High-dose cytosine arabinoside and daunorubicin as consolidation therapy for acute nonlymphocytic leukemia in first remission: a pilot study

High-dose (HD) cytosine arabinoside (ARA-C) is more effective treatment than conventional-dose ARA-C regimens for patients with relapsed acute nonlymphocytic leukemia (ANLL). We report here that HD ARA-C given during the first remission of ANLL has resulted in long remission durations and a high proportion of patients who survive more than three years free of disease. From August 1979 to September 1983, 36 adult patients with ANLL in first remission received one to three courses of HD ARA-C (3 g/m2 by one-hour infusion every 12 hours for 12 doses on days 1 through 6) alone or with daunorubicin (30 mg/m2 for two or three doses on days 7 through 9). Three patients died of sepsis or hemorrhage during consolidation, and 14 patients have relapsed from five to 48 months after diagnosis. The remaining 19 patients are in continued complete remission (CCR) from 11 to 62 months. Denoting all deaths in remission as relapse, the actuarial probability of CCR is 42% at 62 months, with an apparent plateau in the survival curve. Of the first 22 patients treated, ten remain in CCR from 37 to 62 months with no therapy for at least three years. Due to its heightened anti-leukemic activity, HD ARA-C allows brief but effective consolidation of ANLL in first remission, with long-term disease-free survival comparable to other approaches.     

Liver X receptors orchestrate osteoblast/osteoclast crosstalk and counteract pathologic bone loss

Osteoporosis is characterized by enhanced differentiation of bone‐resorbing osteoclasts, resulting in a rapid loss of functional trabecular bone. Bone‐forming osteoblasts and osteoblast‐derived osteocytes perform a key role in the regulation of osteoclast development by providing both the pro‐osteoclastogenic cytokine receptor activator of NF‐κB ligand (RANKL) and its natural decoy receptor osteoprotegerin (OPG). By regulating the RANKL/OPG ratio, osteoblasts hence determine the rate of both osteoclast differentiation and bone turnover. Here, we describe a novel role for liver X receptors (LXRs) during the crosstalk of bone‐forming osteoblasts and bone‐resorbing osteoclasts. By using a system of osteoblast/osteoclast cocultures, we identify LXRs as regulator of RANKL expression and the RANKL/OPG ratio in osteoblasts. Activation of LXRs drastically reduced the RANKL/OPG ratio and interfered with osteoblast‐mediated osteoclast differentiation in vitro. During an ovariectomy (OVX)‐induced model of postmenopausal osteoporosis, the application of an LXR agonist shifted the RANKL/OPG ratio in vivo, ameliorated the enhanced osteoclast differentiation, and provided complete protection from OVX‐induced bone loss. These results reveal an unexpected involvement of LXRs in the regulation of bone turnover and highlight a potential role for LXRs as novel targets in the treatment of osteoporosis and related diseases. © 2012 American Society for Bone and Mineral Research.     

Obturator Canal Lymph Node Metastasis from Rectal Carcinoid Tumors: Total Mesorectal Excision May Be Insufficient

Background

Optimal surgical treatment for small early rectal carcinoids is controversial. Large tumors (greater than 2 cm) and those with imaging evidence of lymph node metastasis are generally treated by low anterior resection (LAR) with total mesorectal excision (TME). We first observed and reported that midgut carcinoid with extensive mesenteric lymphadenopathy often develops alternated lymphatic drainage pathways. We hypothesize that rectal carcinoids have the same potential to develop alternated lymphatic pathways outside the mesorectal envelope, which allows tumor deposits to be missed by traditional TME.

Methods

Twenty-two consecutive rectal carcinoid surgical patient charts were reviewed to determine if alternated lymphatic drainage occurred and resulted in extra-mesorectal metastasis. We attempted to identify any risk factor(s) that may lead to developing such alternated lymphatic drainage pathways.

Results

Thirteen patients underwent initial LAR with TME (13/22, 59 %) and nine underwent a staged debulking for locoregional residual disease or regional/distant metastasis after previous resection (9/22, 41 %). Fourteen (14/22, 64 %) underwent radio-guided surgery in attempt to achieve a higher level of pelvic/distant metastatic disease detection and debulking. Six patients (6/22, 27 %) had obturator canal lymph node metastases confirmed histologically.

Conclusions

Based on our study, at least 27 % of rectal carcinoid patients may have extra-mesorectal metastasis that would be missed by the traditional TME. Radio-guided surgery can identify and remove such metastasis. The effect of having such extra-mesorectal metastasis and its surgical removal on long-term survival has yet to be determined.

     

Reduced frequencies and suppressive function of CD4+CD25hi regulatory T cells in patients with chronic lymphocytic leukemia after therapy with fludarabine

Globally suppressed T-cell function has been described in many patients with cancer to be a major hurdle for the development of clinically efficient cancer immunotherapy. Inhibition of antitumor immune responses has been mainly linked to inhibitory factors present in cancer patients. More recently, increased frequencies of CD4+CD25hi regulatory T cells (Treg cells) have been described as an additional mechanism reducing immunity. We assessed 73 patients with B-cell chronic lymphocytic leukemia (CLL) and 42 healthy controls and demonstrated significantly increased frequencies of cytotoxic T lymphocyte-associated protein 4 (CTLA4+)-, Forkhead box P3 (FOXP3+)-, glucocorticoid-induced tumor necrosis factor receptor-related protein (GITR+)-, CD62L+-, transforming growth factor beta1 (TGF-beta1+)-, interleukin 10 (IL-10+)-Treg cells in patients with CLL, with highest frequencies in untreated or progressing patients presenting with extended disease. Most surprisingly, in the majority of patients with CLL treated with fludarabine-containing therapy regimens the inhibitory function of Treg cells was decreased or even abrogated. In addition, frequencies of Treg cells were significantly decreased after therapy with fludarabine. In light of similar findings for cyclophosphamide the combination of fludarabine and cyclophosphamide might be further exploited in strategies reducing immunosuppression prior to cancer immunotherapy.     

Dominance of nonmalignant T-cell clones and distortion of the TCR repertoire in the peripheral blood of patients with cutaneous CD30+ lymphoproliferative disorders

The CD30-positive cutaneous lymphoproliferative disorders (CLPD) include lymphomatoid papulosis (LyP) and primary cutaneous anaplastic large T-cell lymphoma (cALCL). Despite the malign-appearing histology, an excellent prognosis and spontaneous regression of single lesions characterize LyP. Even after years of clinical remission newly erupting lesions often harbor a T-cell clone identical to the initial one. This fact raises the question whether the clonal T-cell population persists in the peripheral blood. Therefore we investigated genomic DNA of 126 samples of lesional skin and peripheral blood from 31 patients with CLPD, obtained during both active disease and clinical remission. We performed molecular genetic analysis by combining T-cell receptor (TCR)-gamma PCR with the GeneScan technique and assessed the TCR repertoire in selected blood samples by beta-variable complementarity-determining region 3 (CDR3) spectratyping qualitatively and quantitatively. We were able to detect a clonal T-cell population in 36/43 (84%) skin samples and in 35/83 (42%) blood samples. Comparison of the compartments in each patient demonstrated different T-cell clones in skin and blood, suggesting a reactive nature of the clonal T cells in the blood. Moreover, CDR3 spectratyping revealed a restricted T-cell repertoire in the blood, suggesting T-cell stimulation by an unknown antigen.     

精神分裂症患者血浆高香草酸浓度与临床症状、性别和药物治疗的关系

目的：通过分析精神分裂症患者中枢多巴胺代谢产物－血浆高香草酸浓度（ｐＨＶＡ）与临床指征的关系,进一步探讨多巴胺神经递质及其药物治疗在精神分裂症的作用。方法在４６例长期药物治疗、５８例未治疗精神分裂症患者中,采用高液相色谱连接电化学分析仪测定ＰＨＶＡ;测前评定阳性症状量表（ＳＡＰＳ）和阴性症状量表（ＳＡＮＳ）。结果（１）与６２例健康对照组比,治疗组ＰＨ－ＶＡ显著减低,未治疗组显著增高,以阴性症状组为     

Von der Funktionsstörung zur Funktionskrankheit

Background

Despite high acceptance of manual medicine and proven positive for diseases of the locomotor system in particular, it is not recognized by or established in academic medicine. The reason for this might be the lack of a defined therapeutic target. No other medical field is defined by the diagnosis and treatment of clinical findings (somatic dysfunction).

Methods

Based on an expert panel and relevant literature, somatic dysfunction, the development of functional diseases, and factors influencing their chronification are discussed and defined.

Results

The diagnostic and therapeutic target of manual medicine is the functional disease as well as the underlying primary and secondary somatic dysfunction. Functional diseases of the locomotor system are characterized by the following cardinal symptoms: pain and deficits in function, participation, and activities. Somatic dysfunctions are the result of a discrepancy between burden and endurance of the structure and/or tissues. Somatic dysfunctions precede functional diseases and are the basis thereof.

Discussion

In order to establish manual medicine in academic medicine, an accepted definition of functional diseases as diagnostic and therapeutic target is essential. Specific primary and secondary somatic dysfunctions are the cause for functional diseases and should therefore be diagnosed and treated. Other factors can also influence functional diseases and play an important role in their chronification. For chronic functional diseases, a multimodal interdisciplinary diagnosis is essential for the therapeutic strategy.

     

Differential Rate and Potassium-Dependent Effects of the Class III Agents d-Sotalol and Dofetilide on Guinea Pig Papillary Muscle

The class III agents d-sotalol and dofetilide have been shown to exhibit differential effects in large controlled clinical trials. The aim of this study was to investigate the basic electrophysiological properties of these two antiarrhythmia agents in an in vitro experimental model with regard to potential antiarrhythmic and proarrhythmic action. Using standard microelectrode techniques, we evaluated the electrophysiological effects of d-sotalol and dofetilide on action potential parameters recorded from guinea pig papillary muscle at 2.5 mM, 3.5 mM, and 5.6 mM extracellular potassium concentrations. The following parameters were recorded: resting membrane potential (RMP), action potential amplitude (APA), action potential duration at 90% repolarization (APD 90), and maximum upstroke velocity (Vmax). Under all conditions studied, both d-sotalol and dofetilide exhibited highly selective reverse rate-dependent class III action. In contrast to dofetilide, the class III activity of d-sotalol was markedly influenced by changes in extracellular potassium concentrations, predominantly at low pacing rates. Hypokalemia enhanced the action potential–prolonging effects of d-sotalol, whereas hyperkalemia diminished this effect. In addition, reverse rate dependence associated with dofetilide was significantly more pronounced than reverse rate dependence associated with d-sotalol. Our observations provide a potential electrophysiological basis for differential antiarrhythmic and proarrhythmic mechanisms associated with these two drugs.