Combined treatment with arsenic trioxide and all-trans-retinoic acid in patients with relapsed acute promyelocytic leukemia.

PURPOSE: Arsenic trioxide (ATO) is capable of inducing a high hematologic response rate in patients with relapsed acute promyelocytic leukemia (APL). Preclinical observations have indicated that all-trans-retinoic acid (ATRA) may strongly enhance the response to ATO. PATIENTS AND METHODS: Between 1998 and 2001, we conducted a randomized study of ATO alone versus ATO plus ATRA in 20 patients with relapsed APL, all previously treated with ATRA-containing chemotherapy. The primary objective was to demonstrate a significant reduction in the time necessary to obtain a complete remission (CR) in the ATO/ATRA group compared with the ATO group. Secondary objectives were safety and molecular response. RESULTS: The CR rate after one ATO with or without ATRA induction cycle was 80%. Clinical and pharmacokinetic observations indicated that the main mechanism of action of ATO in vivo was the induction of APL cell differentiation. Hematologic and molecular response, time necessary to reach CR, and outcome were comparable in both treatment groups. Of 16 CR patients, three patients who reached a molecular remission after one induction cycle had all received chemotherapy for a treatment-induced hyperleukocytosis. Three additional patients who received further additional ATO with or without ATRA cycles converted later to molecular negativity. CONCLUSION: ATRA did not seem to significantly improve the response to ATO in patients relapsing from APL. Other potential combinations, including ATO plus chemotherapy, have to be tested.     

Semimonthly versus monthly regimen of fluorouracil and leucovorin administered for 24 or 36 weeks as adjuvant therapy in stage II and III colon cancer: results of a randomized trial.

PURPOSE: This randomized, 2 x 2 factorial study compared a semimonthly (LVFU2) with a monthly (FULV) regimen of fluorouracil and leucovorin and 24 versus 36 weeks of each regimen as adjuvant treatment of patients with stage II (Dukes' B2) and III (Dukes' C) colon cancer. PATIENTS AND METHODS: LVFU2 was administered semi-monthly for 2 consecutive days as dl- or l-leucovorin (200 or 100 mg/m2, respectively) as a 2-hour infusion, followed by a 400 mg/m2 FU bolus and 600 mg/m2 of FU as a 22-hour continuous infusion. FULV was administered monthly for 5 consecutive days as a 15-minute infusion of dl- or l-leucovorin, followed by 400 mg/m2 of FU as a 15-minute infusion. RESULTS: A total of 905 patients were randomly assigned. The median follow-up was 41 months. Disease-free survival was similar between the LVFU2 and FULV groups (127 v 124 events; hazard ratio [HR] = 1.04; P =.74) and between 24 and 36 weeks of therapy (128 v 123 events; HR = 0.94; P =.63). Analysis of overall survival showed a slight excess in the number of deaths in LVFU2 compared with FULV (73 v 59), but this difference was not statistically significant (HR = 1.26; 95% confidence interval, 0.90 to 1.78; P =.18). The most commonly observed grade 3 to 4 toxicities were neutropenia, diarrhea, and mucositis. Toxicities were significantly lower in the LVFU2 group (all toxicities, P <.001). CONCLUSION: Our data confirm that LVFU2 is less toxic than FULV. At a median follow-up of 41 months, no statistically significant difference could be detected in disease-free or overall survival between the treatment groups or treatment durations.     

CT-based delineation of lymph node levels and related CTVs in the node-negative neck: DAHANCA, EORTC, GORTEC, NCIC,RTOG consensus guidelines.

BACKGROUND AND PURPOSE: The appropriate application of 3-D CRT and IMRT for HNSCC requires a standardization of the procedures for the delineation of the target volumes. Over the past few years, two proposals--the so-called Brussels guidelines from Grégoire et al., and the so-called Rotterdam guidelines from Nowak et al.--emerged from the literature for the delineation of the neck node levels. Detailed examination of these proposals however revealed some important discrepancies. MATERIALS AND METHODS: Within this framework, the Brussels and Rotterdam groups decided to review their guidelines and derive a common set of recommendations for delineation of neck node levels. This proposal was then discussed with representatives of major cooperative groups in Europe (DAHANCA, EORTC, GORTEC) and in North America (NCIC, RTOG), which, after some additional refinements, have endorsed them. The objective of the present article is to present the consensus guidelines for the delineation of the node levels in the node-negative neck. RESULTS AND CONCLUSIONS: First a short discussion of the discrepancies between the previous Brussels and the Rotterdam guidelines is presented. The general philosophy of the consensus guidelines and the methodology used to resolve the various discrepancies are then described. The consensus proposal is then presented and representative CTVs that are consistent with these guidelines are illustrated on CT sections. Last, the limitations of the consensus guidelines are discussed and some concerns about the direct applications of these guidelines to the node-positive neck and the post-operative neck are described.     

Estrogen receptor negative and progesterone receptor positive primary breast cancer: Pathological characteristics and clinical outcome

The expression of estrogen (ER) and progesterone (PgR) receptors was analyzed in a retrospective series of 3000 patients who had operable primary breast cancer. Patients were stratified according to ER and PgR status and the study was focused on the two groups (ER–PgR+ and ER–PgR–) of patients whose tumors contained low levels of ER (< 15 fmol/mg protein), regarding potential response to endocrine therapy. The comparison of clinical or histological characteristics between ER–PgR+ and ER–PgR– patients was analyzed as well as the disease-related death and survival. The mean follow-up was 86.3 months. Among the 529 ER–patients, 62 were PgR+ (12%), whereas 467 were PgR– (88%). The ER–PgR+ and ER–PgR– populations represented 2% and 15.6% of the overall population, respectively. In ER– tumors, the PgR status was significantly related to: age, menopausal status, tumor size, SBR grade, and histological type, but not to the type of surgical treatment or to lymph node involvement. ER–PgR+ tumors had smaller size (64% T1 vs 43%) (p=0.004) and were more frequently grade I (28% vs 12%) than ER–PgR– ones (p < 0.001). In addition, the patients with ER–PgR+ tumors were significantly younger (49.4 years vs 58.4 years; p < 0.0001), and were more frequently premenopausal (76% vs 36%; p < 0.001). The disease-free interval and the metastasis-free survival tended to be worse for ER–PgR– than for ER–PgR+ patients, but the difference was not statistically significant at 10 years. However, a small but significant difference in overall survival, in favor of the PgR+ group, was observed between the two groups during the first 5 years (p=0.03).We conclude that in combination with ER, PgR status defines a group of patients with clinical and biological specificity, which could be considered for specific endocrine therapy.     

Characterization of T cell receptors reactive to HCRTNH2, pHA273-287, and NP17-31 in control and narcolepsy patients

Narcolepsy type 1 (NT1), a disorder caused by hypocretin/orexin (HCRT) cell loss, is associated with human leukocyte antigen (HLA)-DQ0602 (98%) and T cell receptor (TCR) polymorphisms. Increased CD4⁺ T cell reactivity to HCRT, especially DQ0602-presented amidated C-terminal HCRT (HCRT_NH2), has been reported, and homology with pHA_273–287 flu antigens from pandemic 2009 H1N1, an established trigger of the disease, suggests molecular mimicry. In this work, we extended DQ0602 tetramer and dextramer data to 77 cases and 44 controls, replicating our prior finding and testing 709 TCRs in Jurkat 76 T cells for functional activation. We found that fewer TCRs isolated with HCRT_NH2 (∼11%) versus pHA_273–287 or NP_17–31 antigens (∼50%) were activated by their ligand. Single-cell characterization did not reveal phenotype differences in influenza versus HCRT_NH2-reactive T cells, and analysis of TCR CDR3αβ sequences showed TCR clustering by responses to antigens but no cross-peptide class reactivity. Our results do not support the existence of molecular mimicry between HCRT and pHA_273–287 or NP_17–31.

Narcolepsy type 1 (NT1) is caused by a loss of hypocretin/orexin (HCRT) neurons in the mediolateral hypothalamus (1–3), with recent data suggesting reversion of the human and animal phenotype with orexin agonists. The disease is strongly associated with human leukocyte antigen (HLA) DQB1*06:02/DQA1*01:02 (98% vs. 25%) (DQ0602) and displays weaker genetic associations with other immune loci, thus suggesting autoimmunity (4–9), although not meeting all criteria for being classified as an autoimmune disease (10). Like other autoimmune diseases, NT1 presents with increased comorbidity with other autoimmune conditions and asthma (11–13).Onset of NT1 is often abrupt and seasonal, and association with both Streptococcus pyogenes (14, 15) and influenza A infections (16) suggests that it may be triggered by winter infections. Most strikingly, prevalence of NT1 increased several folds in mainland China and Taiwan following the 2009 to 2010 “swine flu” H1N1 influenza pandemic (pH1N1) (4, 17, 18), although association with the pandemic is less clear in other countries (19). Vaccination with the pH1N1 vaccine Pandemrix has also been associated with an elevated relative risk for developing narcolepsy of 5- to 14-fold in children and adolescents and 2- to 7-fold in adults (18, 20–22). As Pandemrix is an AS03-adjuvanted vaccine containing the artificially produced reassortant strain X-179A, a mix of A/Puerto Rico/8/1934 (PR8), an old H1N1 strain derived from pre-2009 seasonal H1N1, and the key H1N1 2009 surface proteins hemagglutinin (HA) and neuraminidase (NA) (23), flu proteins are likely critically involved in triggering NT1. Evidence showing that HLA and T cell receptor (TCR) genetic associations are universal (9, 24–27) is also consistent with a flu trigger, as influenza A infections occur on a global basis (28). Importantly, however, even with Pandemrix vaccination in Europe, only ∼1 in 16,000 vaccinated children developed NT1, thus demanding the consideration of additional factors to fully explain the initiation of NT1 (29).Unlike in other autoimmune diseases, autoantibodies against HCRT cell proteins, HCRT itself (30–32), or other targets such as TRIB2 (33, 34) or HCRT receptor 2 (35–38) have not been consistently found. This has led to the suggestion that HCRT cell loss may be primarily T cell mediated, with limited or no involvement of autoantibodies. Consistent with this hypothesis, mounting evidence suggests involvement of CD4⁺ T cell reactivity to HCRT in NT1 (39–41), notably toward amidated fragments of the secreted, mature peptide (HCRT_54–66-NH2 and HCRT_86–97-NH2, homologous peptides collectively denoted as HCRT_NH2) (42), as critical factors in the development of the disease. Furthermore, CD8⁺ mediation of HCRT cell death has also been shown to cause NT1 in an animal model (43) and Pedersen and colleagues (44) recently highlighted the presence of CD8⁺ T cell responses against intracellular proteins contained in HCRT neurons in narcolepsy patients. Of additional interest is the observation that the TCR polymorphisms associated with NT1 are quantitative trait loci for TRAJ24 (decreasing), TRAJ28, and TRBV4-2 (increasing) usage in peripheral T cells in both controls and patients (29). A significant L to F coding polymorphism located within the antigen-binding complementarity-determining region (CDR) 3 loop of TRAJ24 expressing TCRs is also associated with NT1. Altogether, this suggests that T cell responses involving TRAJ24- or TRAJ28- and TRBV4-2–bearing TCRs may be bottleneck responses in a causative autoimmune T cell response, leading to HCRT cell death (4, 14, 17–19, 45).Based on the evidence provided above, our group hypothesized that a CD4⁺ T cell–mediated response directed against specific flu epitopes could lead to molecular mimicry with HCRT itself, potentially HCRT_NH2, subsequently recruiting CD8⁺ cytotoxic T cells and leading to HCRT cell death. To test this hypothesis, we screened 135 DQ0602 tetramers binding peptides originating from Pandemrix, wild-type 2009 H1N1, and two autoantigens (HCRT and RFX4) for the presence of antigen-restricted CD4⁺ T cells (42). After this systematic survey, it was established that CD4⁺ T cell populations recognizing influenza pHA_273–287 (pH1N1 specific) and PR8 (H1N1 pre-2009 and H2N2)-restricted NP_17–31 epitopes were increased in NT1 versus DQ0602 controls. Supporting this finding, this difference was also present in post-Pandemrix cases versus controls and was stronger in recent onset cases (42). Additionally, studies of single cells recognizing these peptides revealed that TCR clones carrying TRBV4-2 and TRAJ24 were retrieved from both HCRT_NH2 and pHA_273–287 tetramers (42), suggesting involvement of these clones in molecular mimicry and disease pathophysiology. Similarly, Jiang et al. (39) isolated TRAJ24-positive cells recognizing DQ0602 bound to HCRT_87–100 tetramer, many of which expressed perforin and granzyme-B, suggesting a terminally differentiated effector T cell (T_EMRA) phenotype. In one case, a TRAJ24 clone isolated from a narcoleptic patient showed elevated TCR reactivity toward HCRT_87–97-NH2 when transfected in Jurkat 76 (J76) cells, thus implying a role for TRAJ24 reactivity toward DQ0602-HCRT in narcolepsy autoimmunity (39).Here, we extend prior work from our group by doubling the number of patients and controls and increasing the representation of TRAJ24F narcolepsy susceptibility–associated alleles in these subjects. Results validated an increased frequency of pHA_273–287 and HCRT_54–66-NH2 tetramer-positive CD4⁺ T cells in NT1, while also testing isolated T cell clones for potential activation by their cognate ligands when expressed in J76 cells. Importantly, we also analyzed TCR CDR3αβ sequences in this larger dataset and conducted expression profiling of the corresponding T cells, providing insights into T cell characteristics in narcolepsy.     

Effect of hepatic impairment on the pharmacokinetics of pasireotide (SOM230): results from a multicenter phase I study

Pasireotide is a novel, multireceptor-targeted somatostatin analogue with high affinity for sst(1,2,3) and sst(5) under clinical evaluation in tumors of neuroendocrine origin, including Cushing's disease, acromegaly, and neuroendocrine tumors. In this phase I, open-label, multicenter study, the pharmacokinetics and safety of a single subcutaneous (SC) injection of pasireotide 600 μg were evaluated in adults with normal hepatic function (n = 15) and mild (n = 6), moderate (n = 7), or severe hepatic impairment (n = 6). Following a single dose of pasireotide SC 600 μg, there were no significant differences in the plasma exposure of pasireotide between participants with normal hepatic function or mild hepatic impairment. Subjects with moderate and severe hepatic impairment showed an increase in AUC(∞) by 56% and 42%, respectively; this increase was 60% and 79% respectively, after adjusting for differences in age, BMI, and baseline serum albumin level between treatment groups. The incidence and severity of adverse events were similar across cohorts, with no clinically relevant differences in type or frequency of adverse events between cohorts. In conclusion, a single dose of pasireotide SC 600 μg was well tolerated in subjects with hepatic impairment. Drug exposure in subjects with mild hepatic impairment was similar to that seen in healthy volunteers, whereas subjects with moderate and severe hepatic impairment experienced higher exposure to pasireotide. Adjustment of the pasireotide dose may be required for patients with moderate and severe hepatic impairment.     

Endometriosis-associated ileo-cecal perforation in a woman on the pseudopregnancy regimen

Small intestinal obstruction and perforation associated with endometriosis is uncommon. We report a similar effect following treatment with the combined oral contraceptive. Caution should be exercised when prescribing the combined oral contraceptive in women with suggested small intestinal endometriosis. Disease flare-up after therapy may be associated with intestinal obstruction and perforation.