The impact of genetic aberrations on response to radium-223 treatment for castration-resistant prostate cancer with bone metastases.

BACKGROUND: Radium (Ra)-223 is an established treatment option for patients with metastatic castrate-resistant prostate cancer (mCRPC) who have symptomatic bone metastases without soft tissue disease. Studies have indicated genetic aberrations that regulate DNA damage response (DDR) in prostate cancer can increase susceptibility to treatments such as poly ADP-ribose polymerase inhibitors and platinum-based therapies. This study aims to evaluate mCRPC response to Ra-223 stratified by tumor genomics. METHODS: This is a retrospective study of mCRPC patients who received Ra-223 and genetic testing within the Mayo Clinic database (Arizona, Florida, and Minnesota) and Tulane Cancer Center. Patient demographics, genetic aberrations, treatment responses in terms of alkaline phosphatase (ALP) and prostate-specific antigen (PSA), and survival were assessed. Primary end points were ALP and PSA response. Secondary end points were progression-free survival (PFS) and overall survival (OS) from time of first radium treatment. RESULTS: One hundred and twenty-seven mCRPC patients treated with Ra-223 had germline and/or somatic genetic sequencing. The median age at time of diagnosis and Ra-223 treatment was 61.0 and 68.6 years, respectively. Seventy-nine (62.2%) had Gleason score ≥ 8 at time of diagnosis. 50.4% received prior docetaxel, and 12.6% received prior cabazitaxel. Notable alterations include TP53 (51.7%), BRCA 1/2 (15.0%), PTEN (13.4%), ATM (11.7%), TMPRSS2-ERG (8.2%), RB deletion (3.4%), and CDK12 (1.9%). There was no significant difference in ALP or PSA response among the different genetic aberrations. Patients with a TMPRSS2-ERG mutation exhibited a trend toward lower OS 15.4 months (95% confidence interval [CI] 10.0-NR) versus 26.8 months (95% CI 20.9-35.1). Patients with an RB deletion had a lower PFS 6.0 months (95% CI 1.28-NR) versus 9.0 months (95% CI 7.3-11.1) and a lower OS 13.9 months (95% CI 5.2-NR) versus 26.5 months (95% CI 19.8-33.8). CONCLUSIONS: Among mCRPC patients treated with Ra-223 at Mayo Clinic and Tulane Cancer Center, we did not find any clear negative predictors of biochemical response or survival to treatment. TMPRSS2-ERG and RB mutations were associated with a worse OS. Prospective studies and larger sample sizes are needed to determine the impact of genetic aberrations in response to Ra-223.

Testicular Cancer, Version 2.2020, NCCN Clinical Practice Guidelines in Oncology.

Testicular cancer is relatively uncommon and accounts for <1% of all male tumors. However, it is the most common solid tumor in men between the ages of 20 and 34 years, and the global incidence has been steadily rising over the past several decades. Several risk factors for testicular cancer have been identified, including personal or family history of testicular cancer and cryptorchidism. Testicular germ cell tumors (GCTs) comprise 95% of malignant tumors arising in the testes and are categorized into 2 main histologic subtypes: seminoma and nonseminoma. Although nonseminoma is the more clinically aggressive tumor subtype, 5-year survival rates exceed 70% with current treatment options, even in patients with advanced or metastatic disease. Radical inguinal orchiectomy is the primary treatment for most patients with testicular GCTs. Postorchiectomy management is dictated by stage, histology, and risk classification; treatment options for nonseminoma include surveillance, systemic therapy, and nerve-sparing retroperitoneal lymph node dissection. Although rarely occurring, prognosis for patients with brain metastases remains poor, with >50% of patients dying within 1 year of diagnosis. This selection from the NCCN Guidelines for Testicular Cancer focuses on recommendations for the management of adult patients with nonseminomatous GCTs.

Proposed prognostic scoring system evaluating risk factors for biochemical recurrence of prostate cancer after salvage radiation therapy.

OBJECTIVE: To update a previously proposed prognostic scoring system that predicts risk of biochemical recurrence (BCR) after salvage radiation therapy (SRT) for recurrent prostate cancer when using additional patients and a PSA value of 0.2 ng/mL and rising as the definition of BCR. PATIENTS AND METHODS: We included 577 patients who received SRT for a rising PSA after radical prostatectomy in this retrospective cohort study. Clinical, pathological, and SRT characteristics were evaluated for association with BCR using relative risks (RRs) from multivariable Cox regression models. RESULTS: With a median follow-up of 5.5 years after SRT, 354 patients (61%) experienced BCR. At 5 years after SRT, 40% of patients were free of BCR. Independent associations with BCR were identified for the PSA level before SRT (RR [doubling]: 1.25, P < 0.001), pathological tumour stage (RR [T3a vs T2] 1.21, P = 0.19; RR [T3b/T4 vs T2] 2.09, P < 0.001; overall P < 0.001), Gleason score (RR [7 vs <7] 1.63, P < 0.001; RR [8-10 vs <7] 2.28, P < 0.001; overall P < 0.001), and surgical margin status (RR [positive vs negative] 0.71, P = 0.003). We combined these four variables to create a prognostic scoring system that predicted BCR risk with a c-index of 0.66. Scores ranged from 0 to 7, and 5-year freedom from BCR for different levels of the score was as follows: Score = 0-1: 66%, Score = 2: 46%, Score = 3: 28%, Score = 4: 19%, and Score = 5-7: 15%. CONCLUSION: We developed a scoring system that provides an estimation of the risk of BCR after SRT. These findings will be useful for patients and physicians in decision making for radiation therapy in the salvage setting.

Assessment of bladder filling during prostate cancer radiation therapy with ultrasound and cone-beam CT.

Prostate cancer patients undergoing external beam radiation therapy (EBRT) benefit from a full bladder to decrease bowel and bladder toxicity. Ultrasound may offer a proxy metric for evaluation, sparing CBCT dosing. Patients were prospectively enrolled pre-simulation from January 2017 to February 2018. Bladder volume was evaluated prior to RT using US daily and CBCT for three daily treatments and then weekly unless otherwise indicated. 29 patients completed median 40 days of RT, resulting in 478 CBCT and 1,099 US bladder volumes. 21 patients were treated to intact glands and 8 to the post-prostatectomy bed. Median patient age was 70 years. Bladder volume on CBCT and US positively correlated (r = 0.85), with average bladder volume for all patients of 162 mL versus 149 mL, respectively. Bladder volume during treatment was consistently lower than the volume at CT simulation (153 mL vs 194 mL, p<0.01) and progressively declined during treatment. Patients older than 70 years presented with lower average bladder volumes than those < 70 years (122 mL vs 208 mL, respectively, p<0.01). Patients with the highest agreement between CBCT and US (<10% variability) had higher average bladder volumes (192 mL vs 120 mL, p=0.01). US was found to be an accurate measure of bladder volume and may be used to monitor daily bladder volumes in patients being treated with radiation for prostate cancer.

Dosimetric Analysis of Axillary Lymph Node Coverage Using High Tangents in the Prone Position for Left-Sided Breast Cancers.

AIM/OBJECTIVE: Prone positioning is often used to reduce the dose to organs at risk during adjuvant breast irradiation. High tangents are used with supine treatments in patients with the low-volume nodal disease to increase nodal coverage while minimizing toxicities. Our study aims to evaluate nodal coverage for patients treated in the prone position with high tangents. MATERIALS AND METHODS: Our study analyzed the plans for 20 patients with early-stage, left-sided breast cancers treated at our institution from 2018 to 2019. All patients were treated in the prone position. Axillary nodal levels I-III were contoured, and treatment plans were generated using high tangents. The heart, bilateral lungs, and breast tissue were retrospectively contoured. All plans were evaluated to a dose of 42.4 Gy in 16 fractions. RESULTS: Level I lymph node levels had a mean coverage of 99% of the prescription dose (range: 98-100%). Similarly, level II coverage was approximately 88% (range: 65-100%). The mean coverage for level III was approximately 25% (range: 0-52%). The mean heart dose, mean lung volume receiving ≥20 Gy (V20) for the bilateral lungs, and ipsilateral V20 were 1.69 Gy, 1.64%, and 3.56%, respectively. CONCLUSION: Treating patients in the prone position with high tangents provides excellent coverage of axillary levels I and II, although there is minimal coverage of axillary level III. Prospective trials are needed to evaluate the clinical outcomes when treating patients with high tangents in the prone position.

Molecular Investigation of miRNA Biomarkers as Chemoresistance Regulators in Melanoma: A Protocol for Systematic Review and Meta-Analysis.

INTRODUCTION: Melanoma is a global disease that is predominant in Western countries. However, reliable data resources and comprehensive studies on the theragnostic efficiency of miRNAs in melanoma are scarce. Hence, a decisive study or comprehensive review is required to collate the evidence for profiling miRNAs as a theragnostic marker. This protocol details a comprehensive systematic review and meta-analysis on the impact of miRNAs on chemoresistance and their association with theragnosis in melanoma. Methods and analysis: The articles will be retrieved from online bibliographic databases, including Cochrane Review, EMBASE, MEDLINE, PubMed, Scopus, Science Direct, and Web of Science, with different permutations of 'keywords'. To obtain full-text papers of relevant research, a stated search method will be used, along with selection criteria. The Preferred Reporting Items for Systematic Reviews and Meta-Analysis for Protocols 2015 (PRISMA-P) standards were used to create this study protocol. The hazard ratio (HR) with a 95% confidence interval will be analyzed using Comprehensive Meta-Analysis (CMA) software 3.0. (CI). The pooled effect size will be calculated using a random or fixed-effects meta-analysis model. Cochran's Q test and the I2 statistic will be used to determine heterogeneity. Egger's bias indicator test, Orwin's and the classic fail-safe N tests, the Begg and Mazumdar rank collection test, and Duval and Tweedie's trim and fill calculation will all be used to determine publication bias. The overall standard deviation will be evaluated using Z-statistics. Subgroup analyses will be performed according to the melanoma participants' clinicopathological and biological characteristics and methodological factors if sufficient studies and retrieved data are identified and available. The source of heterogeneity will be assessed using a meta-regression analysis. A pairwise matrix could be developed using either a pairwise correlation or expression associations of miRNA with patients' survival for the same studies.

Crizotinib-associated renal cyst development may be associated with prolonged progression-free survival in patients with ALK-positive non-small-cell lung cancer: Case report and review of the literature.

Non-small cell lung cancer patients with anaplastic lymphoma kinase or c-ros oncogene 1 mutations who are treated with the tyrosine kinase inhibitor crizotinib rarely develop crizotinib-associated renal cysts (CARCs). Here, we present a case report and review of the literature supporting the hypothesis that CARCs may correlate positively with progression-free survival.

Public interest in stereotactic body radiation therapy (SBRT) and stereotactic radiosurgery (SRS) in the United States.

Stereotactic body radiation therapy (SBRT) and stereotactic radiosurgery have become widely used in both palliative and curative treatments for variety of primary and secondary malignancies. Although the indications and use of stereotactic techniques have increased substantially in the past decades, there been no studies to date analyzing public interest in these techniques. Using Google Trends (Google LLC, Mountain View, CA), four search terms ("SBRT," "stereotactic radiosurgery," "Gamma Knife" and "Cyberknife") were analyzed in the U.S. from January 2004 to June 2019. Each term was assigned a relative interest score based on frequency of searches. "SBRT" is becoming an increasingly popular search term, reaching peak interest in October 2018. Conversely, "stereotactic radiosurgery" and "Gamma Knife" radiosurgery initially had high interest, before declining over the past decade. "Cyberknife" was most popular in the mid-2000s but decreased steadily since that time. These trends were subsequently compared against PubMed publication data over the same time.

Current use of stereotactic body radiation therapy for low and intermediate risk prostate cancer: A National Cancer Database Analysis.

BACKGROUND: Recent studies have demonstrated both safety and efficacy of stereotactic body radiation therapy (SBRT) as monotherapy in the treatment of low and intermediate risk prostate cancer. Our study aims to provide an update analyzing the use of SBRT compared with conventional and hypofractionated regimens in the United States from 2004 to 2015. METHODS: This retrospective review was conducted using the National Cancer Database. We identified 114,931 patients with sufficient diagnostic and treatment information treated with definitive radiation therapy in the United States from 2004 to 2015. The relative utilization of conventional fractionation (defined as 180-200 cGy per fraction and >5 fractions), moderate hypofractionation (defined as >200 cGy per fraction and >5 fractions), and SBRT (defined as >200 cGy per fraction and 5 fractions or less) were compared over the same time period. Logistic regression models were used to estimate trends. Demographic factors were collected and analyzed using chi-squared tests and independent t-tests. RESULTS: The proportion of prostate cancer patients receiving SBRT increased substantially from 0.9% in 2004 to 19.5% in 2015. Moderate hypofractionation exhibited some growth, increasing from 2.7% of patients to 4.7% in 2015. Conventional fractionation use declined significantly from 96.3% in 2004 to 75.8% in 2015. Notably, there was a sharp decline in the absolute number of patients receiving conventional fractionation in 2011, from 14,699 patients treated in 2009 to 1492 in 2011. Patients treated with SBRT were more likely to be treated in academic centers, younger, and have higher income than other fractionation groups. The most frequently used fractionation schedule was 3625 cGy in five fractions. CONCLUSIONS: The use of SBRT for low and intermediate risk prostate cancer has increased significantly from 2004 to 2015, coinciding with recently published data supporting the efficacy and favorable toxicity profile of this technique.

The management of elderly patients with brain metastases from breast cancer.

Breast cancer is the most common type of malignancy diagnosed in women worldwide, as well as the second most common cause of metastatic brain lesions in the general population. Most breast cancer patients enrolled in clinical trials are relatively young. Elderly patients, as compared to their younger counterparts, pose unique clinical scenarios because there is limited data in this subpopulation of patients with brain metastases from breast cancer. Elderly patients are commonly treated with less aggressive therapies, perhaps due to comorbid conditions, patient preference, or other age-related concerns. Current treatment modalities offering more favorable toxicity profiles, along with more accurate prognosis, can represent an opportunity to offer improved care for this patient population. From the few efforts studying brain metastatic disease in the elderly, it is be possible to infer that age alone may not play an independent role in treatment selection and that a patient-specific evaluation and ultimate clinical judgment should guide clinical decision-making.

Clinical Theragnostic Potential of Diverse miRNA Expressions in Prostate Cancer: A Systematic Review and Meta-Analysis.

Background: Prostate cancer (PrC) is the second-most frequent cancer in men, its incidence is emerging globally and is the fifth leading cause of death worldwide. While diagnosis and prognosis of PrC have been studied well, the associated therapeutic biomarkers have not yet been investigated comprehensively. This systematic review and meta-analysis aim to evaluate the theragnostic effects of microRNA expressions on chemoresistance in prostate cancer and to analyse the utility of miRNAs as clinical theragnostic biomarkers. Methods: A systematic literature search for studies reporting miRNA expressions and their role in chemoresistance in PrC published until 2018 was collected from bibliographic databases. The evaluation of data was performed as per PRISMA guidelines for systematic review and meta-analysis. Meta-analysis was performed using a random-effects model using Comprehensive Meta-Analysis (CMA) software. Heterogeneity between studies was analysed using Cochran's Q test, I2 and the Tau statistic. Quality assessment of the studies was performed using the Newcastle-Ottawa Scale (NOS) for the methodological assessment of cohort studies. Publication bias was assessed using Egger's bias indicator test, Orwin and classic fail-safe N test, Begg and Mazumdar rank collection test, and Duval and Tweedie's trim and fill methods. Findings: Out of 2909 studies retrieved, 79 studies were shortlisted and reviewed. A total of 17 studies met our eligibility criteria, from which 779 PrC patients and 17 chemotherapy drugs were examined, including docetaxel and paclitaxel. The majority of the drug regulatory genes reported were involved in cell survival, angiogenesis and cell proliferation pathways. We studied 42 miRNAs across all studies, out of which two miRNAs were found to be influencing chemosensitivity, while 21 were involved in chemoresistance. However, the remaining 19 miRNAs did not appear to have any theragnostic effects. Besides, the prognostic impact of the miRNAs was evaluated and had a pooled HR value of 1.960 with 95% CI (1.377-2.791). Interpretation: The observation of the current study depicts the significance of miRNA expression as a theragnostic biomarker in medical oncology. This review suggests the involvement of specific miRNAs as predictors of chemoresistance and sensitivity in PrC. Hence, the current systematic review and meta-analysis provide insight on the use of miRNA as PrC biomarkers, which can be harnessed as molecular candidates for therapeutic targeting.

Trends in the initial management of vestibular schwannoma in the United States.

INTRODUCTION: Vestibular schwannomas are benign tumors of the 8th cranial nerve. Initial treatment options include active surveillance, surgery, and/or radiation therapy. We analyzed the United States National Cancer Database (NCDB) for patients with vestibular schwannomas and evaluated the initial management trends after diagnosis. METHODS: We queried the NCDB for patients with vestibular schwannomas, excluding patients who did not have schwannomas of the vestibulocochlear nerve. Categorical and continuous variables were analyzed, and multivariate Cox regression analyses were performed to investigate for predictors of initial local therapy at diagnosis. All statistical analyses were performed using commercially available software (SPSS, Version 22; SPSS Inc., Chicago, IL). RESULTS: A total of 28,446 patients met the inclusion criteria. In this cohort, 7351 (25.8%) underwent observation, 12,362 (43.5%) underwent surgical resection, 7785 (27.4%) underwent SRS, 824 (2.9%) underwent EBRT, and 124 (0.4%) underwent RT NOS. On multivariate analysis, younger age, increased distance to treating facility, Charlson/Deyo score of 1, primary payer insurance, facility location and facility type (academic or cancer center) (p < 0.001) were all factors that predicted patients undergoing initial definitive treatment. CONCLUSION: Age, distance to treating facility, Charlson/Deyo score, primary payer, facility location, and facility type are factors that influence initial treatment for patients with vestibular schwannoma. Clinical stratification systems are needed to identify which patients would benefit most from initial local therapy versus active surveillance.

Treatment of a glioblastoma multiforme dural metastasis with stereotactic radiosurgery: A case report and select review of the literature.

Glioblastoma multiforme (GBM) is a primary brain neoplasm accounting for approximately 75% of all high grade gliomas. It is diffusely infiltrative and exhibits rapid proliferation with a poor overall prognosis. Maximum surgical resection and postoperative radiotherapy, accompanied by concurrent and adjuvant temozolomide chemotherapy, remain the standard of care without major therapeutic advances over the past 10 years. Herein, we present the case of a 64-year-old Caucasian male with a GBM who subsequently developed a left frontal dural metastasis, subsequently treated with stereotactic radiosurgery (20 Gy in 1 fraction). With six month follow-up, the patient showed near complete resolution of his dural metastases and no overall change in neurological symptoms or side effects following radiosurgery. Due to the paucity of clinical literature regarding dural metastases from GBM, its optimal treatment remains unknown. While the role of SRS has yet to be defined in this setting, here we provide evidence suggesting its overall efficacy in the treatment of select dural GBM metastases.

Data collection of patient outcomes: one institution's experience.

Patient- and provider-reported outcomes are recognized as important in evaluating quality of care, guiding health care policy, comparative effectiveness research, and decision-making in radiation oncology. Combining patient and provider outcome data with a detailed description of disease and therapy is the basis for these analyses. We report on the combination of technical solutions and clinical process changes at our institution that were used in the collection and dissemination of this data. This initiative has resulted in the collection of treatment data for 23 541 patients, 20 465 patients with provider-based adverse event records, and patient-reported outcome surveys submitted by 5622 patients. All of the data is made accessible using a self-service web-based tool.

GATA2 expression and biochemical recurrence following salvage radiation therapy for relapsing prostate cancer.

OBJECTIVE: High GATA2 expression has been associated with an increased risk of poor clinical outcomes after radical prostatectomy; however, this has not been studied in relation to risk of biochemical recurrence (BCR) after salvage radiation therapy (SRT) for recurrent prostate cancer after radical prostatectomy. Our aim was to evaluate the association between protein expression levels of GATA2 in primary prostate cancer tumour samples and the risk of BCR after SRT. METHODS: 109 males who were treated with SRT were included. The percentage of cells with nuclear staining and GATA2 staining intensity were both measured. These two measures were multiplied together to obtain a GATA2 H-score (range 0-12) which was our primary GATA2 staining measure. RESULTS: In unadjusted analysis, the risk of BCR was higher for patients with a GATA2 H-score >4 (hazard ratio = 2.04, p = 0.033). In multivariable analysis adjusting for SRT dose, pre-SRT PSA, pathological tumour stage and Gleason score, this association weakened substantially (hazard ratio = 1.45, p = 0.31). This lack of an independent association with BCR appears to be the result of correlations between GATA2 H-score >4 and higher pre-SRT PSA (p = 0.021), higher Gleason score (p = 0.044) and more severe pathological tumour stage (p = 0.068). CONCLUSION: Higher levels of GATA2 expression appear to be a marker of prostate cancer severity; however, these do not provide independent prognostic information regarding BCR beyond that of validated clinicopathological risk factors. Advances in knowledge: A higher GATA2 expression level appears to be correlated with known measures of prostate cancer severity and therefore is likely not an independent marker of outcome after SRT.

Factors Associated With Survival Following Radium-223 Treatment for Metastatic Castration-resistant Prostate Cancer.

BACKGROUND: Radium-223 (223Ra) improves survival in patients with metastatic castration-resistant prostate cancer (mCRPC). This retrospective analysis was performed to better understand its efficacy in routine clinical practice and identify factors associated with survival. MATERIALS AND METHODS: Sixty-four patients with mCRPC who received 223Ra between 2013 and 2015 were the basis of this retrospective study. Clinical outcomes and patient characteristics were obtained. Potential prognostic factors for survival were evaluated by univariate analysis using the log-rank test and multivariate analysis using the Cox proportional hazard method. RESULTS: The median survival was 12.9 months. Twenty-one patients (33%) developed a skeletal event, and the median time to the first skeletal event was 4.4 months. In univariate analysis, factors significantly associated with survival included: no prior chemotherapy, ≤ 5 bone metastases, baseline prostate-specific antigen (PSA) ≤ 36 ng/mL, baseline alkaline phosphatase (ALP) < 115 U/L, baseline hemoglobin > 12 g/dL, ALP response after 223Ra treatment, PSA decrease during 223Ra treatment, and absence of > 25% PSA increase during 223Ra treatment. In multivariate analysis, 4 factors remained significant: no prior chemotherapy, ≤ 5 bone metastases, baseline ALP < 115 U/L, and ALP response after 223Ra treatment. CONCLUSION: When 223Ra is administered in routine clinical practice, clinical outcomes can be more variable than those reported in the randomized study owing to patient heterogeneity. Four factors were identified to be significantly associated with survival after 223Ra treatment. These pretreatment factors may be used as stratification factors in future studies to investigate whether 223Ra would be more effective for patients with newly diagnosed metastatic disease that is sensitive to androgen deprivation therapy.

Patient-reported distress and survival among patients receiving definitive radiation therapy.

OBJECTIVE: Patient-reported distress (PRD) has not been well assessed in association with survival after radiation therapy (RT). The aims of this study were to evaluate the association between PRD level and survival after definitive RT and to identify the main causes of distress in definitive RT patients. METHODS AND MATERIALS: A total of 678 consecutive patients receiving definitive RT at our institution from April 2012 through May 2015 were included. All patients answered a PRD questionnaire that contained 30 items related to possible causes of distress, which could be rated from 1 (no distress) to 5 (high distress). Additionally, patients were asked to rate their overall distress level from 0 (no distress) to 10 (extreme distress). This overall distress level was our primary patient-reported distress measure and was examined as a continuous variable and as a categorical variable with 3 PRD levels (low, 0-3 [n = 295]; moderate, 4-6 [n = 222]; and high, 7-10 [n = 161]). RESULTS: As a continuous variable in multivariable Cox regression analysis, a higher overall PRD level was associated with poorer survival after RT (hazard ratio [HR], 1.39; P = .004). As a categorical variable, compared with patients with low distress, survival was poorer for patients with moderate distress (HR, 1.62; P = .038) or high distress (HR, 1.49; P = .12), but the latter difference was not significant. When the moderate and high distress levels were combined, survival was significantly poorer compared with the low distress level (HR, 1.57; P = .034). The top 5 specific causes of distress that patients mentioned were "How I feel during treatment," "Fatigue," "Out-of-pocket medical costs," "Pain that affects my daily functioning," and "Sleep difficulties." CONCLUSIONS: PRD before or during RT is a prognostic factor associated with decreased survival. Distress screening guidelines and interventions should be implemented for patients receiving definitive RT.

Failed adoptive immunotherapy with tumor-specific T cells: reversal with low-dose interleukin 15 but not low-dose interleukin 2.

Adoptive immunotherapy with tumor-specific T cells has emerged as a valid approach for prevention or treatment of diseases, such as melanoma and EBV-associated lymphoma. As interleukin (IL) 15 promotes survival of CD8(+) memory CTLs, we hypothesized that it could be used to enhance antitumor immunity in vivo through the maintenance of adoptively transferred memory CTL. To test this, we treated mice bearing P1A(+) tumors with adoptively transferred T cells possessing a transgenic Valpha8(+) T-cell receptor specific for the P1A tumor antigen (called P1CTL). Mice were then randomized to receive daily low-dose IL-15 (0.5 microg/day) or PBS. Mice receiving the transgenic P1CTL and IL-15 experienced a significantly delayed tumor relapse or complete tumor regression (P < 0.002 compared with PBS), with a striking persistence of the CD8(+) Valpha8(+) P1CTL compared with mice receiving the CD8(+) Valpha8(+) P1CTL and PBS vehicle (26.3 versus 5.1% P < 10(-5)). Animals exhibiting complete tumor regression had a significant population of CD8(+) Valpha8(+) P1CTL (46%) that persisted with IL-15 treatment until 140 days after adoptive transfer and successfully defended them against tumor rechallenge without IL-15. Low-dose IL-2 afforded no protection over vehicle and resulted in lower percentages of T cells with an activated memory phenotype, lower Bcl-2 expression, and lower ex vivo antitumor cytotoxicity compared with mice treated with IL-15. Collectively, the data support the notion that exogenous low-dose IL-15 therapy can enhance and even reverse the limited efficacy of adoptively transferred tumor-specific T-cell therapy and may do so in a fashion that is superior and distinct from exogenous IL-2 therapy.

Treatment of in-transit and metastatic melanoma in two patients treated with ipilimumab and topical imiquimod.

Checkpoint blockade inhibitors have revolutionized the treatment of metastatic melanoma. Despite the success of these agents in improving the overall survival of patients with metastatic melanoma, not all patients achieve clinical benefit, leaving room for improvement. The presence of cutaneous metastases in patients with metastatic melanoma provides the unique opportunity to treat the cutaneous lesions with a local modality while simultaneously treating systemic disease with systemic therapy. Herein, we describe the treatment of two patients with both in-transit and metastatic melanoma with the combination of the topical toll-like receptor 7 agonist imiquimod with systemic ipilimumab. Both patients appeared to have progressed and developed new cutaneous and systemic metastases while on single agent ipilimumab only to respond when started on topical imiquimod. Both patients tolerated the combination of imiquimod and ipilimumab without serious adverse events, and both patients had excellent clinical responses. These cases provide a proof of principle of the possibility of the combination of toll-like receptor 7 agonists with immune checkpoint blockade inhibitors.

Small Cell Carcinoma of the Prostate in an Elderly Patient: A Case Report and Review of the Literature.

Prostate cancer is the most common malignancy of men in the United States. Small-cell carcinoma (SCC), which typically presents as an aggressive lung malignancy, is a rare diagnosis within the setting of prostate cancer pathology. Due to its limited prevalence, little information regarding the treatment and prognosis of this disease in large populations is available. To date our current knowledge base is largely limited to case reports and retrospective case reviews. The mainstay of treatment for this particular histology most often involves a multimodality approach utilizing chemotherapy in conjunction with radiation therapy, androgen deprivation therapy, or prostatectomy. Here we present the case of an elderly 89-year-old Caucasian male who was diagnosed with SCC of the prostate. Despite proceeding with a course of definitive radiotherapy, the patient experienced rapid progression of disease and ultimately elected to discontinue radiation therapy and receive hospice care.