Danish Mazhar

Should Cervical Cancer Be an Acquired Immunodeficiency Syndrome-Defining Cancer?

In 1987, the Centers for Disease Control and Prevention created a list of clinical diagnoses that defined the types of AIDS that were indicative of severe immunosuppression, especially defective cell-mediated immunity. Kaposi’s sarcoma (KS) and high-grade non-Hodgkin’s lymphoma (NHL) were included in this list of AIDS-defining illnesses. More precisely, KS and primary cerebral NHL in people less than 60 years old were AIDS-defining illnesses even in the absence of HIV serology. In contrast, systemic highgrade B-cell NHL had to have either small noncleaved (Burkitt’s and Burkitt’s-like) or immunoblastic histology and have positive HIV serology to be an AIDS-defining illness. 1

Chemotherapy for advanced cholangiocarcinoma: what is standard treatment?

Cholangiocarcinoma is a relatively uncommon malignancy, that presents late in the vast majority of cases. Overall survival rates are extremely poor and treatment options remain limited in patients with inoperable, recurrent or metastatic disease. Systemic chemotherapy has historically had little impact on the natural history of this disease, owing to both the absence of agents with substantial activity and the overall morbidity of treatment in this patient population. Response rates with 5-fluorouracil have been 10% at best, with a median survival of 6 months. However, there has been interest in the use of newer cytotoxic drugs and combination regimens in advanced cholangiocarcinoma, and Phase II trials have reported much improved results. This review examines this data and assesses whether a new standard of care for advanced cholangiocarcinoma can be found.

Inhibiting estrogen responses in breast cancer cells using a fusion protein encoding estrogen receptor-α and the transcriptional repressor PLZF

Estrogen receptor α (ERα) is a ligand-inducible transcription factor that acts to regulate gene expression by binding to palindromic DNA sequence, known as the estrogen response element, in promoters of estrogen-regulated genes. In breast cancer ERα plays a central role, where estrogen-regulated gene expression leads to tumor initiation, growth and survival. As an approach to silencing estrogen-regulated genes, we have studied the activities of a fusion protein between ERα and the promyelocytic leukemia zinc-finger (PLZF) protein, a transcriptional repressor that acts through chromatin remodeling. To do this, we have developed lines from the estrogen-responsive MCF-7 breast cancer cell line in which the expression of the fusion protein PLZF-ERα is conditionally regulated by tetracycline and shows that these feature long-term silencing of the expression of several well-characterized estrogen-regulated genes, namely pS2, cathepsin-D and the progesterone receptor. However, the estrogen-regulated growth of these cells is not inhibited unless PLZF-ERα expression is induced, an observation that we have confirmed both in vitro and in vivo. Taken together, these results show that PLZF-ERα is a potent repressor of estrogen-regulated gene expression and could be useful in distinguishing estrogen-regulated genes required for the growth of breast cancer cells.

Bone metastases in germ cell tumours: lessons learnt from a large retrospective study.

To determine the characteristics of patients with germ cell cancer and bone metastases.

Non-Hodgkin’s lymphoma and the CNS: prophylaxis and therapy in immunocompetent and HIV-positive individuals

The involvement of the CNS in individuals with non-Hodgkin’s lymphoma is a well-recognised complication. Despite the progress that has been made in controlling cancer at most sites in the body, the outcome of individuals affected by meningeal infiltration is dismal and few patients survive for more than a few months. There are few studies that have addressed the management of CNS disease in AIDS-associated non-Hodgkin’s lymphoma, and treatment algorithms have been formulated secondary to protocols in immunocompetent individuals. The prevention and treatment of CNS disease is an important aspect of lymphoma management, and new medications, such as a sustained-release formulation of intrathecal cytarabine, will have an increasingly relevant role.

Second-line systemic therapy for metastatic urothelial carcinoma of the bladder

While platinum-based combination chemotherapy leads to high response rates in patients with advanced urothelial cancer of the bladder, most patients will ultimately progress and optimal treatment in the second-line setting still needs to be determined. Advanced age, poor performance status, comorbidities and rapidly progressive disease have rendered accrual into trials difficult. Vinflunine is the only cytotoxic agent to demonstrate survival benefit in a randomized Phase III setting, but its response rate is disappointing and it has not been compared with other currently used agents such as taxanes. Recent years have seen a better definition of prognostic and predictive factors in patients with relapsed urothelial cancer. In addition, several trials have investigated novel biological agents to target chemoresistant disease. This review provides an update on the current systemic management of advanced urothelial cancer on progression following first-line chemotherapy, and discusses emerging data from recent Phase II/III trials.

Accelerated BEP: a phase I trial of dose-dense BEP for intermediate and poor prognosis metastatic germ cell tumour.

Background:We used bleomycin, etoposide, cisplatin (BEP), the most effective regimen in the treatment of germ cell tumours (GCTs) and increased dose-density by using pegfilgrastim to shorten cycle length. Our aim was to assess safety and tolerability.Methods:Sixteen male patients with intermediate or poor prognosis metastatic GCT were treated with four cycles of 3-day BEP with G-CSF on a 14-day cycle for a planned relative dose-density of 1.5 compared with standard BEP.Results:Eleven intermediate and five poor prognosis patients were treated. In all, 14 of 16 patients completed the study treatment. Toxicities were comparable to previous studies using standard BEP, except for mucositis and haematological toxicity that were more severe. The overall relative dose-density for all 16 patients was mean 1.38 (range 0.72–1.5; median 1.46). Complete response was achieved after chemotherapy alone in two patients (13%) and following chemotherapy plus surgery in nine additional patients (56%). Four patients (25%) had a partial response and normalised their marker levels. At a median follow-up of 4.4 years (range 2.1–6.8) the estimated 5-year progression-free survival probability is 81% (95% CI 64–100%).Conclusion:Accelerated BEP is tolerable without major additional toxicity. A randomised controlled trial will be required to obtain comparative efficacy data.

Diet and Prostate Cancer

There are four mini‐reviews in this section, all on different areas of urological interest. Diet and prostate cancer continues to offer areas of clinical and laboratory research for investigation. Not every urologist looks after patients with spinal cord injury, but neuropathic bladder problems caused by other conditions are common. One of the acute conditions in these patients is autonomic dysreflexia, and this is covered here. I am about to introduce a series of papers which will form a consensus on the management of genitourinary trauma, which appears elsewhere in the journal. In this section this month, authors from Germany describe the diagnosis and treatment of male genital injuries. Finally, the concept that the urologists who operate on the largest volume of cases have the best outcomes from a particular operation is examined.

Recent advances in the systemic management of colorectal cancer.

Colorectal cancer represents one of the most prevalent malignancies. There have been considerable improvements in the management of the disease in the last decade, including advances in surgery. In terms of systemic management, 5-fluorouracil, usually with leucovorin, has remained the mainstay of chemotherapy for colorectal cancer in both the adjuvant and metastatic settings. In the late 1990s, irinotecan and oxaliplatin reached the clinical arena, and the introduction of these agents has led to significant improvements in outcomes. More recently, several biopharmaceuticals, including the monoclonal antibodies bevacuzimab and cetuximab, have shown promise in clinical studies. These novel agents are now being incorporated into treatment schedules for colorectal cancer. This review assesses recent improvements in the systemic management of large bowel cancer and highlights future challenges.

Silencing of androgen-regulated genes using a fusion of AR with the PLZF transcriptional repressor

The androgen receptor (AR) is a member of the nuclear receptor superfamily of ligand-activated transcription factors and plays a key role in the development and progression of prostate cancer. Current therapies include the use of antiandrogens aimed at inhibiting the transcriptional activation of AR-regulated genes by AR. Here, we explore a strategy aimed at obtaining silencing of AR-regulated genes, based on the properties of the transcriptional repressor promyelocytic leukamia zinc-finger protein (PLZF). In order to do this, we have made a fusion protein between PLZF and AR, named PLZF-AR, and show that PLZF-AR is able to bring about silencing of genomically encoded AR-regulated genes and inhibit the androgen-regulated growth of LNCaP prostate cancer cells. Together, our results show that this strategy is able to bring about potent repression of AR-regulated responses and, therefore, could be of value in the development of new therapies for prostate cancer.