Cary N. Robertson

A progress report on the treatment of 157 patients with advanced cancer using lymphokine-activated killer cells and interleukin-2 or high-dose interleukin-2 alone.

We studied the effects of adoptive immunotherapy with lymphokine-activated killer (LAK) cells plus interleukin-2 or therapy with high-dose interleukin-2 alone in 157 patients with metastatic cancer for whom standard therapy had proved ineffective or no standard effective treatment was available. One hundred eight patients were treated with 127 courses of LAK cells plus interleukin-2, and 49 patients were treated with 53 courses of high-dose interleukin-2 alone. Of 106 evaluable patients receiving LAK cells plus interleukin-2, 8 had complete responses, 15 had partial responses, and 10 had minor responses. The median duration of response was 10 months among those with complete responses and 6 months among those with partial responses; the patient with the longest complete response was still in remission 22 months after treatment. Of 46 evaluable patients treated with high-dose interleukin-2 alone, 1 had a complete response (remission greater than 4 months), 5 had partial responses (2, greater than 3, greater than 5, 7, and greater than 11 months), and 1 had a minor response. Seven of the total of nine complete responses still remain in remission. Hypotension, weight gain, oliguria, and elevation of bilirubin and creatinine levels were common, but these side effects resolved promptly after interleukin-2 administration was stopped. There have been four treatment-related deaths among these 157 patients. This immunotherapeutic approach can result in marked tumor regression in some patients for whom no other effective therapy is available at present. Determining its ultimate role in cancer therapy awaits further attempts to increase the therapeutic efficacy of treatment and decrease its toxicity and complexity.

Immunotherapy of patients with advanced cancer using tumor-infiltrating lymphocytes and recombinant interleukin-2: a pilot study.

Clinical investigations using the adoptive transfer of lymphokine-activated killer (LAK) cells and recombinant interleukin-2 (rIL-2) to treat patients with advanced cancer have yielded encouraging results. We have thus sought ways to enhance the effectiveness of adoptive immunotherapy while minimizing its toxic side effects. Murine experiments have identified tumor-infiltrating lymphocytes (TIL) as killer cells more effective than LAK cells and less dependent on adjunctive systemically administered IL-2 to mediate antitumor effects. Accordingly, we performed a pilot protocol to investigate the feasibility and practicality of administering IL-2-expanded TIL to humans with metastatic cancers. Twelve patients, including six with melanoma, four with renal cell carcinoma, one with breast carcinoma, and one with colon carcinoma, were treated with varying doses and combinations of TIL (8.0 X 10(9) to 2.3 X 10(11) cells per patient), IL-2 (10,000 to 100,000 U/kg three times daily to dose-limiting toxicity), and cyclophosphamide (CPM) (up to 50 mg/kg). Two partial responses (PR) to therapy were observed: pulmonary and mediastinal masses regressed in a patient with melanoma, and a lymph node mass regressed in a patient with renal cell carcinoma. One additional patient with breast cancer experienced a partial regression of disease in lymph nodal and cutaneous sites with complete elimination of malignant cells from a pleural effusion, although cutaneous disease recurred at 4 weeks. The toxicities of therapy were similar to those ascribed to IL-2; no toxic effects were directly attributable to TIL infusions. In five of six melanoma patients, TIL demonstrated lytic activity specific for the autologous tumor target in short-term chromium-release assays, distinct from the nonspecific lytic activity characteristic of LAK cells. This study represents an initial attempt to identify and use lymphocyte subsets with enhanced tumoricidal capacity in the adoptive immunotherapy of human malignancies.

A retrospective comparison of anesthetic management of robot-assisted laparoscopic radical prostatectomy versus radical retropubic prostatectomy

STUDY OBJECTIVE To compare anesthetic management and postoperative outcomes in patients undergoing robot-assisted laparoscopic radical prostatectomy (RALP) and radical retropubic prostatectomy (RRP) with general anesthesia. DESIGN Retrospective database study of RALP and RRP patients at Duke University Medical Center from 6/2003 to 6/2006. SETTING University teaching hospital. PATIENTS 541 ASA physical status I, II, and III men, 280 of whom were RRP patients and 256 RALP patients. MEASUREMENTS Patient demographics, intraoperative fluids and blood products, hemodynamic parameters, pain scores in the Postanesthesia Care Unit (PACU), intraoperative and postoperative analgesic consumption, need for rescue antiemetics in the PACU, and intraoperative use of vasopressors and antihypertensives, were all recorded. Additional data included postoperative transfusion data; clinical status of the patients cancer preoperatively and postoperatively; hematocrit, platelet count, and creatinine levels; and length of hospital stay. MAIN RESULTS Estimated blood loss (EBL) was higher for RRP than RALP patients (mean +/- SD; 1,087 +/- 853 mL vs. 287 +/- 317 mL; P < 0.0001). Likewise, 24% of RRP patients received red blood cell (RBC) transfusions intraoperatively, compared with 0.4% RALP patients (P < 0.0001). Intraoperatively, RALP patients received more antihypertensive agents (37% vs. 21%; P < 0.0001), and fewer vasopressors (63% vs. 78%; P < 0.0001) than did RRP patients. The two groups had similar morphine-equivalent opioid use intraoperatively, but in the PACU, RALP patients required fewer morphine equivalents (mean +/- SD; 11.4 +/- 7.7 mg vs. 14.9 +/- 9.8 mg; P < 0.0001). The RALP patients had longer surgical times (mean +/- SD; 296 +/- 76 vs.193 +/- 69 min; P < 0.0001) but shorter PACU stays (mean +/- SD; 113 +/- 55 min vs. 143 +/- 58 min; P < 0.0001) and shorter hospital stays (mean +/- SD; 44 +/- 77 hrs vs. 56 +/- 26 hrs; P = 0.009). CONCLUSIONS Duration of surgery was greater with RALP, but it was associated with less EBL, fewer transfusions of blood products, and shorter PACU and hospital stays.

Comparison of [18F]Fluorocholine and [18F]Fluorodeoxyglucose for Positron Emission Tomography of Androgen Dependent and Androgen Independent Prostate Cancer

Purpose: Positron emission tomography (PET) imaging is used for the metabolic evaluation of cancer. [18F]fluorodeoxyglucose (FDG) is commonly used as a radiotracer but its low cellular uptake rate in prostate cancer limits its usefulness. We evaluated the novel choline analog [18F]fluorocholine (FCH) for detecting androgen dependent and androgen independent prostate cancer, and its metastases.Materials and Methods: The cellular uptake of FCH and FDG was compared in cultured prostate cancer cells (LNCaP and PC-3). FCH and FDG were injected into nude mice xenografts (CWR-22 and PC-3) and radiotracer uptake in various organs were evaluated. Patients with androgen dependent (9) and independent (9) prostate cancer were studied by FCH and FDG PET.Results: FCH uptake was 849% and 60% greater than FDG uptake in androgen dependent (LNCaP) and independent (PC-3) cells, respectively. The addition of hemicholinium-3 (5 mM.) 30 minutes before radiotracer administration inhibited FCH uptake by 79% and 70% in LNCaP and ...

PILOT STUDY OF DIETARY FAT RESTRICTION AND FLAXSEED SUPPLEMENTATION IN MEN WITH PROSTATE CANCER BEFORE SURGERY: EXPLORING THE EFFECTS ON HORMONAL LEVELS, PROSTATE-SPECIFIC ANTIGEN, AND HISTOPATHOLOGIC FEATURES

OBJECTIVES Dietary fat and fiber affect hormonal levels and may influence cancer progression. Flaxseed is a rich source of lignan and omega-3 fatty acids and may thwart prostate cancer. The potential effects of flaxseed may be enhanced with concomitant fat restriction. We undertook a pilot study to explore whether a flaxseed-supplemented, fat-restricted diet could affect the biomarkers of prostatic neoplasia. METHODS Twenty-five patients with prostate cancer who were awaiting prostatectomy were instructed on a low-fat (20% of kilocalories or less), flaxseed-supplemented (30 g/day) diet. The baseline and follow-up levels of prostate-specific antigen, testosterone, free androgen index, and total serum cholesterol were determined. The tumors of diet-treated patients were compared with those of historic cases (matched by age, race, prostate-specific antigen level at diagnosis, and biopsy Gleason sum) with respect to apoptosis (terminal deoxynucleotidyl transferase [TdT]-mediated dUTP-biotin nick end-labeling [TUNEL]) and proliferation (MIB-1). RESULTS The average duration on the diet was 34 days (range 21 to 77), during which time significant decreases were observed in total serum cholesterol (201 +/- 39 mg/dL to 174 +/- 42 mg/dL), total testosterone (422 +/- 122 ng/dL to 360 +/- 128 ng/dL), and free androgen index (36.3% +/- 18.9% to 29.3% +/- 16.8%) (all P <0.05). The baseline and follow-up levels of prostate-specific antigen were 8.1 +/- 5.2 ng/mL and 8.5 +/- 7.7 ng/mL, respectively, for the entire sample (P = 0.58); however, among men with Gleason sums of 6 or less (n = 19), the PSA values were 7.1 +/- 3.9 ng/mL and 6.4 +/- 4.1 ng/mL (P = 0.10). The mean proliferation index was 7.4 +/- 7.8 for the historic controls versus 5.0 +/- 4.9 for the diet-treated patients (P = 0.05). The distribution of the apoptotic indexes differed significantly (P = 0.01) between groups, with most historic controls exhibiting TUNEL categorical scores of 0; diet-treated patients largely exhibited scores of 1. Both the proliferation rate and apoptosis were significantly associated with the number of days on the diet (P = 0.049 and P = 0.017, respectively). CONCLUSIONS These pilot data suggest that a flaxseed-supplemented, fat-restricted diet may affect prostate cancer biology and associated biomarkers. Further study is needed to determine the benefit of this dietary regimen as either a complementary or preventive therapy.

Collecting duct carcinoma of the kidney

Collecting duct carcinoma is an unusual variant of renal cell carcinoma, whose appearance and behavior are not well established. We identified six cases of collecting duct carcinoma in our files. The clinical, pathologic, and immunohistochemical characteristics of these tumors are reported. The most common symptom was gross hematuria (four cases). Two patients had cervical adenopathy due to metastatic tumor. Four rapidly developed systemic metastases and died within 4 to 24 months. The primary renal tumors were located predominantly in the renal medulla and pelvis and had a partially cystic white-gray appearance. Histologic examination showed prominent tubulopapillary structures, nests of clear cells, and infiltrating tubules in a dense desmoplastic stroma. Atypical hyperplastic changes were found in some of the adjacent collecting ducts. Mucicarminophilic material was present in glandular elements in all six cases. Immunohistochemical studies revealed positivity with antibodies to epithelial membrane antigen, keratins, peanut agglutinin, vimentin, Leu M1 and lysozyme. The location of this tumor in the medulla, its distinctive histologic appearance, mucin positivity, expression of high molecular weight cytokeratins, and peanut agglutinin suggest that this is a distinct clinicopathologic entity which has an aggressive clinical course.

Helping patients with localized prostate carcinoma manage uncertainty and treatment side effects: nurse-delivered psychoeducational intervention over the telephone.

The objective of this study was to test the efficacy of an individualized uncertainty management intervention delivered by telephone to Caucasian and African‐American men with localized prostate carcinoma and directed at managing the uncertainties of their disease and treatment.

Flaxseed Supplementation (Not Dietary Fat Restriction) Reduces Prostate Cancer Proliferation Rates in Men Presurgery

Background: Prostate cancer affects one of six men during their lifetime. Dietary factors are postulated to influence the development and progression of prostate cancer. Low-fat diets and flaxseed supplementation may offer potentially protective strategies. Methods: We undertook a multisite, randomized controlled trial to test the effects of low-fat and/or flaxseed-supplemented diets on the biology of the prostate and other biomarkers. Prostate cancer patients (n = 161) scheduled at least 21 days before prostatectomy were randomly assigned to one of the following arms: (a) control (usual diet), (b) flaxseed-supplemented diet (30 g/d), (c) low-fat diet (<20% total energy), or (d) flaxseed-supplemented, low-fat diet. Blood was drawn at baseline and before surgery and analyzed for prostate-specific antigen, sex hormone-binding globulin, testosterone, insulin-like growth factor-I and binding protein-3, C-reactive protein, and total and low-density lipoprotein cholesterol. Tumors were assessed for proliferation (Ki-67, the primary endpoint) and apoptosis. Results: Men were on protocol an average of 30 days. Proliferation rates were significantly lower (P < 0.002) among men assigned to the flaxseed arms. Median Ki-67-positive cells/total nuclei ratios (×100) were 1.66 (flaxseed-supplemented diet) and 1.50 (flaxseed-supplemented, low-fat diet) versus 3.23 (control) and 2.56 (low-fat diet). No differences were observed between arms with regard to side effects, apoptosis, and most serologic endpoints; however, men on low-fat diets experienced significant decreases in serum cholesterol (P = 0.048). Conclusions: Findings suggest that flaxseed is safe and associated with biological alterations that may be protective for prostate cancer. Data also further support low-fat diets to manage serum cholesterol. (Cancer Epidemiol Biomarkers Prev 2008;17(12):3577–87)

Adjuvant radiotherapy for pathologic stage T3 4 adenocarcinoma of the prostate: Ten-year update

PURPOSE To determine the role of adjuvant postoperative radiotherapy (RT) following radical prostatectomy (RP) in a group of patients with pathologic Stage T3/4 adenocarcinoma of the prostate followed for a median of 10 years after treatment. METHODS AND MATERIALS Between 1970 and 1983, 159 patients underwent RP for newly diagnosed adenocarcinoma of the prostate and were found to have pathologic Stage T3/4. Forty-six received adjuvant RT and 113 did not. Radiotherapy usually consisted of 45-50 Gy to the whole pelvis followed by a boost to the prostate bed of 10-15 Gy, to a total dose of 55-65 Gy. Patients were analyzed with respect to survival, disease-free survival, local control, and freedom from distant metastases. A rising prostate-specific antigen in the absence of other evidence of relapse was scored as a separate category of recurrence. RESULTS Both groups of patients have been followed for a median of 10 years. The actuarial survival at 10 and 15 years was 62% and 62% for the RT group compared to 52% and 37%, respectively, for the RP group (p = 0.18). The disease-free survival for the Rt group was 55% and 48% at 10 and 15 years, respectively, compared to 37% and 33% for the RP group (p = 0.16). Similarly, there was no difference in the rate of distant metastases between the two groups. In contrast, the local relapse rate was significantly reduced by the addition of postoperative radiotherapy. The actuarial local control rate at 10 and 15 years was 92% and 82%, respectively, for the RT group vs 60% and 53% for the RP group (p = 0.002). CONCLUSIONS While postoperative pelvic RT significantly improves local control compared to RP alone for pathologic Stage T3/4 prostate cancer, it has no impact on distant metastases and consequently does not improve survival. These data are consistent with the conclusion that many patients with pathologic Stage T3/4 prostate cancer have occult metastases at presentation and will not be cured by local therapies alone. The optimal treatment for this patient population remains to be established.

High-intensity focused ultrasound for prostate cancer: comparative definitions of biochemical failure.

To compare the specificity and sensitivity of different definitions of biochemical failure in patients treated with high‐intensity focused ultrasound (HIFU) for prostate cancer, to identify the most accurate predictor of clinical failure after HIFU.