'ACOPP' chemotherapy for older and less fit patients with Hodgkin lymphoma-A multicentre, retrospective study.

Management of classical Hodgkin lymphoma in older patients is challenging due to poor tolerance of the chemotherapy regimens used in younger patients. We modified the BEACOPP regimen (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine and prednisolone), whereby bleomycin and etoposide were removed and cyclophosphamide dose was reduced, for older patients with co-morbidities. Here we present data from the first 41 patients treated with 'ACOPP' across 3 centres, demonstrating that it can be delivered, with a favourable toxicity profile (TRM 2%) and promising efficacy (2-year PFS and OS, 73% (95% CI: 52-94) and 93% (95% CI: 80-100) respectively).

Rapidly progressive intravascular primary effusion lymphoma in an HIV-positive renal transplant recipient.

We describe the clinical and post-mortem findings of a case of rapidly progressive, ultimately fatal primary effusion lymphoma (PEL) arising in an HIV-positive man 2 years after renal transplantation. Disseminated multi-organ involvement associated with a peculiar intravascular pattern of growth, as seen in this case, has only been reported once previously. This is also, to our knowledge, the first detailed description of a lymphoma arising post-transplant in an HIV-positive patient.

NCRI phase II study of CHOP in combination with ofatumumab in induction and maintenance in newly diagnosed Richter syndrome.

Richter syndrome (RS) is associated with chemotherapy resistance and a poor historical median overall survival (OS) of 8-10 months. We conducted a phase II trial of standard CHOP-21 (cyclophosphamide, doxorubicin, vincristine, prednisolone every 21 d) with ofatumumab induction (Cycle 1: 300 mg day 1, 1000 mg day 8, 1000 mg day 15; Cycles 2-6: 1000 mg day 1) (CHOP-O) followed by 12 months ofatumumab maintenance (1000 mg given 8-weekly for up to six cycles). Forty-three patients were recruited of whom 37 were evaluable. Seventy-three per cent were aged >60 years. Over half of the patients received a fludarabine and cyclophosphamide-based regimen as prior CLL treatment. The overall response rate was 46% (complete response 27%, partial response 19%) at six cycles. The median progression-free survival was 6·2 months (95% confidence interval [CI] 4·9-14·0 months) and median OS was 11·4 months (95% CI 6·4-25·6 months). Treatment-naïve and TP53-intact patients had improved outcomes. Fifteen episodes of neutropenic fever and 46 non-neutropenic infections were observed. There were no treatment-related deaths. Seven patients received platinum-containing salvage at progression, with only one patient obtaining an adequate response to proceed to allogeneic transplantation. CHOP-O with ofatumumab maintenance provides minimal benefit beyond CHOP plus rutuximab. Standard immunochemotherapy for RS remains wholly inadequate for unselected RS. Multinational trials incorporating novel agents are urgently needed.

Catheter-related thrombosis in cancer patients.

Central venous catheters are commonly used in haematology departments for the administration of chemotherapy, blood products and parenteral nutrition in patients with haematological malignancy. Thrombosis is a recognized complication of such devices especially in oncology patients. Catheter-related thrombi (CRT) may lead to pulmonary embolism and infection, as well as catheter failure and potential delays in treatment. The vast majority of CRT are asymptomatic, thus a high index of suspicion is required in making the diagnosis. Doppler ultrasound or venography may be employed to identify CRT. Once confirmed, the initiation of treatment is a balance between the risks of anticoagulation against potential complications of CRT. A number of risk factors for CRT are discussed along with an overview of catheter types, their appropriate choice and intravascular positioning.

The number of cytomegalovirus-specific CD4+ T cells is markedly expanded in patients with B-cell chronic lymphocytic leukemia and determines the total CD4+ T-cell repertoire.

B-cell chronic lymphocytic leukemia is associated with immune suppression and an altered T-cell repertoire with expansion of memory cells. Cytomegalovirus (CMV) is a common herpes virus that elicits a strong virus-specific T-cell immune response after infection. We studied the CMV-specific CD4(+) T-cell response in 45 patients and 35 control subjects and demonstrated that it was markedly expanded in the patient group, averaging 11% of the CD4(+) pool compared with 4.7% in controls. The magnitude of the CMV-specific CD4(+) immune response increased with disease stage and was particularly high in patients who received chemotherapy. Within this group, the CMV-specific response comprised over 46% of the CD4(+) T-cell repertoire in some patients. Serial analysis revealed that CMV-specific immunity increased during treatment with chemotherapy and remained stable thereafter. CMV-seropositive patients exhibited a markedly altered CD4(+) T-cell repertoire with increased numbers of CD45R0(+) T cells and a reduction in CD27, CD28, and CCR7 expression. Overall survival was reduced by nearly 4 years in CMV-seropositive patients, although this did not reach statistical significance. CLL patients therefore demonstrate an expansion of the CD4(+) CMV-specific immune response, which is likely to contribute to the immunological and clinical features of this disease.

Combined bezafibrate and medroxyprogesterone acetate have efficacy without haematological toxicity in elderly and relapsed acute myeloid leukaemia (AML).

Acute myeloid leukaemia (AML) causes life-threatening deficits of functional blood cells that require management using red cell and platelet transfusion and aggressive treatment of neutropenic infections. Current cytotoxic chemotherapy further worsens the problem of reduced haemopoiesis and two-thirds of patients are too frail to tolerate intensive chemotherapy at all. Median survival amongst these patients remains at <3 months emphasizing the urgent need for anti-AML therapies that do not suppress haemopoiesis. Our laboratory studies showed combined Bezafibrate and Medroxyprogesterone acetate (BaP) had activity against AML without toxicity to normal stem cells. Here we report the safety and efficacy of BaP in 20 patients (19 AML, 1 high-risk myelodysplasia) for whom intensive chemotherapy was not an option. No patient exhibited haematological toxicity from BaP. Eleven patients took BaP alone for >4 weeks. One reverted from high risk myelodysplasia and remains transfusion independent after 201 weeks of therapy. Three AML patients gained major haematological improvements for 22-30 weeks; in one, marrow was available to document a partial AML response. Thus, this trial indicates that BaP therapy has potential for treatment of elderly and relapsed AML.

Single arm phase II trial assessing the safety, compliance with and activity of Bezafibrate and medroxyProgesterone acetate (BaP) therapy against myeloid and lymphoid cancers.

We previously reported the safety and efficacy of low dose BaP [Bezafibrate (Bez) and Medroxyprogesterone acetate (MPA)] in 20 acute myeloid leukaemia (AML) patients for whom chemotherapy was not an option. This study provided evidence that BaP had anti-AML activity and improved haemopoiesis; absence of haematological toxicity allowed continuous daily administration. Similarly a previous trial in endemic Burkitt lymphoma demonstrated anti-B cell lymphoma activity of low and high dose BaP again in the absence of toxicity. We conducted a study to further evaluate the safety and activity of high dose BaP therapy in adults with AML (and high risk Myelodysplastic Syndromes (MDS)), chronic lymphocytic leukaemia (CLL) or B-cell Non-Hodgkin Lymphoma (BHNL). Eighteen patients were recruited to the study over 20 months, 16 AML/MDS, 1 CLL, and 1 BNHL. Although MPA was well tolerated throughout the study, only 2 patients were able to tolerate Bez treatment for their whole trial duration, indicating that Bez escalation is not feasible in the setting of adult AML/MDS. Thus there has been no obvious benefit in improved haemopoiesis or overt anti-leukaemia activity from the attempts to escalate BaP dose over previous published studies. Since current therapeutic options in MDS are restricted it may be now of value to continue to evaluate low dose BaP based approaches in low risk MDS rather than AML/high risk MDS. Furthermore, screening of low dose BaP against libraries of other already available dugs may identify an addition to BaP that augments the anti-neoplastic efficacy without significant toxicity.

Aurora kinase inhibitor nanoparticles target tumors with favorable therapeutic index in vivo.

Efforts to apply nanotechnology in cancer have focused almost exclusively on the delivery of cytotoxic drugs to improve therapeutic index. There has been little consideration of molecularly targeted agents, in particular kinase inhibitors, which can also present considerable therapeutic index limitations. We describe the development of Accurin polymeric nanoparticles that encapsulate the clinical candidate AZD2811, an Aurora B kinase inhibitor, using an ion pairing approach. Accurins increase biodistribution to tumor sites and provide extended release of encapsulated drug payloads. AZD2811 nanoparticles containing pharmaceutically acceptable organic acids as ion pairing agents displayed continuous drug release for more than 1 week in vitro and a corresponding extended pharmacodynamic reduction of tumor phosphorylated histone H3 levels in vivo for up to 96 hours after a single administration. A specific AZD2811 nanoparticle formulation profile showed accumulation and retention in tumors with minimal impact on bone marrow pathology, and resulted in lower toxicity and increased efficacy in multiple tumor models at half the dose intensity of AZD1152, a water-soluble prodrug of AZD2811. These studies demonstrate that AZD2811 can be formulated in nanoparticles using ion pairing agents to give improved efficacy and tolerability in preclinical models with less frequent dosing. Accurins specifically, and nanotechnology in general, can increase the therapeutic index of molecularly targeted agents, including kinase inhibitors targeting cell cycle and oncogenic signal transduction pathways, which have to date proved toxic in humans.

Is iron overload in alcohol-related cirrhosis mediated by hepcidin?

In this case report we describe the relationship between ferritin levels and hepcidin in a patient with alcohol-related spur cell anemia who underwent liver transplantation. We demonstrate a reciprocal relationship between serum or urinary hepcidin and serum ferritin, which indicates that inadequate hepcidin production by the diseased liver is associated with elevated serum ferritin. The ferritin level falls with increasing hepcidin production after transplantation. Neither inflammatory indices (IL6) nor erythropoietin appear to be related to hepcidin expression in this case. We suggest that inappropriately low hepcidin production by the cirrhotic liver may contribute substantially to elevated tissue iron stores in cirrhosis and speculate that hepcidin replacement in these patients may be of therapeutic benefit in the future.

Combined bezafibrate and medroxyprogesterone acetate: potential novel therapy for acute myeloid leukaemia.

BACKGROUND: The majority of acute myeloid leukaemia (AML) patients are over sixty years of age. With current treatment regimens, survival rates amongst these, and also those younger patients who relapse, remain dismal and novel therapies are urgently required. In particular, therapies that have anti-leukaemic activity but that, unlike conventional chemotherapy, do not impair normal haemopoiesis. PRINCIPAL FINDINGS: Here we demonstrate the potent anti-leukaemic activity of the combination of the lipid-regulating drug bezafibrate (BEZ) and the sex hormone medroxyprogesterone acetate (MPA) against AML cell lines and primary AML cells. The combined activity of BEZ and MPA (B/M) converged upon the increased synthesis and reduced metabolism of prostaglandin D(2) (PGD(2)) resulting in elevated levels of the downstream highly bioactive, anti-neoplastic prostaglandin 15-deoxy Delta(12,14) PGJ(2) (15d-PGJ(2)). BEZ increased PGD(2) synthesis via the generation of reactive oxygen species (ROS) and activation of the lipid peroxidation pathway. MPA directed prostaglandin synthesis towards 15d-PGJ(2) by inhibiting the PGD(2) 11beta -ketoreductase activity of the aldo-keto reductase AKR1C3, which metabolises PGD(2) to 9alpha11beta-PGF(2alpha). B/M treatment resulted in growth arrest, apoptosis and cell differentiation in both AML cell lines and primary AML cells and these actions were recapitulated by treatment with 15d-PGJ(2). Importantly, the actions of B/M had little effect on the survival of normal adult myeloid progenitors. SIGNIFICANCE: Collectively our data demonstrate that B/M treatment of AML cells elevated ROS and delivered the anti-neoplastic actions of 15d-PGJ(2). These observations provide the mechanistic rationale for the redeployment of B/M in elderly and relapsed AML.

Normalized differential detection by use of smart pixels with smart illumination.

Smart pixels permit rapid signal processing through the use of integrated photodetectors and processing electronics on a single semiconductor chip. Smart pixels with smart illumination can increase the dynamic range and functionality of smart pixels by employing optoelectronic feedback to control the illumination of a scene. This combination of smart pixels and optoelectronic feedback leads to many potential sensor applications, including normalized differential detection, which is modeled and demonstrated here.