Extended follow-up and impact of high-risk prognostic factors from the phase 3 RESONATE study in patients with previously treated CLL/SLL.

In the phase 3 RESONATE study, ibrutinib demonstrated superior progression-free survival (PFS), overall survival (OS) and overall response rate (ORR) compared with ofatumumab in relapsed/refractory CLL patients with high-risk prognostic factors. We report updated results from RESONATE in these traditionally chemotherapy resistant high-risk genomic subgroups at a median follow-up of 19 months. Mutations were detected by Foundation One Heme Panel. Baseline mutations in the ibrutinib arm included TP53 (51%), SF3B1 (31%), NOTCH1 (28%), ATM (19%) and BIRC3 (14%). Median PFS was not reached, with 74% of patients randomized to ibrutinib alive and progression-free at 24 months. The improved efficacy of ibrutinib vs ofatumumab continues in all prognostic subgroups including del17p and del11q. No significant difference within the ibrutinib arm was observed for PFS across most genomic subtypes, although a subset carrying both TP53 mutation and del17p had reduced PFS compared with patients with neither abnormality. Reduced PFS or OS was not evident in patients with only del17p. PFS was significantly better for ibrutinib-treated patients in second-line vs later lines of therapy. The robust clinical activity of ibrutinib continues to show ongoing efficacy and acceptable safety consistent with prior reports, independent of various known high-risk mutations.

Mutations in NOTCH1 PEST domain orchestrate CCL19-driven homing of chronic lymphocytic leukemia cells by modulating the tumor suppressor gene DUSP22.

Even if NOTCH1 is commonly mutated in chronic lymphocytic leukemia (CLL), its functional impact in the disease remains unclear. Using CRISPR/Cas9-generated Mec-1 cell line models, we show that NOTCH1 regulates growth and homing of CLL cells by dictating expression levels of the tumor suppressor gene DUSP22. Specifically, NOTCH1 affects the methylation of DUSP22 promoter by modulating a nuclear complex, which tunes the activity of DNA methyltransferase 3A (DNMT3A). These effects are enhanced by PEST-domain mutations, which stabilize the molecule and prolong signaling. CLL patients with a NOTCH1-mutated clone showed low levels of DUSP22 and active chemotaxis to CCL19. Lastly, in xenograft models, NOTCH1-mutated cells displayed a unique homing behavior, localizing preferentially to the spleen and brain. These findings connect NOTCH1, DUSP22, and CCL19-driven chemotaxis within a single functional network, suggesting that modulation of the homing process may provide a relevant contribution to the unfavorable prognosis associated with NOTCH1 mutations in CLL.

BTK inhibition targets in vivo CLL proliferation through its effects on B-cell receptor signaling activity.

Bruton agammaglobulinemia tyrosine kinase (BTK), a cytoplasmic protein tyrosine kinase, is a component of the B-cell receptor signaling pathway. Ibrutinib, a BTK inhibitor, has demonstrated a significant clinical activity against chronic lymphocytic leukemia (CLL) in early clinical trials. Understanding the molecular mechanisms of action would shed light on CLL pathophysiology and provide additional opportunities for the development of new therapies. In this study, we have chosen an in vivo approach by employing an ongoing phase 1b trial of ibrutinib. We prospectively collected and analyzed serial samples from the CLL patients before and after the initiation of ibrutinib. We found that the blockage of cell proliferation was one of the primary effects of ibrutinib against leukemic CLL cells in vivo. Using a co-culture system that induces CLL proliferation in vitro, analysis of several parameters, including Ki-67 expression and bromodeoxyuridine (BrdU) incorporation, revealed that the proliferation of CLL cells was directly inhibited by ibrutinib. Furthermore, activities of BTK and phospholipase Cγ2 as well as downstream signaling molecules, AKT and ERK, were all coordinately downregulated over time in ibrutinib-treated patients. Our findings suggest that the cell proliferation is one of the essential properties of CLL. Blocking cell proliferation via inhibition of BTK-mediated signaling may contribute to clinical responses in ibrutinib-treated patients.

Terminal complement inhibitor eculizumab in atypical hemolytic-uremic syndrome.

BACKGROUND: Atypical hemolytic-uremic syndrome is a genetic, life-threatening, chronic disease of complement-mediated thrombotic microangiopathy. Plasma exchange or infusion may transiently maintain normal levels of hematologic measures but does not treat the underlying systemic disease. METHODS: We conducted two prospective phase 2 trials in which patients with atypical hemolytic-uremic syndrome who were 12 years of age or older received eculizumab for 26 weeks and during long-term extension phases. Patients with low platelet counts and renal damage (in trial 1) and those with renal damage but no decrease in the platelet count of more than 25% for at least 8 weeks during plasma exchange or infusion (in trial 2) were recruited. The primary end points included a change in the platelet count (in trial 1) and thrombotic microangiopathy event-free status (no decrease in the platelet count of >25%, no plasma exchange or infusion, and no initiation of dialysis) (in trial 2). RESULTS: A total of 37 patients (17 in trial 1 and 20 in trial 2) received eculizumab for a median of 64 and 62 weeks, respectively. Eculizumab resulted in increases in the platelet count; in trial 1, the mean increase in the count from baseline to week 26 was 73×10(9) per liter (P<0.001). In trial 2, 80% of the patients had thrombotic microangiopathy event-free status. Eculizumab was associated with significant improvement in all secondary end points, with continuous, time-dependent increases in the estimated glomerular filtration rate (GFR). In trial 1, dialysis was discontinued in 4 of 5 patients. Earlier intervention with eculizumab was associated with significantly greater improvement in the estimated GFR. Eculizumab was also associated with improvement in health-related quality of life. No cumulative toxicity of therapy or serious infection-related adverse events, including meningococcal infections, were observed through the extension period. CONCLUSIONS: Eculizumab inhibited complement-mediated thrombotic microangiopathy and was associated with significant time-dependent improvement in renal function in patients with atypical hemolytic-uremic syndrome. (Funded by Alexion Pharmaceuticals; C08-002 ClinicalTrials.gov numbers, NCT00844545 [adults] and NCT00844844 [adolescents]; C08-003 ClinicalTrials.gov numbers, NCT00838513 [adults] and NCT00844428 [adolescents]).

Surveillance CT scans are a source of anxiety and fear of recurrence in long-term lymphoma survivors.

BACKGROUND: We aimed to assess anxiety and the psychological impact of routine surveillance scans in long-term survivors of adult aggressive lymphoma. PATIENTS AND METHODS: In this cross-sectional observational study of 70 survivors of curable adult aggressive lymphoma, we measured anxiety and the doctor-patient relationship and performed a qualitative interview (n = 30) focused on patient perception of routine follow-up imaging studies. RESULTS: Participants were diagnosed with aggressive lymphoma a median of 4.9 years (2.4-38.0 years) before enrollment. Thirty-seven percent of patients were found to meet criteria for clinically significant anxiety, which was not associated with years since diagnosis. In multivariate analysis, history of relapse and a worse doctor-patient relationship were independently associated with higher anxiety levels. Despite representing a largely cured population, in qualitative interviews patients reported fear of recurrence as a major concern and considerable anxiety around the time of a follow-up imaging scan. CONCLUSIONS: Routine surveillance scans exacerbate underlying anxiety symptoms and fear of recurrence in survivors of aggressive lymphoma. Strategies to minimize follow-up imaging and to improve doctor-patient communication should be prospectively evaluated to address these clinically significant issues.

Is ritual circumcision a risk factor for neonatal urinary tract infections?

OBJECTIVE: Although circumcision is commonly believed to protect against urinary tract infection (UTI), it is not unusual in neonates in Israel, where almost all male infants are circumcised. The aim of the study was to evaluate the burden of neonatal UTI in Israel and its relationship to circumcision. DESIGN: Medical records of neonates (< or =2 months old) hospitalised with UTI were reviewed and demographic and clinical data were collected. The second part of the study consisting of a telephone survey to assess timing and details concerning the circumcision, included two groups: a study group consisting of parents of male infants, aged 8-30 days, hospitalised with UTI, and a control group consisting of healthy neonates. RESULTS: 162 neonates (108 males, 54 females) were hospitalised with UTI. Mean age at admission was significantly lower in males (27.5 vs 37.7 days, p = 0.0002). The incidence of UTI in males peaked at 2-4 weeks of age, that is, the period immediately following circumcision. In females, the incidence tended to rise with age. Accordingly, male predominance disappeared at 7 weeks and the male-to-female ratio reversed. In the second part of the study, 111 males (< or =1 month old) were included: 48 post-UTI and 63 as a control group. While evaluating the impact of circumcision technique, we found that UTI occurred in six of the 24 infants circumcised by a physician (25%), and in 42 of the 87 infants (48%) circumcised by a religious authority; the calculated odds ratio for contracting UTI was 2.8 (95% CI 1 to 9.4). CONCLUSIONS: There was a higher preponderance of UTI among male neonates. Its incidence peaked during the early post-circumcision period, as opposed to the age-related rise in females. UTI seems to occur more frequently after traditional circumcision than after physician-performed circumcision. We speculate that changes in the haemostasis technique or shortening the duration of the shaft wrapping might decrease the rate of infection after Jewish ritual circumcision.

Intensive treatment strategies may not provide superior outcomes in mantle cell lymphoma: overall survival exceeding 7 years with standard therapies.

BACKGROUND: Reported median overall survival (OS) in patients with mantle cell lymphoma (MCL) has been reported to be just 3-4 years. As a consequence, first-line treatment has become more aggressive. Single-center studies with R-Hyper-CVAD and/or autologous stem-cell transplant (ASCT) have produced 3-year OS rates >80%, prompting many to adopt their use. We evaluated outcomes from a single-center cohort managed in a more traditional fashion. METHODS: We identified patients with MCL evaluated at Weill Cornell Medical Center since 1997, and included those with known date of diagnosis. An online social security database was used to verify survival. RESULTS: We identified 181 patients with MCL, and date of diagnosis could be determined in 111. Three-year OS from diagnosis was 86% [95% confidence interval (CI) 78% to 92%]. Median OS was 7.1 years (95% CI 63-98 months). Adequate information on therapy was available for 75 patients. Only five were treated upfront with (R)-Hyper-CVAD or ASCT while an additional four patients received one of these regimens subsequently. Treatment type had no significant effect on OS. CONCLUSION: Outcomes with standard approaches can yield similar survival to that achieved with more intensive approaches. Biases may account for the perceived superiority of aggressive strategies.

Preventive care of older urban American Indians and Alaska natives in primary care.

Little is known about prevention among elderly or urban American Indian/Alaska Native (AI/AN) populations. We reviewed the medical records of 550 older urban AI/AN primary care patients to evaluate how frequently preventive measures were received. Adherence to guidelines was examined by a culturally appropriate (> or =50 years) and standard age threshold (> or =65 years), and by performance of preventive measures at any time ("ever") and in the past year. Lifetime performance was inadequate for the many measures, including mammograms (56%), fecal occult blood testing (37%), audiometry (33%), visual acuity testing (50%), smoking cessation counseling (50%), and pneumococcal (22%) and influenza (49%) vaccinations. Performance of the measures was less frequent in the prior year, but did not differ by age threshold. Predictors of adherence included female gender, having insurance, and having more health problems and medications. Nonadherence infrequently resulted from patients' failure to comply with recommendations. We conclude that use of most preventive services among elderly urban AI/ANs is suboptimal and should be improved.

Physical abuse of urban Native Americans.

To ascertain the extent of, and risk factors for, physical abuse among older urban American Indian/Alaska Natives (AI/ANs), we conducted a chart review of 550 urban AI/AN primary care patients >/=50 years old seen during 1 year. Mistreatment was documented in 10%. A logistic regression found younger age (P <.001), female gender (P <.001), current depression (P <.001), and dependence on others for food (P <.05) to be significant correlates of physical abuse. In only 31% of instances of definite abuse were the authorities notified. We conclude that providers should be alert to the possibility of physical mistreatment among older urban AI/ANs. Improvements in detection and management are sorely needed.

Influenza and pneumococcal vaccination among Native American elders in a primary care practice.

BACKGROUND: More than 2 million Native Americans (ie, Native Americans and Native Alaskans) live in the United States; 60% reside in cities. This population, especially its elders, is especially susceptible to respiratory diseases; yet, adherence to guidelines for influenza and pneumococcal immunizations is unknown. OBJECTIVES: To evaluate how frequently older and high-risk adults received vaccinations for influenza and pneumococcal infection and to identify patient characteristics associated with adherence to published recommendations. METHODS: Retrospective medical record review of 550 Native American elders seen in an urban primary care practice defined using a culturally appropriate age threshold (> or =50 years) and standard criteria (> or =65 years). Univariate analyses examined demographic and clinical information by vaccination status. Logistic regressions identified factors associated with adherence to immunization guidelines. RESULTS: Among patients aged 50 years and older with any indication according to published recommendations, rates were low for influenza (31%) and pneumococcal (21%) immunizations. Likewise, few subjects at least 65 years of age had been immunized appropriately against influenza (38%) or pneumococcus (32%). Younger age and alcohol use were significantly associated with less frequent immunization; Medicare insurance, depression, and more health problems and taking more medications predicted significantly higher immunization rates. Aged 65 years or older and having cardiovascular disease or diabetes mellitus were specific indications significantly correlated with receipt of influenza and pneumococcal vaccine. CONCLUSIONS: Regardless of age or risk, inadequate vaccination rates were observed in elderly Native Americans. Our findings suggest the need to identify obstacles to immunization and to conduct prospective and elderly intervention studies in Native American populations.

Modulation of NF-kappa B activity and apoptosis in chronic lymphocytic leukemia B cells.

Chronic lymphocytic leukemia (CLL) is an indolent malignancy of CD5+ B lymphocytes. CLL cells express CD40, a key regulator of B cell proliferation, differentiation, and survival. In nonmalignant B cells, CD40 ligation results in nuclear translocation and activation of NF-kappaB proteins. Based on observations that in some CLL cases, the tumor cells express both CD40 and its ligand, CD154 (CD40 ligand), we proposed a model for CLL pathogenesis due to CD40 ligation within the tumor. To evaluate this issue, we used freshly isolated CLL B cells to examine constitutive and inducible NF-kappaB activity by electrophoretic mobility shift assay. We consistently observed high levels of nuclear NF-kappaB-binding activity in unstimulated CLL B cells relative to that detected in nonmalignant human B cells. In each case examined, CD40 ligation further augmented NF-kappaB activity and prolonged CLL cell survival in vitro. The principle NF-kappaB proteins in stimulated CLL cells appear to be quite similar to those in nonmalignant human B cells and include p50, p65, and c-Rel. In a CD154-positive case, blocking CD154 engagement by mAb to CD154 resulted in inhibition of NF-kappaB activity in the CLL cells. The addition of anti-CD154 mAb resulted in accelerated CLL cell death to a similar degree as was observed in cells exposed to dexamethasone. These data indicate that CD40 engagement has a profound influence on NF-kappaB activity and survival in CLL B cells, and are consistent with a role for CD154-expressing T and B cells in CLL pathogenesis. The data support the development of novel therapies based on blocking the CD154-CD40 interaction in CLL.

The use of balloon-expandable metallic stents in the treatment of pediatric tracheomalacia and bronchomalacia.

OBJECTIVE: To evaluate the use of balloon-expandable metallic stents in the treatment of children with tracheomalacia and bronchomalacia in whom conventional therapy has failed. DESIGN: Retrospective case series. SETTING: Tertiary pediatric otolaryngology and cardiothoracic surgery referral center. PATIENTS: Six patients were identified as having undergone bronchoscopic placement of metallic balloon-expandable stents between 1994 and 1997. The age at stent placement, prior surgical interventions, and indications for and sites of stent placement were noted. Also, the complications related to stent placement and the current airway status of the patients were reviewed. INTERVENTIONS: Twelve balloon-expandable metallic angioplasty stents (Palmaz; Johnson & Johnson Interventional Systems Co, Warren, NJ) were placed bronchoscopically in 6 patients. Six stents were placed in the lower trachea, and 6 were placed in the main bronchi. The stents were balloon expanded under fluoroscopic guidance. MAIN OUTCOME MEASURE: Discontinuation of mechanical ventilation. RESULTS: The age at stent placement ranged from 1.5 to 38 months (mean age at placement, 10 months). The indications for stent placement were (1) tracheomalacia or bronchomalacia, (2) pericardial patch or slide tracheoplasty failure, and (3) bronchomalacia caused by tetralogy of Fallot and large pulmonary arteries. The primary complication of stent placement was postoperative granulation tissue formation. One patient required the removal of 2 tracheal stents because of granulation tissue formation. There were 2 deaths in the series, 1 possibly related to stent placement. Four of the 6 patients were weaned from mechanical ventilation, and 3 experienced prolonged relief of airway obstruction. CONCLUSIONS: Metallic balloon-expandable stents are effective in relieving lower tracheomalacia and bronchomalacia in select patients. Only patients in whom conventional therapy has failed should be considered for stent placement.

Estudio comparativo de los efectos psicológicos de la infertilidad en hombres y mujeres chilenos / Comparative study of the psychological effects of the infertility in chilean men and women

La infertilidad produce un fuerte desgaste emocional en las parejas que la padecen.Los efectos en la mujer han sido previamente estudiados, pero se desconoce la vivencia masculina de la infertilidad. El objtivo de este estudio fue comparar la reacción emocional de marido y mujer frente a su problema de infertilidad conyugal. Se evaluaron 107 parejas tratadas en dos centros de infertilidad (Policlínico y Programa de Fertilización in vitro) mediante un cuestionario. Se observó que las mujeres, en general, mostraron un mayor desajuste personal que sus maridos. Al considerar la procedencia, se vio que las parejas del Grupo Policlínico estaban más afectadas emocionalmente que las parejas del Grupo de Fertilización in vitro. Al ajustar estas diferencias por: nivel de educación, duración de la relación de pareja, duración de la infertilidad y edad, se vio que la edad tuvo un efecto atenuante del desajuste emocional. Se comentan estos resultados en relación a la naturaleza de las terapéuticas médicas y a factores sociales

Recurrent coumadin-induced soft tissue necrosis resulting in mastectomy.

A 58-year-old woman developed Coumadin-induced necrosis of the left breast, resulting in a mastectomy. This patient had experienced an earlier episode of coumadin-induced necrosis that resolved spontaneously. The etiology of this rare complication is unknown. The literature has suggested that patients can be restarted on Coumadin without difficulty. This case and others in the literature suggest that this may not be true. Patients requiring long-term anticoagulation should be considered for other treatment modalities if they develop Coumadin-induced skin necrosis.

Divalent effects on cGMP-activated currents in excised patches from amphibian photoreceptors.

The light-sensitive current in photoreceptors is conducted by a single class of ion channels gated by the binding of multiple molecules of cytoplasmic cGMP. Both Na and Ca ions enter the outer segment through this channel and Ca behaves as a blocking ion, greatly reducing the influx of Na. Because intracellular Ca functions as the cytosolic messenger for light adaptation, and this channel is the major entry point for Ca into the outer segment, we seek a better understanding of the selectivity properties of the channel and how they affect intracellular Ca levels. In these studies, we added divalent cations to the cytoplasmic face of an excised patch at constant, symmetrical [Na]. Our results suggest a novel high-affinity divalent binding site at the internal face of the channel. At constant low levels of cGMP, the addition of 10-100 nM cytoplasmic Ca or Mg attenuated the current 5- to 10-fold. There is also a low-affinity site, midway through the transmembrane field; saturation of this site reduces the divalent-free current approximately 100-fold. The presence of a high-affinity cytoplasmic site raises the question of whether Ca regulates the photoreceptor current through a direct interaction with the channel perhaps altering the channel selectivity or kinetics.