The clinical dilemma of JAK inhibitor failure in myelofibrosis: Predictive characteristics and outcomes

Two Janus-associated kinase inhibitors (JAKi) (initially ruxolitinib and, more recently, fedratinib) have been approved as treatment options for patients who have intermediate-risk and high-risk myelofibrosis (MF), with pivotal trials demonstrating improvements in spleen volume, disease symptoms, and quality of life. At the same time, however, clinical trial experiences with JAKi agents in MF have demonstrated a high frequency of discontinuations because of adverse events or progressive disease. In addition, overall survival benefits and clinical and molecular predictors of response have not been established in this population, for which the disease burden is high and treatment options are limited. Consistently poor outcomes have been documented after JAKi discontinuation, with survival durations after ruxolitinib ranging from 11 to 16 months across several studies. To address such a high unmet therapeutic need, various non-JAKi agents are being actively explored (in combination with ruxolitinib in first-line or salvage settings and/or as monotherapy in JAKi-pretreated patients) in phase 3 clinical trials, including pelabresib (a bromodomain and extraterminal domain inhibitor), navitoclax (a B-cell lymphoma 2/B-cell lymphoma 2-xL inhibitor), parsaclisib (a phosphoinositide 3-kinase inhibitor), navtemadlin (formerly KRT-232; a murine double-minute chromosome 2 inhibitor), and imetelstat (a telomerase inhibitor). The breadth of data expected from these trials will provide insight into the ability of non-JAKi treatments to modify the natural history of MF.     

Factors leading to long-term hospitalization after laparoscopic appendectomy.

BACKGROUND: Randomized studies demonstrate that laparoscopic appendectomy yields better results compared with open techniques. We sought to identify factors that determine an extended hospital stay among patients undergoing laparoscopic appendectomy. METHODS: This was a prospective study including 669 patients undergoing laparoscopic appendectomy. We analyzed variables that can predict the length of hospital stay. RESULTS: Of 669 patients undergoing laparoscopic appendectomy, 141 stayed in the hospital for > or = 5 days (Group 1), and 97 stayed in the hospital for < or = 1 day after surgery (Group 2). The univariate analysis demonstrated that fever (P<0.0001), nausea and vomiting (P=0.060), leukocytosis (P<0.0001), gangrened or perforated intraoperative appearance of the appendix (P<0.0001), and appendix position behind the ileocecal junction (P<0.001) were related to a longer hospital stay. The multivariate analysis through logistical regression showed that the factors independently and significantly associated with an extended hospital stay were presurgical fever, appendix position behind the ileocecal junction, and intraoperative gangrened or perforated appearance of the appendix. CONCLUSION: Fever, appearance, and position of the appendix are factors related to an extended hospital stay.     

Gene Delivery to Human B-Precursor Acute Lymphoblastic Leukemia Cells

Autologous leukemia cells engineered to express immune-stimulatingmolecules may be used to elicit antileukemia immune responses. Genedelivery to human B-precursor acute lymphoblastic leukemia (ALL) cellswas investigated using the enhanced green fluorescent protein (EGFP) asa reporter gene, measured by flow cytometry. Transfection of the Nalm-6and Reh B-precursor ALL leukemia cell lines with an expression plasmidwas investigated using lipofection, electroporation, and a polycationiccompound. Only the liposomal compound Cellfectin showed significantgene transfer (3.9% to 12% for Nalm-6 cells and 3.1% to 5% for Rehcells). Transduction with gibbon-ape leukemia virus pseudotyped Moloneymurine leukemia virus (MoMuLV)-based retrovirus vectors wasinvestigated in various settings. Cocultivation of ALL cell lines withpackaging cell lines showed the highest transduction efficiency forretroviral gene transfer (40.1% to 87.5% for Nalm-6 cells and 0.3%to 9% for Reh cells), followed by transduction with viral supernatant on the recombinant fibronectin fragment CH-296 (13% to 35.5% for Nalm-6 cells and 0.4% to 6% Reh cells), transduction on human bonemarrow stroma monolayers (3.2% to 13.3% for Nalm-6 cells and 0% to0.2% Reh cells), and in suspension with protamine sulfate (0.7% to3.1% for Nalm-6 cells and 0% for Reh cells). Transduction of bothNalm-6 and Reh cells with human immunodeficiency virus-type 1 (HIV-1)-based lentiviral vectors pseudotyped with the vesicular stomatitis virus-G envelope produced the best gene transfer efficiency, transducing greater than 90% of both cell lines. Gene delivery intoprimary human B-precursor ALL cells from patients was then investigatedusing MoMuLV-based retrovirus vectors and HIV-1-based lentivirusvectors. Both vectors transduced the primary B-precursor ALL cells withhigh efficiencies. These studies may be applied for investigating genedelivery into primary human B-precursor ALL cells to be used forimmunotherapy.     

Inhibition of HIV-1 infection by monoclonal antibodies to carbohydrates of Schistosoma mansoni

Patients infected with HIV-1 develop a potent humoral immune response against the virus, but HIV-1 primary isolates are remarkably resistant to neutralizing antibodies. Considering that the envelope glycoprotein of HIV-1 (gp120/41) is heavily glycosylated, we investigated whether anti-carbohydrate antibodies could inhibit HIV-1 infection in vitro. We studied the neutralizing activity of three monoclonal antibodies (mAbs) raised to carbohydrates of Schistosoma mansoni, against seven primary isolates of HIV-1. Assays were performed infecting peripheral blood mononuclear cells from normal donors with viral isolates previously treated with mAbs. Viral strains used were tropic for the coreceptors CCR5, CXCR4, and dual-tropic ones. We found that the anti-glycan mAbs vigorously inhibited HIV-1 infection, regardless of the preferential coreceptor usage of the isolate, in a dose-response manner. Importantly, five isolates were resistant to neutralization by two HIV-1 antibody-positive human sera endowed with potent anti-HIV-1 inhibitory activity. Our findings suggest that carbohydrates of the HIV-1 viral envelope may be a target of an effective humoral immune response elicited by vaccination.The first two authors contributed equally to this work     

Characteristics,anticoagulation, and outcomes of portal vein thrombosis after intra-abdominal surgery

BackgroundIntra-abdominal surgery is a cause of portal vein thrombosis; however, postsurgical portal vein thrombosis has not been extensively described.MethodsThis is a retrospective study of 107 patients with postsurgical portal vein thrombosis followed for a median 25 months (interquartile range 11–51). Outcomes were complete radiographic resolution of portal vein thrombosis and development of clinical portal hypertension.ResultsSurgeries associated with portal vein thrombosis included colectomy (n = 42), bariatric surgery (n = 25), and splenectomy (n = 11). Presentations were nonspecific, typically characterized by abdominal pain. Sixty-three patients (59%) achieved complete radiographic resolution. On univariable analysis, provoking surgery, occlusivity of portal vein thrombosis, and anticoagulant used were associated with complete radiographic resolution. Colectomy was associated with a complete radiographic resolution rate of 30/42 (71%), bariatric 10/25 (40%), splenectomy 2/11 (18%), and other 21/29 (72%), (log rank P = .0033). Nonocclusive thrombus was associated with a complete radiographic resolution rate of 44/62 (71%), occlusive thrombus 19/45 (42%), (log rank P = .0101). Direct oral anticoagulants were associated with a complete radiographic resolution rate of 27/35 (77%), enoxaparin 20/29 (69%), warfarin 14/31 (45%), and no anticoagulant 2/12 (17%), (log rank P = .0002). On multivariable analysis, only anticoagulant choice was significantly associated with complete radiographic resolution. Using direct oral anticoagulants as reference, no anticoagulant yielded an adjusted hazard ratio of 0.10 for complete radiographic resolution (95% confidence interval 0.023–0.44), warfarin 0.40 (95% confidence interval 0.20–0.78), and enoxaparin 0.64 (95% confidence interval 0.49–1.60). Failure to achieve complete radiographic resolution was associated with greater risk of future clinical portal hypertension. Twenty-three patients (21%) went on to develop clinical portal hypertension; 20 who failed to achieve complete radiographic resolution (45%), and only 3 who achieved complete radiographic resolution (5%), (log rank P < .0001).ConclusionThe natural history of postsurgical portal vein thrombosis is variable and influenced by type of surgery, degree of occlusion, and, most notably, type of anticoagulant used. Failure to recanalize the portal vein carries considerable risk of future clinical portal hypertension.     

Bone Mineral Density and Androgen Levels in Elderly Males

To clarify the relationship of sex male hormones and bone in men, we studied in 140 healthy elderly men (aged 55–90 years) the relation between serum levels of androgens and related sex hormones, bone mineral density (BMD) at different sites, and other parameters related to bone metabolism. Our results show a slight decrease of serum-free testosterone with age, with an increase of follicle stimulating hormone (FSH) and luteinizing hormone (LH) in a third of the elderly subjects studied. BMD decreased significantly with age in all regions studied, except in the lumbar spine. We found a positive correlation between body mass index (BMI) and BMD at the lumbar spine and femoral neck (P < 0.001). No relationship was found (uni- and multivariate regression analysis) between serum androgens or sex hormone-binding globulin (SHBG) and BMD. We found a positive correlation of vitamin D binding protein (DBP) and osteocalcin with lumbar spine BMD and with BMI, DBP, IGF-1, and PTH with femoral neck BMD. In conclusion, there is a slight decline in free testosterone and BMD in the healthy elderly males. However, sex male hormones are not correlated to the decrease in hip BMD. Other age-related factors must be associated with bone loss in elderly males. Received: 29 April 1997 / Accepted: 9 November 1997     

The ovulation method in developing countries with special reference to India

Time may prove that no equal exists to natural family planning (NFP) methods in regard to safe and wide applicability without much sacrifice of reliability, especially in developing countries because of its inexpensiveness and dependence on the couple rather than doctors or paramedical staff. In India, for example, the vast majority of Indians, regardless of caste of religion, are indoctrinated to practice abstinence of various kinds: fasting for either religious or social reasons, abstinence from sleep, abstinence from speech, sexual abstinence during Ramzan (Muslims) and Adimasam (South Indians). With this background, there is great scope for wider use of the Ovulation-Method (Billings). NFP helps in the establishment of a "self-energized family," which is the aim of community health workers in developing countries. A World Health Organization (WHO) study conducted in India, Philippines, and El Salvador revealed some salient findings: the days of menstruation were only 4.4 days (5.6 days in developed countries); and the fertile period, defined as days of sticky mucus plus slippery mucus (3 days), averaged 8 days (10.6 days in developed countries). In 149 women there was only 1 day of mucus before the peak day (PD); there were 2 days of mucus in 479 women (7%); and there were days of mucus in 649 (10%). Illiteracy, poverty, and marital problems were encountered in many couples. Continuation rates were significantly high in the WHO study (1979) and the Karnataka State Study (1981). Friction caused by abstinence was experienced by only 1.7-4.6% of husbands in the Karnataka Study of 2790 couples with detailed records on this aspect. In developing countries where the dignity of a woman needs to be raised, an educational method that lends itself to the integrated teaching of health, hygiene, and nutrition concepts and practices is appealing. The responsible behavior of the husband together with the wife's effort in recording her fertility creates a marital partnership with the woman sharing on an equal basis with her husband.     

Rotavirus serotypes and electropherotypes identified among hospitalised children in São Luís, Maranhão, Brazil

During June 1997-June 1999 rotavirus infection was screened in infants aged up to 2 years and hospitalised with acute diarrhoea in S?o Luís, Northeastern Brazil. Altogether, 128 stool samples were collected from diarrhoeic patients and additional 122 faecal specimens from age and temporal matched inpatients without diarrhoea were obtained; rotavirus positivity rates for these groups were 32.0% (41/128) and 9.8% (12/122), respectively (p < 0.001). Both electropherotyping and serotyping could be performed in 42 (79.2%) of the 53 rotavirus-positive stool samples. Long and short electropherotypes were detected at similar rates--38.1% and 40.5% of specimens, respectively. Overall, a G serotype could be assigned for 35 (83.3%) of specimens, the majority of them (66.7%) bearing G1-serotype specificity. Taking both electropherotypes and serotypes together, G1 rotavirus strains displaying long and short RNA patterns accounted for 30.9% and 19.0% of tested specimens, respectively; all G2 strains had short electropherotype. Rotavirus gastroenteritis was detected year-round and, in 1998, the incidence rates tended to be higher during the second semester than in the first semester: 45.2% and 26.1% (p = 0.13), respectively. Rotavirus infections peaked at the second semester of life with frequencies of 30.1% and 13.5% for diarrhoeic children and controls, respectively. While the six rotavirus strains bearing G2-type specificity were circulating throughout the whole study period, G1 serotypes (n = 27) emerged as from June 1998 onwards, 20 (74.1%) of which clustering in 1998. These data underscore the importance of rotaviruses in the aetiology of severe infantile gastroenteritis in Northeastern Brazil and sustain the concept that a future vaccine should confer protection against more than one serotype.