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Ramaswami R.,National Center for Malignancies | Chia G.,Imperial College London | Pria A.D.,National Center for Malignancies | Pinato D.J.,National Center for Malignancies | And 3 more authors.
Journal of Acquired Immune Deficiency Syndromes

Introduction: The emergence of combined antiretroviral therapy (cART) and improvements in the management of opportunistic infections have altered the HIV epidemic over the last 30 years. We aimed to assess changes to the biology and outcomes of HIVassociated lymphomas over this period at the national center for HIV oncology in the United Kingdom. Methods: Clinical characteristics at lymphoma diagnosis have been prospectively collected since 1986, along with details of lymphoma treatment and outcomes. The clinical features and outcomes were compared between 3 decades: pre-cART decade (1986-1995), earlycART decade (1996-2005), and late-cART decade (2006-2015). Results: A total of 615 patients with HIV-associated lymphoma were included in the study: 158 patients in the pre-cART era, 200 patients in the early-cART era, and 257 patients in the late-cART era. In more recent decades, patients were older (P , 0.0001) and had higher CD4 cell counts (P , 0.0001) at lymphoma diagnosis. Over time, there has also been a shift in lymphoma histological subtypes, with an increase in lymphoma subtypes associated with moderate immunosuppression. The overall survival for patients with HIV-associated lymphoma has dramatically improved over the 3 decades (P , 0.0001). Conclusion: Over the last 30 years, the clinical demographic of HIV-associated lymphomas has evolved, and the outcomes have improved. Source

Tuthill M.H.,Imperial College London | Tuthill M.H.,National Center for Malignancies | Montinaro A.,Imperial College London | Montinaro A.,University College London | And 15 more authors.

Tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) induces apoptosis in cancer cells while sparing normal tissues. Despite promising preclinical results, few patients responded to treatment with recombinant TRAIL (Apo2L/Dulanermin) or TRAIL-R2-specific antibodies, such as conatumumab (AMG655). It is unknown whether this was due to intrinsic TRAIL resistance within primary human cancers or insufficient agonistic activity of the TRAIL-receptor (TRAIL-R)-targeting drugs. Fcγ receptors (FcγR)-mediated crosslinking increases the cancer-cell-killing activity of TRAIL-R2-specific antibodies in vivo. We tested this phenomenon using FcγR-expressing immune cells from patients with ovarian cancer. However, even in the presence of high numbers of FcγR-expressing immune cells, as found in ovarian cancer ascites, AMG655-induced apoptosis was not enabled to any significant degree, indicating that this concept may not translate into clinical use. On the basis of these results, we next set out to determine whether AMG655 possibly interferes with apoptosis induction by endogenous TRAIL, which could be expressed by immune cells. To do so, we tested how AMG655 affected apoptosis induction by recombinant TRAIL. This, however, resulted in the surprising discovery of a striking synergy between AMG655 and non-tagged TRAIL (Apo2L/TRAIL) in killing cancer cells. This combination was as effective in killing cancer cells as highly active recombinant isoleucine-zipper-tagged TRAIL (iz-TRAIL). The increased killing efficiency was due to enhanced formation of the TRAIL death-inducing signalling complex, enabled by concomitant binding of Apo2L/TRAIL and AMG655 to TRAIL-R2. The synergy of AMG655 with Apo2L/TRAIL extended to primary ovarian cancer cells and was further enhanced by combination with the proteasome inhibitor bortezomib or a second mitochondrial-derived activator of caspases (SMAC) mimetic. Importantly, primary human hepatocytes were not killed by the AMG655-Apo2L/TRAIL combination, also not when further combined with bortezomib or a SMAC mimetic. We therefore propose that clinical-grade non-tagged recombinant forms of TRAIL, such as dulanermin, could be combined with antibodies such as AMG655 to introduce a highly active TRAIL-R2-agonistic therapy into the cancer clinic. © 2015 Macmillan Publishers Limited All rights reserved. Source

Venturelli S.,Chelsea and Westminster Hospital | Pria A.D.,National Center for Malignancies | Stegmann K.,Chelsea and Westminster Hospital | Smith P.,University College London | Bower M.,National Center for Malignancies
British Journal of Cancer

Background:The prognosis of non-Hodgkin lymphoma and Hodgkin lymphoma is not affected by HIV serostatus, yet people living with HIV (PLWH) are frequently excluded from clinical trials in lymphoma.Methods:The UK NIHR Clinical Research Network Study Portfolio website was used to identify all the open clinical trials in lymphoma in the United Kingdom in January 2015. Trials that excluded PLWH were further investigated to evaluate if the exclusion was justified by scientific evidence.Results:We identified 56 multicentre open clinical trials in lymphoma including 46 interventional trials. People living with HIV were excluded from 32 interventional trials (70%). We identified a biologically valid reason (a potential increased risk of greater immunosuppression) for excluding PLWH from one trial and possibly for one optional arm in another study.Conclusions:There was no scientific or safety justification for excluding PLWH from most lymphoma clinical trials included on the NIHR portfolio. A clear justification for excluding PLWH was not offered in the available protocols. The exclusion of PLWH should be explicitly justified on scientific grounds in protocols to minimise stigmatisation. Source

Dalla Pria A.,National Center for Malignancies | Alfa-Wali M.,National Center for Malignancies | Fox P.,Chelsea and Westminster Hospital | Holmes P.,Chelsea and Westminster Hospital | And 3 more authors.

Background: The ability to detect and treat pre-malignant anal lesions suggests screening may prevent anal cancer. The incidence of anal cancer in men who have sex with men (MSM) living with HIV exceeds that of cervical cancer before screening was introduced. Methods: High-resolution anoscopy (HRA) with intervention for high-grade squamous intraepithelial lesions (HSILs) was offered to asymptomatic HIV-positive MSM. Patients with HSILs were treated and follow-up HRA performed after 6 months, whilst patients with low-grade squamous intraepithelial lesions had a repeat HRA after 12 months. Results: Three hundred and sixty-eight asymptomatic MSM had a total of 1497 HRAs during a median follow-up of 4.2 years (maximum 13 years). At first HRA, 36% had normal appearances, 16% had no dysplasia, 15% anal intraepithelial neoplasia (AIN)-1, 19% AIN-2 and 13% AIN-3. During follow-up, five patients (1.4%) developed invasive anal cancer (incidence 2.7 per 1000 person-years). The 5-year cancer rate for the 368 patients was 0.3% [95% confidence interval (CI) 0-0.6%]. Progression to cancer was associated with higher age (P=0.049) and AIN-3 (P=0.024). Ninety patients had AIN-3 present at least at one HRA. The cumulative risk of cancer from first AIN-3 diagnosis was 3.2% (95% CI 0-7.8%) at 5 years. One hundred and seventy-one patients had HSILs (AIN-2 or 3) present at least once. The cumulative risk of cancer from first HSIL diagnosis was 0.6% (95% CI 0-1.8%) at 5 years. Conclusion: AIN-3 is a significant risk factor for subsequent anal cancer, although the tumours detected in screened patients were small localized, and generally the outcomes were favourable. © 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins. Source

Bower M.,National Center for Malignancies | Dalla Pria A.,National Center for Malignancies | Coyle C.,National Center for Malignancies | Andrews E.,National Center for Malignancies | And 3 more authors.
Journal of Clinical Oncology

Purpose: Combination antiretroviral therapy (cART) is standard of care for patients with HIV diagnosed with Kaposi's sarcoma (KS), but the current role of systemic chemotherapy is undefined. Patients and Methods Since 1998, a prospective stage-stratified approach has been adopted for 469 patients with HIV with KS. Patients with early-stage (T0) KS are treated with cART alone; patients with advanced-stage (T1) KS receive cART plus liposomal anthracycline chemotherapy. Clinical characteristics, overall survival, and KS progression- free survival were analyzed according to stage at presentation and treatment received. Results: A total of 303 patients presented with T0 stage KS, including 237 who were not receiving cART, and 166 patients had T1 stage KS. Patients with T0 KS had higher CD4 cell counts (P < .001); 90% of patients with T0 KS who were not receiving cART and 84% of those with T1 KS were treated in accordance with the stage-stratified approach. Median follow-up was 4.6 years, and 5-year overall survival was 89%; 54 patients have died, 15 as a result of KS. Overall 5-year survival was 92% for T0 KS and 83% to T1 KS (P = .0024). On-treatment analysis of 213 cART-naive patients with T0 KS treated with cART alone revealed 5-year overall survival of 95% and progression-free survival of 77%. For 140 patients with T1 disease treated with cART and liposomal anthracycline chemotherapy, 5-year overall survival was 85%. Conclusion: This stage-stratified approach to the management of KS achieves high survival in patients with advanced KS and reduces exposure to chemotherapy in patients with early-stage KS. J Clin Oncol 32:409-414. © 2013 by American Society of Clinical Oncology. Source

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