Enterra Therapy reduces symptoms of gastroparesis and improves patient quality of life, this study contributes to the increasing amount of data supporting its use and potential Food and Drug Administration approval.

Relações fisiológicas em mudas de pata-de-vaca (Bauhinia forficata Link) / Physiologic relationships in Brazilian Orchid Tree (Bauhinia forficata Link) seedlings

Os fatores ambientais, tais como: temperatura do ar, umidade relativa do ar e radiação solar, influenciam no comportamento fisiológico dos vegetais refletindo no seu crescimento e desenvolvimento. O objetivo do trabalho foi avaliar o comportamento fisiológico em mudas de pata-de-vaca ao longo do dia e constatar qual o melhor horário para a realização de determinações de trocas gasosas. Para tanto, foram realizadas avaliações de temperatura da folha, radiação fotossinteticamente ativa, resistência estomática e transpiração, utilizando-se um porômetro, das 8:00 às 17:00 horas, em intervalos de uma hora entre as medidas. A espécie apresenta oscilações no seu mecanismo fisiológico em função do horário de avaliação e das condições climáticas, sendo o intervalo mais indicado para a realização de determinações das trocas gasosas das 10:00 às 13:00 horas.

Environmental elements, such as air temperature, relative humidity and solar radiation, affect the physiological behavior of plants, which is reflected in their growth and development. The objective of this study was to evaluate the physiological changes of Brazilian Orchid Tree seedlings over a typical day and find the best time to carry out determinations of gas exchanges. For this end, we evaluated temperature of the leaf, photosynthetically active radiation, stomatal resistance and perspiration, using a porometer, from 8:00 a.m. to 05:00 p.m., in intervals of one hour between measurements. The species presents oscillations in its physiologic mechanism in function of the time of evaluation and climatic conditions, being the most suitable interval to determine gas exchanges from 10:00 a.m. to 01:00 p.m.

Development of JAK2V617F-positive polycythemia vera after chemotherapy-induced remission of primary central nervous system diffuse large B cell non-Hodgkin's lymphoma: a case report and review of the literature.

The coexistence or the development of Philadelphia chromosome-negative myeloproliferative neoplasms after a lymphoproliferative disease in the same patient is an extremely rare event. We report the case of a 72-year-old man who developed JAK2V617F polycythemia vera 3 years after the diagnosis and treatment of primary diffuse large B cell non-Hodgkin's lymphoma of the central nervous system. We also review the literature regarding the pathogenesis underlying the association of myeloproliferative and lymphoproliferative chronic disorders.

Successful treatment with T-depleted autologous peripheral blood stem cell transplantation of refractory chronic autoimmune thrombocytopenic purpura.

Autoimmune thrombocytopenia (AITP) is a disorder due to specific platelet auto-antibodies directed against platelet surface glycoproteins. AITP in adults is usually chronic, idiopathic and frequently refractory to conventional treatments. Myelo- and immuno-suppressive chemotherapy followed by autologous peripheral blood stem cell (PBSC) transplantation is an experimental approach for severe chronic refractory AITP. We report a case of a woman with AITP, refractory to the conventional therapy, submitted to T-cell-depleted autologous PBSC transplantation, which obtained long term stable response on platelet count. We deem that the positive outcome of our patient depends on T-cells depletion of the graft, which reduces autoreactive T clones.

Cytomegalovirus infection after autologous stem cell transplantation: incidence and outcome in a group of patients undergoing a surveillance program.

This study was performed to evaluate the incidence, risk factors, and outcome of cytomegalovirus (CMV) infection in autologous stem cell transplantation (ASCT), with the aim of performing preemptive therapy in patients with antigenemia. Starting from 2001, 171 consecutive ASCTs were performed in 136 patients; 102 of these patients were seropositive for CMV at the onset of hematological disease. In all these patients, a CMV pp65 antigenemia assay was determined weekly, starting from the day when the absolute neutrophil count went above 500/microL, and until day 60 after ASCT; subsequently, antigenemia was determined only when a CMV infection was suspected. Among the 136 transplanted patients, 40 (29.4%) presented a positive antigenemia; all of them were seropositive for CMV before ASCT; and no cases of primary infection were seen. The incidence of CMV infection in the seropositive population was 40/102 (39.3%); 6 patients (5 with multiple myeloma and 1 with non-Hodgkin's lymphoma) who received 2 ASCTs developed CMV infections after both transplantations, so that positive antigenemia developed after 46/171 (26.9%) transplantations. First positive antigenemia presented a median of 32 days (range 7-57) after stem cell reinfusion. The median antigenemia level at the first appearance was 2/200,000 (range 1-1000). No significant prognostic factors could be shown. Enteritis was present in 5 patients; 2 of them also had fever, and 1 of them also had thrombocytopenia. In 5 patients fever without any other clinical signs or symptoms was present; 30 patients were asymptomatic. Fourteen patients were treated with anti-CMV drugs. CMV reactivation was successfully treated in all patients, and no patient died from CMV disease.

Immunohistochemical expression of cyclin D1, cyclin E, p21/waf1 and p27/kip1 in inflammatory bowel disease: correlation with other cell-cycle-related proteins (Rb, p53, ki-67 and PCNA) and clinicopathological features.

BACKGROUND AND AIMS: The expression patterns of cyclins D1 and E as well as cyclin-dependent kinase inhibitors p21/waf1 and p27/kip1 and their correlation with clinical parameters and other cell cycle regulators was investigated in inflammatory bowel disease (IBD). PATIENTS AND METHODS: These molecular markers were localized immunohistochemically using the monoclonal antibodies anti-cyclin D1 (DCS-6), anti-cyclin E (13A3), anti-p21 (4D10) and anti-p27 (1B4) in 70 patients with IBD, 30 patients with colorectal cancer and eight healthy subjects. Data were analyzed statistically using the software program. RESULTS: Cyclin D1 expression was higher in both UC and CD compared with the healthy control group. In addition, CD cyclin D1 expression was higher compared with UC cases and colorectal carcinomas. Cyclin D1 expression was correlated with disease activity and cell proliferation in UC cases. A positive relationship of cyclin D1 with p27/kip1 in both UC and CD was detected. Cyclin E expression was higher in UC, CD and carcinomas compared with healthy control group and its expression correlated with proliferative activity in both UC and CD cases. p21/waf1 expression was higher in IBD cases compared with that of the control group, while a decreased p21/waf1 expression in the group of carcinomas was noted. This expression was correlated with disease activity in UC and the proliferative activity in both UC and CD. The expression of cyclins D1 and E as well as p21/waf1 was also correlated with the existence of dysplastic lesions. A lower p27/kip1 expression in the group of carcinomas compared with IBD cases and healthy controls was found. CONCLUSIONS: The expression patterns of cyclin D1, cyclin E, p21/waf1 and p27/kip1 in IBD may indicate their contribution in epithelial cell turnover and their possible implication in IBD-related dysplasia-carcinoma.

Robotic-assisted thoracoscopic resection of esophageal leiomyoma.

Esophageal leiomyoma represents 70-80% of all benign esophageal tumors but only approximately 0.5% of all esophageal neoplasms; optimal surgical treatment consists of local resection. We present the first reported robotic-assisted thoracoscopic resection of two patients with esophageal leiomyoma using the daVinci Surgical System. Operative technique and technical considerations are presented.

Mini-laparoscopic placement of a peritoneal dialysis catheter.

BACKGROUND: The laparoscopic placement of continuous ambulatory peritoneal dialysis (CAPD) catheters is now an accepted technique. We evaluated a new technique for CAPD catheter placement that requires only a single 2-mm port. METHODS: A pilot study was conducted at an academic minimally invasive surgery center. Seven consecutive patients in whom a CAPD catheter was required underwent placement of a 2-mm Veress port and a laparoscope. A carbon dioxide pneumoperitoneum was induced up to 14 mmHg. Under direct visualization with a 2-mm scope, a CAPD catheter was advanced over the right lower quadrant toward the pelvis using a modified Seldinger technique. RESULTS: Seven patients (four women and three men) with end-stage renal disease underwent mini-laparoscopic placement of a CAPD catheter. Mean patient age was 35.3 +/- 11.3 years (range, 17-50). Mean operative time was 20.7 +/- 5.0 min (range, 14-29). Patients were dialyzed in the immediate postoperative period. No leaks were identified, and there were no intraoperative or postoperative complications. CONCLUSION: A mini-laparoscopic technique using a single 2-mm port and a modified Seldinger technique is feasible, safe, and effective for peritoneal dialysis catheter placements.

[Resection of the sigmoid via laparoscopy: an experimental study of its feasibility]. / Resezione di sigma per via laparoscopica: studio di fattibilità sperimentale.

The authors describe an experimental laparoscopic sigmoid colon resection performed in the porcine model. The operation begins with the introduction of the laparoscope via an umbilical trocar. Five other trocars are then placed allowing different maneuvers. The sigmoid colon is grasped in order to gain access to its mesenteric vessels which are clipped and divided, carrying out the dissection of the entire sigmoid colon. Two modified Endo-GIA are then fired both cranially and caudally, in order to obtain a closed sigmoid specimen and to maintain patent the lumen of the descending colon and rectum. The sigmoid is removed transanally. A P-CEEA stapler is introduced via the rectum and its detached anvil is put into the lumen of the descending colon. A purse-string is applied and closed around the anvil rod. The P-CEEA is retracted, and the rectal stump closed with another Endo-GIA. After reintroducing the trocar-loaded stapler, the trocar is advanced through the suture line of the rectum and removed via a port. The stapler is then reassembled, fired and extracted through the anus. Taking into account the oncologic criteria, we think that this mini-invasive technique could be applied, after an adequate training period on the animal model, to humans also.