HIV-related Merkel cell carcinoma: A report of three cases from the UK.

Merkel cell carcinoma (MCC) of the skin is a rare, aggressive and often fatal neuroendocrine skin cancer. The incidence of MCC has significantly increased in the last decades. Factors that have been associated with the development of MCC include infection with Merkel Cell polyomavirus (MCPyV), ultraviolet exposure, hematologic malignancies and immunosuppression.We present three cases of patients living with HIV who were diagnosed with MCC. HIV cases associated with MCC have been rarely reported and to our knowledge, not yet before in the UK.

Pituitary enlargement following ipilimumab without long term endocrine dysfunction.

Ipilimumab, a monoclonal antibody against CTLA-4, is used in the treatment of melanoma and renal cell cancer. Hypophysitis is one of the more common adverse events, usually presenting with headache, pituitary enlargement and hypopituitarism, mostly ACTH deficiency, which is usually permanent. We describe a series of 3 cases developing pituitary enlargement in keeping with hypophysitis after ipilimumab without any long-term pituitary hormone deficiencies. This illustrates that a comprehensive endocrine assessment is required even when pituitary enlargement is present.

Additional Treatments to the Local tumour for metastatic prostate cancer-Assessment of Novel Treatment Algorithms (IP2-ATLANTA): protocol for a multicentre, phase II randomised controlled trial.

INTRODUCTION: Survival in men diagnosed with de novo synchronous metastatic prostate cancer has increased following the use of upfront systemic treatment, using chemotherapy and other novel androgen receptor targeted agents, in addition to standard androgen deprivation therapy (ADT). Local cytoreductive and metastasis-directed interventions are hypothesised to confer additional survival benefit. In this setting, IP2-ATLANTA will explore progression-free survival (PFS) outcomes with the addition of sequential multimodal local and metastasis-directed treatments compared with standard care alone. METHODS: A phase II, prospective, multicentre, three-arm randomised controlled trial incorporating an embedded feasibility pilot. All men with new histologically diagnosed, hormone-sensitive, metastatic prostate cancer, within 4 months of commencing ADT and of performance status 0 to 2 are eligible. Patients will be randomised to Control (standard of care (SOC)) OR Intervention 1 (minimally invasive ablative therapy to prostate±pelvic lymph node dissection (PLND)) OR Intervention 2 (cytoreductive radical prostatectomy±PLND OR prostate radiotherapy±pelvic lymph node radiotherapy (PLNRT)). Metastatic burden will be prespecified using the Chemohormonal Therapy Versus Androgen Ablation Randomized Trial for Extensive Disease (CHAARTED) definition. Men with low burden disease in intervention arms are eligible for metastasis-directed therapy, in the form of stereotactic ablative body radiotherapy (SABR) or surgery. Standard systemic therapy will be administered in all arms with ADT±upfront systemic chemotherapy or androgen receptor agents. Patients will be followed-up for a minimum of 2 years. PRIMARY OUTCOME: PFS. Secondary outcomes include predictive factors for PFS and overall survival; urinary, sexual and rectal side effects. Embedded feasibility sample size is 80, with 918 patients required in the main phase II component. Study recruitment commenced in April 2019, with planned follow-up completed by April 2024. ETHICS AND DISSEMINATION: Approved by the Health Research Authority (HRA) Research Ethics Committee Wales-5 (19/WA0005). Study results will be submitted for publication in peer-reviewed journals. TRIAL REGISTRATION NUMBER: NCT03763253; ISCRTN58401737.

PD-L1 expressing granulomatous reaction as an on-target mechanism of steroid-refractory immune hepatotoxicity.

Immune-related hepatitis is an important toxicity from immune-checkpoint inhibitor therapy, affecting up to 20% of patients on dual cytotoxic T-lymphocyte antigen 4/programmed cell death 1 (CTLA-4/PD-1) inhibitors. The mechanisms underlying this type of drug-induced liver injury are poorly understood. We report the case of a patient with immune-checkpoint inhibitor-related hepatitis where the presence of a diffuse granulomatous, PD-L1-positive infiltrate on liver biopsy correlated with poor response to corticosteroids. Our findings suggest a potential role for activation of the PD-1 pathway within the histiocitic infiltrate as a mechanism of toxicity. Further studies should address the role of macrophages in this patient group characterized by steroid-refractoriness.

Association of Prior Antibiotic Treatment With Survival and Response to Immune Checkpoint Inhibitor Therapy in Patients With Cancer.

Importance: Gut dysbiosis impairs response to immune checkpoint inhibitors (ICIs) and can be caused by broad-spectrum antibiotic (ATB) therapy. Objective: To evaluate whether there is an association between ATB therapy administered concurrently (cATB) or prior (pATB) to ICI therapy and overall survival (OS) and treatment response to ICI therapy in patients with cancer treated with ICIs in routine clinical practice. Design, Setting, and Participants: This prospective, multicenter, cohort study conducted at 2 tertiary academic referral centers recruited 196 patients with cancer who received ICI therapy between January 1, 2015, and April 1, 2018, in routine clinical practice rather than clinical trials. Main Outcomes and Measures: Overall survival calculated from the time of ICI therapy commencement and radiologic response to ICI treatment defined using the Response Evaluation Criteria in Solid Tumors (version 1.1), with disease refractory to ICI therapy defined as progressive disease 6 to 8 weeks after the first ICI dose without evidence of pseudoprogression. Results: Among 196 patients (137 men and 59 women; median [range] age, 68 [27-93] years) with non-small cell lung cancer (n = 119), melanoma (n = 38), and other tumor types (n = 39), pATB therapy (HR, 7.4; 95% CI, 4.3-12.8; P < .001), but not cATB therapy (HR, 0.9; 95% CI, 0.5-1.4; P = .76), was associated with worse OS (2 vs 26 months for pATB therapy vs no pATB therapy, respectively) (hazard ratio [HR], 7.4; 95% CI, 4.2-12.9) and a higher likelihood of primary disease refractory to ICI therapy (21 of 26 [81%] vs 66 of 151 [44%], P < .001). Overall survival in patients with non-small cell lung cancer (2.5 vs 26 months, P < .001), melanoma (3.9 vs 14 months, P < .001), and other tumor types (1.1 vs 11, P < .001) was consistently worse in those who received pATBs vs those who did not. Multivariate analyses confirmed that pATB therapy (HR, 3.4; 95% CI, 1.9-6.1; P < .001) and response to ICI therapy (HR, 8.2; 95% CI, 4.0-16.9; P < .001) were associated with OS independent of tumor site, disease burden, and performance status. Conclusions and Relevance: Despite being limited by sample size, geographic origin, and the lack of correlative analyses on patients' gut microbiota, this study suggests that pATB therapy but not cATB therapy is associated with a worse treatment response and OS in unselected patients treated with ICIs in routine clinical practice. Mechanistic studies are urgently required to investigate ATB-mediated alterations of gut microbiota as a determinant of poorer outcome following ICI treatment.

Metabolic activation of temozolomide measured in vivo using positron emission tomography.

The purpose of this research was to quantitate and confirm the mechanism of in vivo metabolic activation of temozolomide. The secondary aims were to evaluate the tumor, normal tissue, and plasma pharmacokinetics of temozolomide in vivo, and to determine whether such pharmacokinetics resulted in tumor targeting. [(11)C]temozolomide kinetics were studied in men using positron emission tomography (PET). It has been postulated that temozolomide undergoes decarboxylation and ring opening in the 3-4 position to produce the highly reactive methyldiazonium ion that alkylates DNA. To investigate this, a dual radiolabeling strategy, with [(11)C]temozolomide separately radiolabelled in the 3-N-methyl and 4-carbonyl positions, was used. We hypothesized that (11)C in the C-4 position of [4-(11)C-carbonyl]temozolomide would be converted to [(11)C]CO(2) if the postulated mechanism of metabolic conversion was true resulting in lower [(11)C]temozolomide tumor exposure. Paired studies were performed with both forms of [(11)C]temozolomide in 6 patients with gliomas. Another PET scan with (11)C-radiolabelled bicarbonate was performed and used to account for the metabolites of temozolomide using a data-led analytical approach. Plasma was analyzed for [(11)C]temozolomide and [(11)C]metabolites throughout the scan duration. Exhaled air was also sampled throughout the scan for [(11)C]CO(2). The percentage ring opening of temozolomide over 90 min was also calculated to evaluate whether there was a differential in metabolic breakdown among plasma, normal tissue, and tumor. There was rapid systemic clearance of both radiolabelled forms of [(11)C]temozolomide over 90 min (0.2 liter/min/m(2)), with [(11)C]CO(2) being the primary elimination product. Plasma [(11)C]CO(2) was present in all of the studies with [4-(11)C-carbonyl]temozolomide and in half the studies with [3-N-(11)C-methyl]temozolomide. The mean contributions to total plasma activity by [(11)C]CO(2) at 10 and 90 min were 12% and 28% with [4-(11)C-carbonyl]temozolomide, and 1% and 4% with [3-N-(11)C-methyl]temozolomide, respectively. There was a 5-fold increase in exhaled [(11)C]CO(2) sampled with [4-(11)C-carbonyl]temozolomide compared with [3-N-(11)C-methyl]temozolomide (P < 0.05). A decrease in tissue exposure [area under the curve between 0 and 90 min (AUC(0-90 min))] to [(11)C]temozolomide was also observed with [4-(11)C-carbonyl] temozolomide compared with [3-N-(11)C-methyl]temozolomide. Of potential therapeutic advantage was the higher [(11)C]radiotracer and [(11)C]temozolomide exposure (AUC(0-90 min)) in tumors compared with normal tissue. [(11)C]temozolomide ring opening over 90 min was less in plasma (20.9%; P < 0.05) compared with tumor (26.8%), gray matter (29.7%), and white matter (30.1%), with no differences (P > 0.05) between tumor and normal tissues. The significantly higher amounts of [(11)C]CO(2) sampled in plasma and exhaled air, in addition to the lower normal tissue and tumor [(11)C]temozolomide AUC(0-90 min) observed with [4-(11)C-carbonyl]temozolomide, confirmed the postulated mechanism of metabolic activation of temozolomide. A higher tumor [(11)C]temozolomide AUC(0-90 min) in tumors compared with normal tissue and the tissue-directed metabolic activation of temozolomide may confer potential therapeutic advantage in the activity of this agent. This is the first report of a clinical PET study used to quantify and confirm the in vivo mechanism of metabolic activation of a drug.

Emerging targeted treatments for malignant glioma.

This paper focuses on the medical management of malignant gliomas, which is currently undergoing change. It suggests that as surgery and radiotherapy are of limited benefit in the treatment of these tumours, medical therapies may have the potential to offer a better alternative. The current therapies for glioma and the targeted agents in clinical trials are reviewed. There is a general acceptance that temozolomide in combination with radiotherapy is replacing radiotherapy alone as first-line therapy in high-grade astrocytic gliomas. Within the realms of clinical research, it can be seen that there is a shift away from therapies targeting the end effect of deregulated cell-cycle control, to targeting specific and individual genetic aberrations in tumours. Finally, the paper questions current clinical trial methodology and tentatively suggests ways in which this may be improved.

Antitumor imidazotetrazines. 40. Radiosyntheses of [4-11C-carbonyl]- and [3-N-11C-methyl]-8-carbamoyl-3-methylimidazo[5,1-d]-1,2,3,5-tetrazin-4(3H)-one (temozolomide) for positron emission tomography (PET) studies.

8-Carbamoyl-3-methylimidazo[5,1-d]-1,2,3,5-tetrazin-4(3H)-one (temozolomide, 1) is an anticancer prodrug. As part of investigations to probe its postulated mode of action using PET we have developed two rapid radiosynthetic routes for the preparation of temozolomide labeled with the short-lived positron emitter, carbon-11 (t(1/2) = 20.4 min). Reaction of 5-diazoimidazole-4-carboxamide (7) with the novel labeling agent [(11)C-methyl]methyl isocyanate (8) gave [3-N-(11)C-methyl]temozolomide (9) in 14-20% radiochemical yield from [(11)C-methyl]methyl isocyanate (8) (decay corrected). The position of radiolabeling in the 3-N-methyl group was confirmed by [(11/13)C]colabeling and subsequent carbon-13 NMR spectroscopy. Similarly, the reaction of 5-diazoimidazole-4-carboxamide (7) with [(11)C-carbonyl]methyl isocyanate (10) gave [4-(11)C-carbonyl]temozolomide (11) in 10-15% radiochemical yield from [(11)C-carbonyl]methyl isocyanate (10) (decay corrected). Apyrogenic samples of [3-N-(11)C-methyl]temozolomide (9) and [4-(11)C-carbonyl]temozolomide (11), with good chemical and radiochemical purities, have been prepared and used in human PET studies.

Preliminary clinical assessment of the relationship between tumor alphavbeta3 integrin and perfusion in patients studied with [(18)F]fluciclatide kinetics and [ (15)O]H 2O PET.

BACKGROUND: [(18)F]fluciclatide, a peptide ligand with high affinity for αvß3/αvß5 integrins, is a proposed biomarker of tumor angiogenesis. The study rationale was to perform a preliminary evaluation of the relationship between tumor [(18)F]fluciclatide uptake and perfusion by [(15)O]H2O PET. METHODS: Patients with non-small cell lung cancer and melanoma underwent dynamic imaging with arterial sampling following injection of [(15)O]H2O and [(18)F]fluciclatide. Quantification was performed using a one-tissue compartmental model for [(15)O]H2O and a two-tissue model for [(18)F]fluciclatide at volume-of-interest level, and SUV at voxel level. RESULTS: Tumor binding potential (k 3/k 4 ratio) of [(18)F]fluciclatide tumor was 5.39 ± 1.46, consistent with previous studies in breast cancer metastases. Voxel-by-voxel maps of [(18)F]fluciclatide delivery strongly correlated with [(15)O]H2O-based perfusion (p < 10(-4) tumor, 1,794 ± 1,331 voxels). Interestingly, this correlation was lost when retention of [(18)F]fluciclatide at late time-points was compared with perfusion (p > 0.15). CONCLUSIONS: Our study suggests tumor [(18)F]fluciclatide retention is unrelated to tumor perfusion, supporting use of late (60-min) imaging protocols in patients.

A validated prognostic index predicting response to dexamethasone and diethylstilbestrol in castrate-resistant prostate cancer.

BACKGROUND: The objective of this study was to identify subgroups of patients with castrate-resistant prostate cancer (CRPC) who had a prolonged response to combined dexamethasone and diethylstilbestrol (DS) therapy by constructing a prognostic index. METHODS: Multivariate and cutoff point analyses with bootstrapping were performed 1 month after commencing DS therapy, and data were validated using an independent external dataset. RESULTS: The median overall survival for 145 patients was 18.3 months (95% confidence interval [CI], 15.4-23.3 months). Only 2 factors were significant on multivariate analysis: a prostate-specific antigen (PSA) level below the median at the start of DS therapy and a decline>50% in the PSA level after 1 month on DS therapy. Subsequent cutoff point analyses revealed that a PSA level<88 ng/mL at the start of DS therapy and a reduction>53.1% in PSA after the first month of treatment were the most significant factors. These 2 factors were used to construct a prognostic index, which was validated successfully by the external dataset (median overall survival, 18.3 months [95% CI, 16.4-28.0 months]; concordance, 72% [95% CI, 68%-76%]). The prognostic index identified 3 prognostic groups: The 2-year overall survival rate for these 3 groups was 68% (95% CI, 57%-98%) for the good prognostic group, 40% (95% CI, 31%-52%) for the intermediate prognostic group, and 12% (95% CI, 5%-25%) for the poor prognostic group. CONCLUSIONS: The easy-to-use prognostic index that the authors developed was able to identify a subgroup of patients with CRPC who had prolonged survival only 1 month after starting DS therapy.

A new model for prediction of drug distribution in tumor and normal tissues: pharmacokinetics of temozolomide in glioma patients.

Difficulties in direct measurement of drug concentrations in human tissues have hampered the understanding of drug accumulation in tumors and normal tissues. We propose a new system analysis modeling approach to characterize drug distribution in tissues based on human positron emission tomography (PET) data. The PET system analysis method was applied to temozolomide, an important alkylating agent used in the treatment of brain tumors, as part of standard temozolomide treatment regimens in patients. The system analysis technique, embodied in the convolution integral, generated an impulse response function that, when convolved with temozolomide plasma concentration input functions, yielded predicted normal brain and brain tumor temozolomide concentration profiles for different temozolomide dosing regimens (75-200 mg/m(2)/d). Predicted peak concentrations of temozolomide ranged from 2.9 to 6.7 microg/mL in human glioma tumors and from 1.8 to 3.7 microg/mL in normal brain, with the total drug exposure, as indicated by the tissue/plasma area under the curve ratio, being about 1.3 in tumor compared with 0.9 in normal brain. The higher temozolomide exposures in brain tumor relative to normal brain were attributed to breakdown of the blood-brain barrier and possibly secondary to increased intratumoral angiogenesis. Overall, the method is considered a robust tool to analyze and predict tissue drug concentrations to help select the most rational dosing schedules.

Phase I pharmacokinetic and pharmacodynamic study of the oral mammalian target of rapamycin inhibitor everolimus in patients with advanced solid tumors.

PURPOSE: To identify the optimal regimen and dosage of the oral mammalian target of rapamycin inhibitor everolimus (RAD001). METHODS: We performed a dose-escalation study in advanced cancer patients administering oral everolimus 5 to 30 mg/wk, with pharmacokinetic (PK) and pharmacodynamic (PD) studies. PD data prompted investigation of 50 and 70 mg weekly and daily dosing at 5 and 10 mg. RESULTS: Ninety-two patients were treated. Dose-limiting toxicity was seen in one patient each at 50 mg/wk (stomatitis and fatigue) and 10 mg/d (hyperglycemia); hence, the maximum-tolerated dose was not reached. S6 kinase 1 activity in peripheral-blood mononuclear cells was inhibited for at least 7 days at doses >or= 20 mg/wk. Area under the curve increased proportional to dose, but maximum serum concentration increased less than proportionally at doses >or= 20 mg/wk. Terminal half-life was 30 hours (range, 26 to 38 hours). Partial responses were observed in four patients, and 12 patients remained progression free for >or= 6 months, including five of 10 patients with renal cell carcinoma. CONCLUSION: Everolimus was satisfactorily tolerated at dosages up to 70 mg/wk and 10 mg/d with predictable PK. Antitumor activity and PD in tumors require further clinical investigation. Doses of 20 mg/wk and 5 mg/d are recommended as appropriate starting doses for these studies.

Molecular positron emission tomography and PET/CT imaging in urological malignancies.

OBJECTIVES: Positron emission tomography (PET) provides unique insights into molecular pathways of diseases. PET using [F-18]-fluorodeoxyglucose (FDG) has gained increasing acceptance for the diagnosis, staging, and treatment monitoring of various tumour types. The aim of this review is to provide an update on the current status of molecular PET and PET/CT imaging in urological malignancies. METHODS: The current literature on PET and PET/CT imaging was reviewed and summarized for prostate cancer, bladder cancer, renal cell carcinoma, and germ cell tumours. RESULTS: Depending on the radiotracer used, PET offers diagnostic information based on glucose, choline or amino acid metabolism and has also been applied to imaging tumour cell proliferation and tissue hypoxia in urological malignancies. The diagnostic performance of FDG-PET is hampered by the renal excretion of FDG and by the low metabolic activity often seen in tumours such as prostate cancer. However, new PET tracers including radiolabelled choline and acetate may offer an alternative approach. There is consistent evidence that FDG-PET provides important diagnostic information in detecting metastatic and recurrent germ cell tumours and it might offer additional information in the staging and restaging of bladder and renal cancer. CONCLUSIONS: Although PET imaging has been shown to be a clinically useful tool, its application in urological malignancies still needs to be fully determined by larger prospective trials. The introduction of novel PET radiopharmaceuticals along with the new technology of PET/CT will likely change the future role of molecular imaging in urological malignancies.

Metastatic ductal eccrine adenocarcinoma masquerading as an invasive ductal carcinoma of the male breast.

We report the case of a 38-year-old man with metastatic ductal eccrine adenocarcinoma (DEA) of the left breast responding to 5-flourouracil, epirubicin and cyclophosphamide (FEC) chemotherapy. He initially presented with a 2-week history of difficulty walking because of bilateral hip and lower back pain. Examination showed an ulcerating cutaneous mass over the left anterior chest wall, left axillary lymphadenopathy and tenderness over the spine. A punch biopsy of the breast lesion resulted in a diagnosis of metastatic invasive ductal carcinoma (IDC) of the breast. He received palliative radiotherapy to the spine and also received six cycles of FEC chemotherapy and was subsequently commenced on tamoxifen and ibandronate. There was a symptomatic and radiological response to the FEC chemotherapy. Referral was subsequently made to our institution where the original punch biopsy was reviewed. This showed tumor cells that were polygonal with darkly stained pleomorphic nuclei and abundant eosinophilic cytoplasm and were also localized to areas of fibrotic stroma containing eccrine glands and ducts but did not appear to involve mammary tissue. Immunohistochemical studies showed the tumors to be cytokeratin 7 and gross cystic disease fluid protein-15/prolactin inducible protein negative and estrogen receptor alpha positive. Both the morphological and the immunohistochemical characteristics of the tumor were consistent with a revised diagnosis of DEA rather than IDC. When last reviewed, the patient remains pain free and his disease stable 17 months after his original presentation. This case emphasizes the challenge in discriminating histopathologically between two rare tumors of the male breast, namely DEA and IDC. In addition, clinical response to FEC by metastatic DEA has not been previously documented, and this therapeutic regimen warrants further investigation.

The efficacy of ritonavir in the prevention of AIDS-related Kaposi's sarcoma.

Angiogenesis is thought to play a major role in the development of Kaposi's sarcoma (KS), considered by many to be a hyperplastic disorder caused in part by local production of inflammatory cytokines. The antiangiogenic effects of protease inhibitors, in particular ritonavir, have been suggested in laboratory work to lead to regression of KS, and recent data have shown the importance of ritonavir as a model of pharmaceutical development. As our clinical cohort data has shown that non-nucleoside reverse transcriptase inhibitor-based regimens are not inferior to protease inhibitor-based therapy in the prevention of KS, we investigated the specific contribution of ritonavir to chemoprevention of this AIDS-defining illness. In a logistic regression analysis, we found that ritonavir-based therapy confers no advantages compared to other regimens in the prevention of KS. This is consistent with data suggesting that regression of KS is mediated by an overall improvement in immune function and not by the effects of specific antiretrovirals.