Gene and immune therapy for renal cell carcinoma

Conventional therapy for metastatic renal cell carcinoma is associated with a poor response rate and few patients are long-term survivors. The occurrence of spontaneous regression and the prolonged latency period between primary tumor removal and the appearance of metastases in some patients suggest the existence of important host immune responses to autologous tumor cells. With the advent of molecular gene transfer techniques and increased knowledge of the basic pathways of immune activation, the field of cancer immunotherapy has finally begun to develop novel and effective approaches for harnessing the immune system as a therapeutic agent. Current immunotherapy and gene therapy strategies, including methods of cytokine delivery and tumor-cell-based vaccines, are presented.     

Ellagitannin-rich pomegranate extract inhibits angiogenesis in prostate cancer in vitro and in vivo

Angiogenesis is critical to tumor growth and is stimulated by tissue hypoxia due to poor oxygen delivery. In turn, cellular hypoxia leads to angiogenesis via the induction of hypoxia-inducible factor-1alpha (HIF-1alpha) and vascular endothelial growth factor (VEGF) at a cellular level. Pomegranate juice and extracts, which are rich sources of ellagitannins, have been shown to have chemopreventive potential against prostate cancer, but there have been no studies on the effects of an ellagitannin-rich pomegranate extract on angiogenesis. Human prostate cancer cells (LNCaP) and human umbilical vein endothelial cells (HUVEC) were incubated with a pomegranate extract standardized to ellagitannin content (POMx), under normoxic and hypoxic conditions in vitro. Human prostate cancer cells (LAPC4) were injected subcutaneously into severe combined immunodeficient (SCID) mice and the effects of oral administration of POMx on tumor growth, microvessel density, and HIF-1alpha and VEGF expression were determined after 4 weeks of treatment. POMx inhibited the proliferation of LNCaP and HUVEC cells significantly under both normoxic and hypoxic conditions. HIF-1alpha and VEGF protein levels were also reduced by POMx under hypoxic conditions. POMx decreased prostate cancer xenograft size, tumor vessel density, VEGF peptide levels and HIF-1alpha expression after 4 weeks of treatment in SCID mice. These results demonstrate that an ellagitannin-rich pomegranate extract can inhibit tumor-associated angiogenesis as one of several potential mechanisms for slowing the growth of prostate cancer in chemopreventive applications. Further studies in humans are needed to confirm that angiogenesis can be inhibited by an ellagitannin-rich pomegranate extract administered orally as a dietary supplement.     

Performance status and cytoreductive nephrectomy: redefining management in patients with poor performance

BACKGROUND.

An Eastern Cooperative Oncology Group performance status (ECOG PS) of 2/3 can quantify cancer patients' well being and may be used to select patients for treatment. The objective of the current study was to investigate the outcomes of cytoreductive nephrectomy (CN) for patients who have an impaired performance status (ECOG PS 2/3).

METHODS.

Patients who underwent CN for renal cell carcinoma (RCC) between 1989 and 2006 were identified. Patient records were reviewed for age, symptoms, ECOG PS, tumor size, stage, grade, histology, sarcomatoid features, lymph node metastasis, site of metastasis, and the presence of bone metastases (BM) in weight‐bearing structures. The relation of ECOG PS to outcome variables was evaluated.

RESULTS.

Four hundred eighteen patients underwent CN, including 117 patients who had an ECOG PS of 0, 274 patients who had an ECOG PS of 1, and 27 patients who had an ECOG PS of 2/3. Patients who had a worse ECOG PS were younger, had higher tumor classification and grade, and more frequently demonstrated anemia and BM. Only 37.5% of patients who had an ECOG PS of 2/3 experienced an improvement in performance in the postoperative period, and only 57.5% went on to receive systemic therapy, of whom none attained an objective responses. The median disease‐specific survival for patients who had an ECOG PS of 0, 1, and 2/3 was 27 months, 13.8 months, and 6.6 months, respectively (P<.001). Patients who had an ECOG PS of 2/3 could be stratified further by the presence or absence of BM into 2 groups (median disease‐specific survival: 17.7 months and 2.1 months, respectively; P = .006).

CONCLUSIONS.

Surgery in patients who have a poor performance may serve a palliative function but should be performed with caution because of the poor outcome of such patients. ECOG PS is influenced strongly by BM. A subset of patients with an ECOG PS of 2/3 that are symptomatic specifically from BM may derive greater benefit from CN than patients who hare symptomatic because of visceral metastases. Cancer 2008. © 2008 American Cancer Society.     

Epidural analgesia for labour and delivery: fentanyl or sufentanil?

Purpose

The highly lipid soluble opioids, fentanyl and sufentanil, are used in combination with local anaesthetics with/ without epinephrine to provide epidural analgesia during labour and delivery. Our aim was to determine whether either opioid was superior when used with low dose local anaesthetic.

Methods

In a double-blind study patients were randomized to two epidural infusion groups: Group I (n = 50) fentanyl 2 μg · ml^?1 with bupivacaine 0.015% and epinephrine 2 μg · ml^?1, Group II (n = 50) sufentanil 1 μg · ml^?1 with bupivacaine 0.015% and epinephrine 2 μg · ml^?1. Following a 20 ml bolus of the study solution an infusion was started at 10 ml · h^?1. To achieve analgesia patients could receive two boluses of 5 ml of the study solution and if analgesia was still inadequate, a further 5 ml bupivacaine 0.25% was used. Pain and overall satisfaction were assessed with a 10-point visual scale. Plasma samples obtained from the mother at the time the infusion was discontinued and from the umbilical cord vein at delivery were assayed to determine opioid concentration.

Results

Pain scores were greater for Group I than for Group II patients throughout the first and second stages of labour (P = 0.002). More patients in Group I (42%) requested a dose of bupivacaine 0.25% than in Group II (6%) (P < 0.0001) and the total dose of bupivacaine given to Group I patients was greater than that of Group II, 26.0 ± 22.0 mg vs. 13.4 ± 12.6 mg, P = 0.005. There were no differences with respect to first or second stage duration, incidence of side effects, infusion duration, outcome of labour or neonatal Apgar scores. There was no opioid accumulation in either maternal or foetal blood.

Conclusion

Epidural opioid infusion with very low dose bupivacaine (0.015%) achieved an overall high level of patient satisfaction in both groups without serious maternal or neonatal side effects. At the fentanyl-to-sufentanil ratio used here patients receiving sufentanil had lower pain scores and substantially fewer patients required bupivacaine rescue.     

A phase 2 study of TMX-101, intravesical imiquimod,for the treatment of carcinoma in situ bladder cancer

Purpose

Imiquimod is a toll-like receptor agonist with proven antitumor activity as a topical treatment for skin cancer. TMX-101 (Vesimune) is a novel liquid formulation of imiquimod optimized for intravesical delivery. The agent demonstrated safety as an intravesical treatment for non–muscle-invasive bladder cancer in a phase 1 clinical trial. We report the results of a phase 2 prospective multicenter clinical trial assessing the safety and activity of TMX-101.

Gain of chromosome 8q is associated with metastases and poor survival of patients with clear cell renal cell carcinoma

BACKGROUND:

The aim of this study was to evaluate the prevalence of chromosome 8q gain in clear cell renal cell carcinoma (CCRCC) and to correlate the findings with tumor phenotype and disease‐specific survival (DSS).

METHODS:

The tumor karyotypes of 336 consecutive patients with CCRCC were prospectively evaluated with classical cytogenetic analysis. Chromosome 8q status was correlated with clinicopathological variables, and its impact on DSS was evaluated.

RESULTS:

Gain of 8q occurred in 28 tumors (8.3%). Gain of 8q was associated with a higher risk of regional lymph node (21.4% vs 6.2%, P = .011) and distant metastases (50.0% vs 24.4%, P = .006), and greater tumor sizes (P = .030). Patients with gain of 8q had a 3.22‐fold increased risk of death from CCRCC (P < .001). In multivariable analysis, gain of 8q was identified as an independent prognostic factor (hazard ratio, 2.37; P = .006). The concordance index of a multivariable base model increased significantly following inclusion of 8q gain (P = .0015).

CONCLUSIONS:

Gain of chromosome 8q occurs in a subset of CCRCCs and is associated with an increased risk of metastases and death from CCRCC. Because the proto‐oncogene c‐MYC is among the list of candidate genes located on 8q, our data suggest that these tumors may have unique pathways activated, which are associated with an aggressive tumor phenotype. If confirmed, defining tumors with gain of 8q may assist in identifying patients who would benefit for specific c‐MYC inhibitors or agents that target the MAPK/ERK (mitogen‐activated protein kinase) pathway. Cancer 2012. © 2012 American Cancer Society.     

Neoadjuvant targeted therapy and advanced kidney cancer: observations and implications for a new treatment paradigm

OBJECTIVE

To evaluate our early experience with neoadjuvant therapy (sunitinib or sorafenib) in advanced renal cell carcinoma (RCC), to explore the effect on both tumour biology and potential for downstaging advanced tumours, as systemic therapy for RCC has historically resulted in little if any primary tumour response, but recent experience with targeted therapy suggests otherwise.

PATIENTS AND METHODS

The preliminary experience with neoadjuvant therapy for the surgical management of RCC was reviewed at two large referral centres. Several unique patients were identified who had a novel response to systemic therapy that altered the surgical strategy.

RESULTS

Four patients who had targeted therapy before surgery are described and in whom there were effects on tumour biology not seen previously with chemotherapy and cytokine therapy. The selected patients who had neoadjuvant targeted therapy had shrinkage of a tumour thrombus in the inferior vena cava, nodal involvement, renal fossa recurrence and tumour within a solitary kidney.

CONCLUSIONS

The introduction of new molecular agents has revolutionized the treatment of patients with metastatic RCC. Responses to targeted therapy within the primary tumour, tumour thrombus, renal fossa recurrence, and lymph node metastases are novel findings not seen during treatment with immunotherapeutic‐based strategies. This might be a signal for urological surgeons to re‐evaluate the paradigm for the surgical management of advanced RCC. Potential applications are presented to encourage further investigations with targeted therapy in the neoadjuvant setting.     

Ureteral tumor thrombus from renal cell carcinoma extending into bladder

Tumor thrombus from renal cell carcinoma (RCC) usually occurs within the renal vein. We present the first report of a tumor thrombus from RCC extending from the kidney down the ureter and into the lumen of the bladder. This case both: (1) provides evidence for growth of RCC along the urinary tract, and (2) poses a staging dilemma.