Real-world experience managing unresectable or metastatic small cell carcinoma of the prostate.

INTRODUCTION: Unresectable and metastatic small cell carcinoma of the prostate (SCPC) is a rare and aggressive disease that is under-represented in clinical trials. We carried out a retrospective chart review of metastatic or unresectable SCPC patients at British Columbia (BC) Cancer centers, studying diagnosis and treatment patterns. METHODS: Drug-dispensing records from the six BC Cancer centers were obtained from 2002-2017. For each patient, information was collected on baseline information prior to therapy and for each line of treatment. Treatments at each line were compared regarding time to progression and overall survival by Kaplan-Meier curves. RESULTS: Forty-one patients received treatment; 65.6% had metastatic disease and 61% had pure small cell carcinoma. Median time from treatment to death was 10 months (95% confidence interval [CI] 6-16). Patients with initially prostate-confined disease had a better median overall survival (mOS) of 21 months (95% CI 13-34) compared to those with initially locally advanced (mOS 19 months, 95% CI 5-37) and metastatic disease (mOS 8 months, 95% CI 6-10) (log-rank p=0.0364). All patients received either cisplatin- or carboplatin-based combination chemotherapy as the first-line treatment and 36.7% received second-line therapy. Time to second-line therapy was eight months for those who presented with metastatic SCPC, compared to 13 months for those with initial non-metastatic SCPC. CONCLUSIONS: This single-province, multi-institution cohort reports data on unresectable and metastatic SCPC and highlights the poor prognosis of this rare disease entity.

Estradiol increases choice of cocaine over food in male rats.

Estradiol modulates the rewarding and reinforcing properties of cocaine in females, including an increase in selection of cocaine over alternative reinforcers. However, the effects of estradiol on male cocaine self-administration behavior are less studied despite equivalent levels of estradiol in the brains of adult males and females, estradiol effects on motivated behaviors in males that share underlying neural substrates with cocaine reinforcement as well as expression of estrogen receptors in the male brain. Therefore, we sought to characterize the effects of estradiol in males on choice between concurrently-available cocaine and food reinforcement as well as responding for cocaine or food in isolation. Male castrated rats (n=46) were treated daily with estradiol benzoate (EB) (5µg/0.1, S.C.) or vehicle (peanut oil) throughout operant acquisition of cocaine (1mg/kg, IV; FI20 sec) and food (3×45mg; FI20 sec) responding, choice during concurrent access and cocaine and food reinforcement under progressive ratio (PR) schedules. EB increased cocaine choice, both in terms of percent of trials on which cocaine was selected and the proportion of rats exhibiting a cocaine preference as well as increased cocaine, but not food, intake under PR. Additionally, within the EB treated group, cocaine-preferring rats exhibited enhanced acquisition of cocaine, but not food, reinforcement whereas no acquisition differences were observed across preferences in the vehicle treated group. These findings demonstrate that estradiol increases cocaine choice in males similarly to what is observed in females.

Preclinical Analysis of JAA-F11, a Specific Anti-Thomsen-Friedenreich Antibody via Immunohistochemistry and In Vivo Imaging.

The tumor specificity of JAA-F11, a novel monoclonal antibody specific for the Thomsen-Friedenreich cancer antigen (TF-Ag-alpha linked), has been comprehensively studied by in vitro immunohistochemical (IHC) staining of human tumor and normal tissue microarrays and in vivo biodistribution and imaging by micro-positron emission tomography imaging in breast and lung tumor models in mice. The IHC analysis detailed herein is the comprehensive biological analysis of the tumor specificity of JAA-F11 antibody performed as JAA-F11 is progressing towards preclinical safety testing and clinical trials. Wide tumor reactivity of JAA-F11, relative to the matched mouse IgG3 (control), was observed in 85% of 1269 cases of breast, lung, prostate, colon, bladder, and ovarian cancer. Staining on tissues from breast cancer cases was similar regardless of hormonal or Her2 status, and this is particularly important in finding a target on the currently untargetable triple-negative breast cancer subtype. Humanization of JAA-F11 was recently carried out as explained in a companion paper "Humanization of JAA-F11, a Highly Specific Anti-Thomsen-Friedenreich Pancarcinoma Antibody and In Vitro Efficacy Analysis" (Neoplasia 19: 716-733, 2017), and it was confirmed that humanization did not affect chemical specificity. IHC studies with humanized JAA-F11 showed similar binding to human breast tumor tissues. In vivo imaging and biodistribution studies in a mouse syngeneic breast cancer model and in a mouse-human xenograft lung cancer model with humanized 124I- JAA-F11 construct confirmed in vitro tumor reactivity and specificity. In conclusion, the tumor reactivity of JAA-F11 supports the continued development of JAA-F11 as a targeted cancer therapeutic for multiple cancers, including those with unmet need.

In vivo expansion and activation of γδ T cells as immunotherapy for refractory neuroblastoma: A phase 1 study.

INTRODUCTION: CD3+ γδ+ T cells comprise 2% to 5% of circulating T cells with Vγ9Vδ2+ cells the dominant circulating subtype. Vγ9Vδ2+ cells recognize non-peptide phosphoantigens and stress-associated NKG2D ligands expressed on malignant cells. Strategies that incorporate the tumoricidal properties of γδ T cells represent a promising immunotherapeutic strategy for treatment of solid malignancies including neuroblastoma (NB). In this prospective, non-randomized Phase I trial, we assessed whether circulating Vγ9Vδ2+ cells could be safely expanded using intravenous ZOL (Zoledronate [Zometa]) and subcutaneous Interleukin-2 (IL-2) in patients with refractory NB. METHODS: Patients 2 to 21 years of age with refractory neuroblastoma with no known curative therapeutic options received ZOL on day 1, and IL-2 on days 1 to 5 and 15 to 19 of each 28-day cycle (n = 4). Lymphocyte immunophenotyping was assessed weekly. Immunophenotyping studies from the treatment group were compared with healthy pediatric controls (n = 16; range, 5y-15y) and of untreated NB disease controls (n = 9; range, 4m-18y). RESULTS: Treatment was well tolerated with no unexpected grade 3 and 4 toxicities. Lymphocyte subset counts did not differ significantly between volunteers and disease controls with the exception of γδ+ T cell counts that were significantly higher in healthy volunteers (212 + 93 vs. 89 + 42, P = 0.05). Study patients showed increases in circulating γδ+ T cell count (3-10 fold) after the first week, increasing into the range seen in healthy volunteers (125 + 37, P = 0.1940). Interestingly, all ZOL + IL-2 treated patients showed significant increases in CD3+CD4+CD27CD127 T cells that rose weekly in 2 patients throughout the 4 weeks of observation (maximum 41% and 24% of total CD3+CD4+ T cells, respectively). CONCLUSIONS: In summary, combined ZOL and IL-2 is well tolerated and restored γδ+ T cell counts to the normal range with a moderate expansion of Natural Killer cells. Progressive increases in circulating CD4+ T cells with a regulatory phenotype cells may offset beneficial effects of this therapy.

Acute Promyelocytic Leukemia: A Review and Discussion of Variant Translocations.

The majority of patients with acute promyelocytic leukemia (APL) manifest the t(15;17)(q24.1;q21.2) translocation; however, a minor but significant proportion of patients with APL harbor complex, cryptic, or variant translocations, which typically involve RARA. With the exception of ZBTB16/RARA, these variants have similar morphologic and immunophenotypic features as classic APL. Study of the variant forms of APL not only gives insight into the pathogenesis of APL but also allows us to understand the mechanism of retinoid therapy. It is important to identify these cryptic and variant translocations because certain variants, including ZBTB16/RARA and STAT5B/RARA, are resistant to treatment with all-trans retinoic acid, arsenic trioxide, and anthracyclines.

Therapy-related myeloid neoplasm with bone marrow involvement, myelosarcoma, and a t(8;16)(p11.2;p13.3)-a case report.

Therapy-related leukemia is a well-documented complication of conventional therapy for cancer. Therapy-related acute myeloid leukemia (t-AML) is grouped along with therapy-related myelodysplastic syndrome (t-MDS) and therapy-related myelodysplastic syndrome/myeloproliferative neoplasms (t-MDS/MPNs) as therapy-related myeloid neoplasms (t-MNs) by the 2008 World Health Organization classification system. Therapy-related myeloid neoplasms differ clinically from their de novo counterparts in terms of response to therapy, aggressiveness of disease, and associated poor prognosis. The occurrence of extramedullary myeloid sarcomas with bone marrow involvement has been shown to be a poor prognostic indicator for patients with t-MN. The karyotype of leukemic blasts has also been reported to have a significant impact in t-MN and may predict survival and outcomes in patients. The t(8;16)(p11.2;p13.3) is a rare, balanced translocation that is frequently associated with the M4/M5 subtype of de novo acute myeloid leukemia. It has also been reported in patients with t-MN, typically in those with poor outcomes. Here we report a case of t-MN with myeloid sarcoma and bone marrow involvement in an adult patient with a karyotype of 47,XY,t(8;16)(p11.2;p13.3),+21 after rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) chemotherapy for follicular lymphoma.

Physician and nurse beliefs of phase 1 trials in pediatric oncology.

BACKGROUND: In order to improve the survival of children with cancer, novel therapies must be identified. Promising agents are tested in phase 1 trials in order to identify appropriate dosing and describe toxicity in children. The identification and referral of candidate patients for phase 1 trials rely heavily on medical providers who must balance their own perceptions of phase 1 trials with the desires and willingness of the patient and his/her family. OBJECTIVE: The goal of the present study was to evaluate and compare physician and nurse perceptions regarding the beliefs, expectations, and perceived benefits of phase 1 clinical trials. METHODS: A survey consisting of 21 questions was sent to 419 physicians and nurses practicing pediatric oncology at 30 different institutions. With the exception of 10 demographic questions, items were either rank ordered or rated on 5-point Likert scales. RESULTS: Ninety-four physicians and 122 nurses completed the online survey. Physicians and nurses differed in their knowledge of the goals and medical effects of phase 1 clinical trials. CONCLUSIONS: Physicians and nurses hold positive beliefs regarding phase 1 clinical trials and support their role in the treatment of children with cancer. Education is necessary to increase nurses' knowledge of the goals and outcomes. IMPLICATIONS FOR PRACTICE: These findings suggest that continued education of nurses as well as physicians about the goals, execution, and monitoring of phase 1 therapy would be worthwhile.

Performance evaluation comparison of 3 commercially available PCR-based KRAS mutation testing platforms.

The identification of KRAS mutations in patients with certain types of cancer, including colonic adenocarcinoma and non-small cell lung carcinoma, has become increasingly important as these patients are contraindicated from receiving epidermal growth factor receptor-targeted therapies. Several polymerase chain reaction (PCR)-based tests are commercially available for KRAS mutation testing including Applied Biosystems KRAS Mutation Analysis on the ABI3130xl, Qiagen therascreen KRAS RGQ PCR on the Rotor-Gene Q MDx, and Qiagen KRAS Pyro on the PyroMark Q24; however, these tests have not been compared side by side. The purpose of this study was to evaluate the performance characteristics and workflow for 3 PCR-based methods of detecting KRAS mutation status. We evaluated the performance characteristics and workflow for 3 commercially available KRAS mutation detection platforms. All of the 188 samples run were successful, with 29% being positive for the KRAS mutation. Of the positive tests, Applied Biosystems detected 84% of the positive cases, whereas Qiagen therascreen RGQ and Qiagen KRAS Pyro detected 100% of the positive cases. In cases of discrepancy between Applied Biosystems and therascreen RGQ, Pyro agreed with therascreen RGQ 95% of the time. Qiagen therascreen RGQ and Pyro were comparable in terms of sensitivity, specificity, positive predictive value, negative predictive value, and accuracy, with all values being 100%. All 3 techniques accurately identified the appropriate mutation in the known control specimens. In summary, all 3 tests are relatively comparable for detecting the KRAS mutation, with Applied Biosystems having a slightly lower sensitivity, negative predictive value, and accuracy than therascreen RGQ and Pyro.

Biomarkers in bladder cancer: translational and clinical implications.

Bladder cancer is associated with high recurrence and mortality rates. These tumors show vast heterogeneity reflected by diverse morphologic manifestations and various molecular alterations associated with these disease phenotypes. Biomarkers that prospectively evaluate disease aggressiveness, progression risk, probability of recurrence and overall prognosis would improve patient care. Integration of molecular markers with conventional pathologic staging of bladder cancers may refine clinical decision making for the selection of adjuvant and salvage therapy. In the past decade, numerous bladder cancer biomarkers have been identified, including various tumor suppressor genes, oncogenes, growth factors, growth factor receptors, hormone receptors, proliferation and apoptosis markers, cell adhesion molecules, stromal factors, and oncoproteins. Recognition of two distinct pathways for urothelial carcinogenesis represents a major advance in the understanding and management of this disease. Nomograms for combining results from multiple biomarkers have been proposed to increase the accuracy of clinical predictions. The scope of this review is to summarize the major biomarker findings that may have translational and clinical implications.

Physician perceptions and beliefs of phase I trials in pediatric oncology.

The identification and referral of candidate patients for phase I trials relies heavily on pediatric oncologists who must balance their own perceptions of phase I trials with the desires of the patient and his/her family. A survey was sent to 419 physicians practicing pediatric oncology at 30 different institutions. Results indicated significant differences between physicians who practiced at institutions that participated in phase I consortia versus those who did not. The findings of the survey may be used to enhance the design and execution of phase I trials and to educate oncologists about the goals of phase I trials.

The utility of fine-needle aspiration in the diagnosis of primary and metastatic tumors to the lung: a retrospective examination of 1,032 cases.

BACKGROUND: With the emergence of improved treatment strategies for patients with malignant lung tumors, it has become increasingly important to adequately diagnose and subclassify lung lesions. In our large retrospective study, we assessed the utility of fine-needle aspiration (FNA) in the diagnosis of primary and metastatic tumors to the lung. METHODS: A computerized search of our laboratory informatics system was performed to identify cases from FNA of the lung and FNA of metastatic lung cancers to other sites. All of the corresponding surgical pathology reports were also reviewed. All of the cases were categorized as atypical (A), benign (B), malignant (M), nondiagnostic (ND), or suspicious (S) for data analysis purposes. RESULTS: A total of 1,032 FNA cases were categorized as follows: 34 (3.3%) A, 142 (13.8%) B, 717 (69.5%) M, 121 (11.7%) ND, and 18 (1.7%) S. Of the 717 cases of malignant FNA, a specific tumor type was able to be rendered on cytomorphology alone or with the help of immunostains in 99% as follows: adenocarcinoma (296 cases, 41%), squamous cell carcinoma (158 cases, 22%), metastatic tumors (123 cases, 17%), small cell carcinoma (56 cases, 8%), non-small cell lung carcinoma (NSCLC) (58 cases, 8%), neuroendocrine carcinoma (15 cases, 2%), and poorly differentiated carcinoma (4 cases, 1%). Out of all NSCLC cases, 89% were able to be subclassified as either adenocarcinoma or squamous carcinoma. The most frequent origins of metastatic tumors to the lung were renal cell carcinoma (n = 22), melanoma (n = 17), colon (n = 15), breast (n = 14), and urothelial carcinoma (n = 10). There was also metastasis from 18 other organs with fewer than 5 cases each. There were 333 correlated histologic specimens including 191 small biopsies and 142 resection specimens. Diagnostic sensitivity and specificity for malignancy were 96 and 100%, respectively. Diagnostic accuracy was 97%. Sampling error resulted in 8 false-negative cases on FNA. CONCLUSIONS: FNA is both sensitive and specific in the diagnosis and subclassification of both primary and metastatic lung tumors. Eighty-nine percent of NSCLC cases were able to be further subclassified as adenocarcinoma or squamous cell carcinoma by FNA.

Lymph node-positive prostate cancer: current issues, emerging technology and impact on clinical outcome.

Lymph node metastasis in patients with prostate cancer indicates a poorer prognosis compared with patients without lymph node metastasis; however, some patients with node-positive disease have long-term survival. Many studies have attempted to discern what characteristics of lymph node metastasis are prognostically significant. These characteristics include nodal tumor volume, number of positive lymph nodes, lymph node density, extranodal extension, lymphovascular invasion and tumor dedifferentiation. Favorable characteristics of regional lymph node involvement included a smaller tumor size and smaller tumor volume. However, the current staging system for prostate cancer does not provide different subclassifications for patients with node-positive prostate cancer. In recent years numerous advanced technologies for the detection of lymph node metastasis have been developed, including molecular imaging techniques and the CellSearch Circulating Tumor Cell System. With the increased detection of patients with prostate cancer, emergence of new technology to identify lymph node metastasis and the number of radical prostatectomies being performed on the rise, subclassifying patients with lymph node-positive disease is imperative. Subclassification would provide a better picture of patient prognosis and allow for a better understanding of targeted therapies to treat patients with lymph node metastasis.