Phase II study of imatinib‐based chemotherapy for newly diagnosed BCR‐ABL‐positive acute lymphoblastic leukemia

This study investigated the efficacy of imatinib based therapy with intensified consolidation therapy in patients with Philadelphia chromosome (Ph)‐positive acute lymphoblastic leukemia (ALL) to prevent early relapse. We conducted a phase II trial of imatinib‐combined chemotherapy for newly diagnosed BCR‐ABL‐positive ALL in adults. Sixty‐eight patients were included in the trial between October 2008 and December 2010. The median age was 49 years, with 28 patients >55 years of age. Sixty‐five patients achieved CR (95.6%). The estimated 2‐year event‐free survival (EFS) and overall survival (OS) were 62.3% and 67.4%, respectively. Allogeneic stem cell transplantation (allo‐SCT) at initial CR was performed in 43 patients. Thirty‐five of 39 patients <55 years and 8 of 26 patients >55 years underwent allo‐SCT at first CR. The 3‐year OS in patients <55 years receiving allo‐SCT at first CR, patients >55 years receiving allo‐SCT at first CR, patients <55 years not receiving allo‐SCT at first CR, and patients >55 years not receiving allo‐SCT at first CR were 80.4%, 41.1%, 32.5%, and 52.0%, respectively (P = 0.058). The three‐year EFS in each group was 76.7%, 53.6%, not reached, and 26.4%, respectively (P = 0.150). A high CR rate was observed with imatinib‐based chemotherapy allowing allo‐SCT in a high proportion of patients, particularly those <55 years. Moreover, intensified consolidation therapy reduced early relapse rates following induction therapy and resulted in improved OS and EFS rates following allo‐SCT. This trial was registered with the UMIN (000001226).     

Characteristics and risk factors of lymphoproliferative disorders among patients with rheumatoid arthritis concurrently treated with methotrexate: a nested case-control study of the IORRA cohort

The purpose of the study is to demonstrate the characteristics of lymphoproliferative disorders (LPDs) in patients with rheumatoid arthritis (RA) and risk factors for LPD among RA patients concurrently treated with methotrexate (MTX). Among patients who participated in the Institute of Rheumatology, Rheumatoid Arthritis (IORRA) cohort study in October 2010, past existence of LPD from patient’s report was confirmed through medical charts. Background factors, LPD pathological findings, and the clinical courses of LPD and RA after LPD were assessed. To analyze the risk of MTX-associated LPD among RA patients concurrently treated with MTX, a nested case-control study design was used to select control patients who had received MTX but did not develop LPD by matching calendar date, sex, and age (within 5 years) at a 1:10 ratio. Odds ratios (ORs) with 95% confidence intervals (95% CIs) for occurrence of LPD were analyzed by multivariate analysis. Forty-eight patients experienced LPD among 5757 patients, and 25 (52.1%) of those had lymphoma. LPD regressed in 60.4% of all LPD patients and 24.0% of lymphoma patients. In the 26 cases who developed LPD during MTX treatment, multivariate analysis revealed that 28-joint disease activity score (DAS28) (OR 1.57 [95% CI, 1.12–1.57]; p < 0.01) and lactate dehydrogenase (LDH) level (OR 1.01 [95% CI, 1.00–1.02]; p < 0.01), but not concomitant dose of MTX, were risk factors for LPD. Among RA patients concomitantly treated with MTX, high disease activity, but not MTX dose, was a risk factor for the occurrence of LPD.     

Fatal submucosal invasive gastric adenosquamous carcinoma detected at surveillance after gastric endoscopic submucosal dissection

An 80-year-old man was under annual surveillance esophagogastroduodenoscopy after endoscopic submucosal dissection(ESD) for early gastric cancer(EGC).Two years after the initial ESD, a 0-Ⅱc type metachronous EGC lesion, 8 mm in size, without an ulcer scar, was found in the gastric antrum.The estimated tumor depth was up to the mucosa, and biopsy revealed well and poorly differentiated adenocarcinoma.ESD was performed for this lesion and en bloc resection with negative margins was achieved.Histopathological examination revealed an adenosquamous carcinoma 8 mm in size invading the deep submucosal layer(1600 μm), with lymphovascular invasion, consistent with the diagnosis of non-curative resection.Additional gastrectomy was recommended for this patient; however, two months after the ESD, preoperative computed tomography revealed multiple liver metastases, and the patient was considered as an unsuitable candidate for surgical resection.Systemic chemotherapy was therefore started; however, the patient died of gastric cancer 27 mo after the second ESD.Early gastric adenosquamous carcinoma localized to the mucosa and submucosa is extremely rare and its clinical behavior is not well known.The present report is very significant in that it underscores the distinct possibility of gastric adenosquamous carcinoma being very aggressive and fatal even when detected at an early cancer.     

Ibudilast, a mixed PDE3/4 inhibitor, causes a selective and nitric oxide/cGMP-independent relaxation of the intracranial vertebrobasilar artery

Ibudilast, a mixed phosphodiesterase (PDE) 3/4 inhibitor, is a cerebral vasodilator widely used in Japan for treating post-stroke dizziness. However, little studies have been conducted on the vasorelaxant effects of PDE inhibitors in the vertebrobasilar artery associated with dizziness onset. The in vitro vasorelaxant properties of ibudilast were, therefore, investigated by comparing with known selective PDE inhibitors, using vertebrobasilar arteries. Vasorelaxant activities of PDE3, PDE4, PDE5 inhibitors, and ibudilast were assessed in 5-hydroxytryptamine precontracted ring preparations from rabbit intracranial and extracranial vertebrobasilar arteries. Ibudilast more selectively relaxed the intracranial than extracranial artery. Similarly, selective PDE3 and PDE4 inhibitors showed higher selectivity for intracranial arteries. Furthermore, like selective PDE4 inhibitor, the vasorelaxation by ibudilast accompanied by increase in cAMP levels was inhibited by the adenylyl cyclase inhibitor SQ22536 in intracranial arteries. Next, it was examined whether nitric oxide (NO)/cGMP signaling is involved in this vasorelaxation in intracranial arteries. The suppression of NO/cGMP signaling by an NO synthase inhibitor or a guanylyl cyclase inhibitor potentiated the vasorelaxion by a PDE3 inhibitor and reduced that by a PDE4 inhibitor, while either suppression of the signaling had little influence on that by ibudilast. These results suggest that ibudilast has the high vasoselectivity for intracranial artery based on a mixed PDE3 and PDE4-inhibition, and effectively relaxes intracranial arteries independently of NO/cGMP signaling because of its vasorelaxation compensated by either PDE3- or PDE4-inhibition depending on the state of NO/cGMP signaling change.     

Neurochemical mechanisms of a novel Alzheimer's disease therapeutics on improvement of cognition and depressive behavior

Loss of cholinergic neurons and/or dysfunction of the glutamatergic system in the central nervous system cause learning impairment in experimental Alzheimer's (Alz) disease animals and Alz patients. Furthermore, the impaired cholinergic system is likely implicated in depressive behaviors in Alz patients. Neurogenesis persistently occurs in the forebrain subventricular zone (SVZ) and hippocampal subgranular zone (SGZ) in rodent and human brains. Notably, impaired neurogenesis in those regions is implicated not only in memory deficits but also in depressive behaviors. We have recently found that olfactory bulbectomized (OBX) mice reveal memory impairment and depressive behaviors. Using this attractive OBX mice model, we discovered a novel cognitive enhancer, spiro[imidazo[1,2-a]pyridine-3,2-indan]-2(3H)-one (ZSET1446/ST101), that is a new azaindolizinone derivative without inhibitory action on acetylcholine esterase (AChE). Interestingly, ZSET1446 improved learning and memory by potentiating nicotine-induced ACh release in the hippocampus of amyloid-beta infused rats. In addition, ZSET1446 restored OBX-induced cognitive deficits in mice. Furthermore, chronic ZSET1446 administration significantly rescues decreased neuronal precursor cell proliferation seen in the dentate gyrus of OBX mice. Consistent with enhanced neurogenesis, chronic ZSET1446 administration improved depressive behavior assessed using the tail suspension test in OBX mice. Protein kinase B (Akt) and extracellular signal-regulated kinase pathways likely mediate ZSET1446-induced neurogenesis. These results suggest that ZSET1446 action via stimulation of the cholinergic system elicits improvement of the depression and cognitive impairment observed in Alz disease patients.     

Erlotinib after gefitinib failure in relapsed non-small cell lung cancer: clinical benefit with optimal patient selection

Background

Recent reports have suggested that erlotinib therapy after gefitinib failure requires optimal patient selection to obtain clinical benefits in relapsed non-small cell lung cancer (NSCLC). However, insufficient evidence exists to determine which clinical factors best identify patients who benefit from erlotinib therapy.

Methods

One hundred twenty-five patients with relapsed NSCLC who had received erlotinib therapy after gefitinib failure were retrospectively evaluated between January 2008 and May 2009.

Results

The response rate (RR), disease control rate (DCR), and median progression-free survival (PFS) for all patients were 9% (95% confidence interval [CI], 5-15%), 44% (95% CI, 35-53%), and 2.0 months (95% CI, 1.4-2.5 months), respectively. The median survival time was estimated to be 11.8 months (95% CI, 6.4-16.0 months). Using multivariate analysis, good performance status (PS), EGFR mutation-positive status, and benefit from prior gefitinib therapy were identified as significant predictive factors for disease control. Using a proportional hazards model, benefit from prior gefitinib therapy, good PS, and insertion of cytotoxic chemotherapies between gefitinib and erlotinib therapies emerged as significant predictive factors for longer PFS. Thirty-two patients with concomitant PS 0/1, benefit from prior gefitinib therapy, and insertion of cytotoxic chemotherapies between gefitinib and erlotinib therapies benefitted more from erlotinib therapy: RR, 25% (95% CI, 12-43%); DCR, 72% (95% CI, 53-86%); and median PFS, 3.4 months (95% CI, 2.4-4.9 months).

Conclusions

Higher efficacy of erlotinib after gefitinib failure can be achieved with proper patient selection criteria, including good PS, benefit from prior gefitinib therapy, and insertion of cytotoxic chemotherapies between gefitinib and erlotinib therapies.