Nishant Tageja

Bendamustine: something old, something new

BackgroundBendamustine (Treanda, Ribomustin) is a water-soluble, bifunctional chemotherapeutic agent that also has potential antimetabolite properties and only partial cross-resistance with other alkylators. Designed in 1963 and re-discovered in 1990s, this drug’s unique mechanism of action and favorable side-effect profile promise a major role in the management of lymphoproliferative disorders. Bendamustine has been designated as an orphan drug in the United States, conferring prolonged market exclusivity.ObjectiveThis article provides a comprehensive review of the data on efficacy and toxicity from trials investigating the use of bendamustine for the treatment of lymphoproliferative neoplasms. The pharmacology, pharmacokinetics, and pre-clinical studies with bendamustine are also reviewed.MethodsMEDLINE and Pubmed databases (1970–2010) were searched using the terms bendamustine, bendamustin, Treanda, Ribomustin, SDX-105, IMET-3393, and Cytostasan. All relevant articles were reviewed and references screened for additional articles. The databases of the American Society of Hematology (2004–2009) and the American Society of Clinical Oncology (1995–2009) were also searched for relevant abstracts.ResultsBendamustine induces a remission in more than three-fourths of patients with rituximab-refractory indolent B cell non-Hodgkin lymphoma (NHL). Combined with rituximab in vitro, bendamustine shows synergistic effects against various leukemia and lymphoma cell lines. Clinical trials supporting these results show that bendamustine plus rituximab is highly effective in patients with relapsed-refractory indolent lymphoma, inducing remissions in 90% or more and a median progression-free survival of 23–24xa0months. Bendamustine has been reasonably well tolerated in clinical trials with low propensity to induce alopecia.ConclusionsCombination of bendamustine and rituximab has the potential to become a new standard first-line treatment option for patients with FL, MCL, and indolent lymphomas. Results of ongoing trials will help to further elucidate the optimal role of bendamustine in indolent NHL.

Squamous cell cancer of the anal canal in HIV-infected patients receiving highly active antiretroviral therapy: a single institution experience.

Background:Human immunodeficiency virus (HIV)-infected patients are at increased risk for squamous cell carcinoma of the anal canal (SCCA) and the incidence of SCCA has increased in the era of highly active antiretroviral therapy. The outcome of SCCA in HIV-positive patients has not been evaluated in prospective trials and the published literature is limited to retrospective case series. The aim of this study is to describe the treatment, toxicity, and overall survival (OS) in patients with and without HIV infection. Methods:We performed a retrospective chart review of all patients treated for invasive SCCA at Karmanos Cancer Institute, Wayne State University from 1991 to 2007 and collected data regarding HIV status, demographics, stage at diagnosis, treatment, response to treatment, toxicity, and survival. Results:Forty-five patients with SCCA were identified, of whom 13 were HIV-positive and 32 were HIV-negative. HIV-positive patients were younger (median age, 45 vs. 57 years) and had a higher frequency of men (89% vs. 37%). Patients were balanced for presenting stage at diagnosis and rates of local recurrence were found to be similar between the 2 groups. HIV-positive patients were less likely to receive full dose chemoradiotherapy. Except for dermatitis, the incidence of grade 3 to 4 toxicities was similar in both groups. Median OS was 33.5 months for HIV-positive patients and 71.8 months for HIV-negative patients. Although limited by the small size of the study, the OS was not statistically significantly different by HIV status (P = 0.787). Conclusion:Although the HIV-positive patients received lower dose chemoradiotherapy, no major difference in local control or overall survival was observed.

Myonecrosis in Sickle Cell Anemia—Overlooked and Underdiagnosed

Medical literature detailing muscular complications of sickle cell anemia is sparse and limited to a few case-reports. Features consistent with myositis and myonecrosis are often overlooked and patients are inadequately treated, leading to unforeseen complications. We report an interesting case of sickle cell myonecrosis and review the existing literature on this subject.

Bendamustine: Safety and Efficacy in the Management of Indolent Non-Hodgkins Lymphoma

Bendamustine (Treanda, Ribomustin) was recently approved by the US Food and Drug Administration (FDA) for treatment of patients with rituximab refractory indolent lymphoma and is expected to turn into a frontline therapy option for indolent lymphoma. This compound with amphoteric properties was designed in the former Germany Democratic Republic in 1960s and re-discovered in 1990s with multiple successive well-designed studies. Bendamustine possesses a unique mechanism of action with potential antimetabolite properties, and only partial cross-resistance with other alkylators. Used in combination with rituximab in vitro, bendamustine shows synergistic effects against various leukemia and lymphoma cell lines. In clinical studies, bendamustine plus rituximab is highly effective in patients with relapsed-refractory indolent lymphoma, inducing remissions in 90% or more and a median progression-free survival of 23–24 months. The optimal dosing and schedule of bendamustine administration is largely undecided and varies among studies. Results of ongoing trials and dose-finding studies will help to further help ascertain the optimal place of bendamustine in the management of indolent NHL.

Hyperammonemic Encephalopathy: A Rare Presentation of Fibrolamellar Hepatocellular Carcinoma

Fibrolamellar carcinoma (FLC) is a rare malignant hepatocellular tumor of unknown etiology, arising almost exclusively from noninfected, noncirrhotic liver of young adults. FLC has traditionally been considered to have better survival than hepatocellular carcinoma; however, this notion might be highly erroneous. Patients with metastatic disease at presentation have a dismal prognosis with 5-year survival of only 15%. We describe a case of highly aggressive metastatic FLC that presented as hyperammonemic encephalopathy, which has never been previously reported in the literature.

New targets for the treatment of follicular lymphoma

The last two decades have witnessed striking advances in our understanding of the biological factors underlying the development of Follicular lymphoma (FL). Development of newer treatment approaches have improved the outlook for many individuals with these disorders; however, with these advances come new questions. Given the long-term survival of patients with FL, drugs with favourable side-effect profile and minimal long-term risks are desired. FL is incurable with current treatment modalities. It often runs an indolent course with multiple relapses and progressively shorter intervals of remission. The identification of new targets and development of novel targeted therapies is imperative to exploit the biology of FL while inherently preventing relapse and prolonging survival. This review summarizes the growing body of knowledge regarding novel therapeutic targets, enabling the concept of individualized targeted therapy for the treatment of FL.

Precursor T Cell Acute Lymphoblastic Lymphoma Presenting as Bilateral Facial Nerve Palsy

was 14.3 g/dl with leukocyte count 9.7 ! 10 3 /ml (normal differential), and platelets 277 ! 10 3 /ml. Urinalysis and blood chemistry tests were normal, as were the electrocardiogram, cranial CT and MRI scans. Serum protein immunoelectrophoresis and serum angiotensin-converting enzyme were normal. Autoantibody screen and extensive serological testing for varied Peripheral cranial nerve palsies usually have a benign cause. However, bilateral facial palsy is an extremely rare clinical entity and may have diverse etiologies. Occasionally it can be the presenting symptom of an occult systemic disease and present a considerable diagnostic dilemma. It is, therefore, important that clinicians are aware of the differential diagnosis when evaluating a case. We describe the first reported case of precursor T cell acute lymphoblastic lymphoma (LBL) presenting as bilateral facial nerve palsy, which was treated using the CALGB 8811 regimen in conjunction with intensive administration of intrathecal methotrexate.

Aprepitant for prevention of nausea and vomiting secondary to high-dose cyclophosphamide administered to patients undergoing autologous peripheral blood stem cells mobilization: a phase II trial

This is a phase II trial evaluating efficacy and safety of aprepitant (AP) in combination with 5-HT3 antagonist and adjusted dose dexamethasone in patients receiving high-dose cyclophosphamide (CY) and filgrastim for stem cell mobilization. We used Simon’s optimal two-stage design constrained to fewer than 40 patients with 10% type I error and 85% statistical power. The first stage of the study required accrual of 18 response-evaluable patients. The primary endpoint was the control of vomiting without the use of any rescue anti-emetics at 24xa0h after the administration of high dose CY (4xa0g/m2). If emesis was controlled in ≥9 patients, an additional cohort of 17 patients would be enrolled. The null hypothesis would be rejected if there were ≥20 responses among 35 patients. Forty patients were enrolled, five of whom were not evaluable for response. Eighteen evaluable patients were enrolled in the first stage. Acute emesis was controlled in 10 patients; therefore, enrollment proceeded to stage 2. An additional 17 patients were enrolled; 20/35 response-evaluable patients (57%) did not develop acute vomiting or require rescue anti-emetics, thus achieving the goal of the study. A total of 22/35 response-evaluable patients (63%) met the secondary endpoint of delayed emesis control (days 2–5). Thirty-three out of 35 patients underwent successful stem cell mobilization. Nou2009≥u2009grade 3 AP-related adverse events were noted. The AP regimen can effectively control acute and delayed emesis in the majority patients receiving high-dose CY.

Prognostic indicators for Ewing's sarcoma

Hagan Klieb and colleagues, April 3, p 1224) describe a case of primary maxillary Ewing’s sarcoma. Although they have done a fi ne job at presenting the case, a couple of points mentioned in the discussion might need attention. Klieb and colleagues describe the two most important prognostic indicators of Ewing’s sarcoma to be “metastasis/stage and tumour volume/ resectability”. Although large tumours have typically been associated with a worse prognosis, this attribute could be less important given the more aggressive treatment used over the past decade or so. For example, in the early St Jude studies, tumours greater than 8 cm were associated with a worse prognosis. However, tumour size has disappeared as a prognostic factor in the more intensive EW92 protocol. In the absence of more standardised criteria for assess ment of tumour size (longitudinal vs volumetric measurements), the value of volume as a prognostic factor will be imperfect. The most important prognostic factor remains the presence of metastatic disease at diagnosis; advances in the treatment of Ewing’s sarcoma have resulted in only modest improvement in the outcomes of this subset of patients. A newer prognostic factor gaining interest in recent years has been the degree of histological response to chemotherapy, the signifi cance of which stands across protocols and seems to be independent of the drugs used. Patients with good histological responses have had a signifi cantly better outcome than those with poor responses in con secutive Italian and German studies.

Multidrug-resistant tuberculosis in India

682 www.thelancet.com Vol 376 August 28, 2010 An average delay of 5 months in obtaining a laboratory diagnosis of MDR tuberculosis was noted in a study at an academic institution with a well established DOT infrastructure in New Delhi, suggesting that many patients are dying while awaiting diagnosis. An average delay of 3·3 months was noted in initiating treatment after establishing the diagnosis, which, in turn, implies an ongoing transmission of infection to others and serves as another indicator of the failure of the Revised National Tuberculosis Control Programme. Morankar and Deshmukh reported that patients make on average one to nine visits to diverse health providers, before as well as after diagnosis. Misuse of antimicrobials in the form of incorrect doses (overprescribing, extravagant prescribing, underprescribing) is prevalent in regional health centres. The prospect of further amplifi cation of resistance associated with clinical deterioration and erratic treatment strategies, and death due to delayed initiation of adequate management cannot be overlooked. The availability of eff ective drugs can do no good in the face of dysfunctional DOTS-Plus programmes. If the state of aff airs in the national capital is as jeopardised as it seems, the condition of primary health centres in the country’s periphery is anybody’s guess. Rapid diagnosis and successful treatment of MDR tuberculosis would demand training of health personnel in the use of all frontline and all six classes of secondline drugs, a standard laboratory facility in every state of the country, and appropriate management of patients with standardised, empirical, and individual regimens.