Efficacy Of Subsequent Therapy Research Articles

Efficacy of subsequent therapies in patients with advanced ovarian cancer who relapse after first-line olaparib maintenance: results of the PAOLA-1/ENGOT-ov25 trial

BackgroundUse of first-line PARP inhibitor maintenance therapy is increasing in advanced ovarian cancer. Understanding the efficacy of first subsequent therapy (FST) in patients experiencing disease progression in the first-line setting is important to optimize post-progression treatments. We evaluated the efficacy of FST in patients from PAOLA-1/ENGOT-ov25 (NCT02477644) who received first-line olaparib maintenance. Patients and methodsThis post hoc analysis evaluated the efficacy of subsequent chemotherapy following disease progression by assessing time from FST to second subsequent therapy (SST) according to whether progression occurred during versus after first-line olaparib maintenance and FST type. A multivariate Cox model was used in the olaparib plus bevacizumab arm to identify prognostic factors influencing the efficacy of subsequent chemotherapy. ResultsOf 806 randomized patients, 544 (67.5%) progressed and received subsequent chemotherapy. The median time from FST to SST was shorter in patients in the olaparib plus bevacizumab arm who progressed during first-line olaparib maintenance (6.1 months) than in those who progressed after first-line olaparib maintenance (11.4 months). Multivariate analysis indicated that progression after (versus during) first-line olaparib maintenance influenced time from FST to SST (hazard ratio 0.65, 95% CI 0.50-0.84; P=0.0011) independently of platinum-free interval or clinical risk. Among patients who progressed and received platinum-based chemotherapy with a PARP inhibitor as FST, the efficacy of subsequent therapies was also dependent upon whether progression occurred during versus after first-line olaparib maintenance. ConclusionsThese results suggest that the timing of disease progression relative to first-line olaparib maintenance may impact the efficacy of subsequent platinum-based chemotherapy. Although results should be interpreted with caution, across all subgroups, including patients who received platinum-based chemotherapy with PARP inhibitor rechallenge as FST, the median time from FST to SST was longer if progression occurred after versus during first-line olaparib maintenance.

The efficacy of subsequent therapy after failure of anti-PD-1 antibody in metastatic renal cell carcinoma.

The optional regimens of subsequent therapy after failure of anti-programmed cell death protein-1 (PD-1) antibody in metastatic renal cell carcinoma (mRCC) remain to be explored. There are reports of the efficacy of single-agent vascular endothelial growth factor receptor tyrosine kinase inhibitor (VEGFR-TKI) in patients with mRCC after failure of anti-PD-1 antibody therapy. However, it is not clear whether it is beneficial for patients to receive anti-PD-1 antibody as post-progression treatment. It has great significance to explore whether continuous application of anti-PD-1 antibody is beneficial for patients with mRCC whose diseases progressed to the state of pre-anti-PD-1 therapy. The purposes of this study are to explore the efficacy and safety of subsequent treatment on whether to continue using anti-PD-1 antibody therapy for patients who have progressive mRCC after prior treatment with anti-PD-1 antibody. The clinical data of patients with mRCC from the Department of Immunotherapy in the Affiliated Cancer Hospital of Zhengzhou University and Henan Cancer Hospital from February 1, 2019 to December 31, 2021 were analyzed retrospectively. The primary endpoints were the objective response rate (ORR) and progression-free survival (PFS). The ORR and disease control rate (DCR) were estimated with Fisher's exact test. PFS and overall survival (OS) were assessed using the Kaplan-Meier method and log-rank tests. The associations between potential prognostic variables and PFS were evaluated with univariate and multivariate Cox regression analyses. A P value of less than or equal to 0.05 was deemed as statistically significant. A total of 35 patients were included in this study, during which 19 received VEGFR-TKI monotherapy and 16 received the VEGFR-TKI plus anti-PD-1 antibody therapy. Until the last follow-up on June 30, 2022, 19 patients experienced progressive disease (PD), five were in remission, and 11 kept stable disease (SD). After a median follow-up of 28.7 [95% confidence interval (CI): 17.0-35.6] months, the median PFS (mPFS) was 11.6 months for the VEGFR-TKI group and 9.1 months for the VEGFR-TKI plus anti-PD-1 antibody group [hazard ratio (HR) =0.81, 95% CI: 0.32-1.03, P=0.44]. Median OS (mOS) were 16.9 and 11.2 months respectively (HR =0.99, 95% CI: 0.44-2.27, P=0.90). The ORRs were 26.3% and 0% (P=0.049), and the DCRs were 47.4% and 43.8% (P=0.55) respectively. Treatment-related adverse events (TRAEs) occurred in 14 patients (73.7%) in the VEGFR-TKI group and 14 patients (87.5%) in the VEGFR-TKI plus anti-PD-1 antibody group (P=0.42); grade 3/4 TRAEs occurred in two patients (10.5%) and six patients (37.5%) respectively (P=0.11). VEGFR-TKI monotherapy is an efficacious regimen for patients with mRCC whose diseases progressed on previous anti-PD-1 antibody therapy, and continuous anti-PD-1 therapy after failure of anti-PD-1 antibody could not provide additional clinical benefit but increased the incidence of TRAEs.

Patient outcomes after therapy with 177Lu-PSMA-617 (LuPSMA) for metastatic castrate-resistant prostate cancer (mCRPC): A tertiary center experience.

87 Background: While LuPSMA has a proven overall survival (OS) benefit in patients (pts) with mCRPC who have received prior taxane chemotherapy and androgen receptor pathway inhibitors, there is limited data on outcomes and efficacy of subsequent therapy in pts who have received LuPSMA. This study aimed to assess the clinical and treatment courses of pts with mCRPC after LuPSMA. Methods: We queried an IRB-approved prospectively maintained registry to evaluate all pts with mCRPC who received standard-of-care LuPSMA at our institution between June 2022 and July 2023. Clinical data pertaining to LuPSMA therapy as well as subsequent treatments were extracted from the medical record, including type and number of subsequent systemic therapies, reason for treatment cessation, hematologic support, and PSA response to subsequent therapy. PSA-50 was defined as a ≥50% decrease in PSA on therapy. Hematologic adverse events to therapies after LuPSMA were recorded and graded per CTCAEv5.0. Results: A total of 96 patients were evaluated; median age was 72 years (range 52-87), and median follow-up was 10 months. 18 pts completed all 6 cycles, 35 discontinued prior to cycle 6 of LuPSMA due to progressive disease, 10 died mid-treatment, and 33 were midway through treatment; median number of cycles received for all pts was 4 (range 1-6). None of the 18 who completed all 6 cycles had yet transitioned to a next line therapy. Of the 35 who discontinued LuPSMA, 17 transitioned to hospice due to disease progression, 15 initiated a subsequent line of therapy, and 3 had a treatment break. Median overall survival was 13 months in the entire cohort. Of the 15 receiving another line of therapy, 11 received cabazitaxel ± carboplatin/cisplatin, 1 received carboplatin with cisplatin substituted during carboplatin shortage, and 4 received other non-chemotherapy regimens; a PSA-50 response to subsequent therapy was seen in 4 patients (27%), all of whom received cabazitaxel ± carboplatin/cisplatin. Of the 12 pts who received chemotherapy, the median number of cycles received was 3 (range 1-7); 4 pts (33%) had grade ≥3 anemia, 2 (17%) had grade ≥3 thrombocytopenia and 7 pts (47%) required platelet growth factor support or transfusion of blood products. Conclusions: 47% of pts discontinuing LuPSMA transitioned to hospice due to disease progression while 44% proceeded to a subsequent line of therapy, the majority of whom received cabazitaxel. Outcomes to subsequent therapy were generally poor, with a 27% PSA-50 response rate. This initial experience may be biased by number of patients with limited standard of care options at the time of FDA approval of LuPSMA and could improve with better patient selection. However, this also highlights the continued need to develop novel therapeutic strategies for CRPC pts post-LuPSMA.

Efficacy of subsequent therapies in patients (pts) with advanced ovarian cancer (AOC) in the phase III PAOLA-1/ENGOT-ov25 trial according to whether disease progression occurred during or after the end of olaparib (ola) maintenance.

5550 Background: In the PAOLA-1/ENGOT-ov25 trial (NCT02477644), maintenance ola (a PARP inhibitor) + bevacizumab (bev) led to prolonged progression-free and overall survival vs placebo (pbo) + bev in AOC pts, specifically those with homologous recombination-deficient (HRD+) tumors (Ray-Coquard et al. ESMO 2022, LBA29). Here, we explore the efficacy of subsequent chemotherapy (CT) in pts after progression on first-line (1L) treatment in PAOLA-1. Methods: The efficacy of subsequent CT was explored by analyzing the median time from first subsequent therapy (FST) to second subsequent therapy (SST). Efficacy was compared by FST type, HRD status, and timing of progression (during/after ola). A multivariate Cox model was used in ola + bev pts to identify prognostic factors influencing time from FST to SST, including HRD status, platinum-free interval (PFI), clinical risk based on disease stage and surgical status, timing of progression, and response to 1L CT. All P values are exploratory. Results: In total, 544/806 (67.5%) pts progressed and received subsequent CT: 338/537 (62.9%) ola + bev pts and 206/269 (76.6%) pbo + bev pts. In the overall population and in the subgroup who received platinum-based combination therapy (PBC), time from FST to SST was shortest in pts who progressed during ola (Table). Pts who progressed after ola had similar outcomes to pbo + bev pts (Table). Efficacy was broadly consistent regardless of HRD status (Table). The multivariate analysis confirmed that progression after (vs during) ola prolonged time from FST to SST (hazard ratio [HR] 0.65, 95% confidence interval [CI] 0.50–0.84; P=0.0011) independently of other known prognostic factors, such as PFI ≥12 vs <12 months (HR 0.38, 95% CI 0.29–0.51; P<0.0001) or lower vs higher clinical risk (0.58, 0.42–0.81; P=0.0015). Conclusions: In this post hoc exploratory analysis of PAOLA-1, the efficacy of subsequent CT at relapse appeared dependent on whether progression occurred during or after the end of ola treatment. Efficacy was reduced when relapse occurred during ola but was comparable between pts who progressed after ola vs pbo + bev pts. Clinical trial information: NCT02477644 . [Table: see text]

Efficacy of Subsequent Therapies in Multiple Myeloma Patients after Progression on a BCMA Targeting Therapy: A Single-Center Experience

Background: Targeting B-cell maturation antigen (BCMA) with antibody-drug conjugates (ADCs), bispecific antibodies, or chimeric antigen receptor t-cells (CAR-Ts) has proven safe and effective in recent clinical trials, but relapses remain common. As most patients treated with BCMA targeting therapies are refractory to conventional anti-myeloma therapies, management of these patients poses unique challenges once they progress, with no data available to guide subsequent therapies. Methods: We performed a retrospective chart review of all relapsed refractory multiple myeloma (RRMM) patients at our institution who progressed while on or after a BCMA targeting therapy and were treated with subsequent therapies. We evaluated the best response achieved and overall survival (OS) measured from progression on BCMA targeting therapies. Kaplan Meier methods were used to estimate OS curves and landmarks between classes of BCMA targeting therapy received (ADC, bispecific antibody or CAR-T), and by type of subsequent therapy. Results: At a median follow up of 6 months, a total of 47 patients were treated with a BMCA targeting therapy. Of those, a total of 21 (44.7%) patients have progressed, with 18 (38.3%) receiving another therapy. Twelve-month overall survival of the patients who received a subsequent treatment was 51.1% (figure 1a), but varied considerably based on the class of BCMA therapy they received (figure 1b). Patients who progressed after a BCMA CAR-T had the best OS (N =2, 6 mo OS: 100%, 12 mo OS: Of the 18 patients who progressed and were treated with subsequent therapies, 7 (38.9%) received 2 lines of therapy, 5 (27.8%) received 3 lines of therapy, and 1 patient (5.6%) received 5 lines of therapy. In the first relapse, 4 (22.2%) patients received infusional chemotherapy with CAR-D PACE or CAR-DCEP, 4 (22.2%) received the combination of elotuzumab, pomalidomide, and dexamethasone (Elo-Pd; one of which was first treated with CAR-DCEP), 3 (16.7%) received selinexor based regimens. The best response seen after first-line post BCMA treatment was a partial response (PR) in 5 (27.8% of patients), whereas 8 (61.5%) patients who received second-line treatment post-BCMA therapy had a PR or better, including 3 (23.1%) who had a very good partial response (VGPR). In the third line post-BCMA, 1 (16.7%) had a VGPR, while 1 (16.7%) had stable disease as their best response. The use of Elo or Dara after anti-BCMA progression seemed to correlate with improved OS (see figure 1c below). While all these patients were Elo naïve, the majority (94.4%) were previously Dara exposed. Conclusions: Our data demonstrate that many RRMM patients who progress on BCMA targeting therapies still derive benefit from subsequent treatment. Early evidence from our experience suggests a survival advantage with monoclonal antibody-based therapies even in patients who had previously been exposed to these agents-suggesting a possible resensitization with BCMA directed therapy. Although our dataset is a single-center experience, to our knowledge it represents the first report of post-BCMA exposed management of RRMM and provides valuable insight into the treatment of this challenging and ever-expanding population. Disclosures Paul: Bristol-Myers Squibb: Other: Stock Ownership (prior employee); Amgen: Consultancy, Speakers Bureau; Regeneron: Membership on an entity's Board of Directors or advisory committees. Bhutani:BMS: Other: Clinical trial funding to institute, Speakers Bureau; Takeda: Other: Clinical trial funding to institute, Speakers Bureau; Prothena: Other: Clinical Trial Funding to Institute; Amgen: Speakers Bureau; MedImmune: Other: Clinical Trial Funding to Institute; Sanofi Genzyme: Consultancy; Janssen: Other: Clinical Trial Funding to Institute. Voorhees:Adaptive Biotechnologies: Other: Personal fees; Bristol-Myers Squibb: Other: Personal fees; Celgene: Other: Personal fees; Janssen: Other: Personal fees; Novartis: Other: Personal fees; Oncopeptides: Other: Personal fees; TeneoBio: Other: Personal fees; Levine Cancer Institute, Atrium Health: Current Employment. Usmani:Celgene: Other; Janssen: Consultancy, Honoraria, Other: Speaking Fees, Research Funding; SkylineDX: Consultancy, Research Funding; Seattle Genetics: Consultancy, Research Funding; Merck: Consultancy, Research Funding; Incyte: Research Funding; Pharmacyclics: Research Funding; Array Biopharma: Research Funding; GSK: Consultancy, Research Funding; Takeda: Consultancy, Honoraria, Other: Speaking Fees, Research Funding; Sanofi: Consultancy, Honoraria, Research Funding; Abbvie: Consultancy; BMS, Celgene: Consultancy, Honoraria, Other: Speaking Fees, Research Funding; Amgen: Consultancy, Honoraria, Other: Speaking Fees, Research Funding. Atrash:BMS, Jansen oncology, Sanofi: Speakers Bureau; Takeda, Amgen, Karyopharm, BMS, Sanofi, Cellactar, Janssen and Celgene: Honoraria; Amgen, GSK, Karyopharm.: Research Funding.

First-line (1L) immuno-oncology (IO) combination therapies in metastatic renal-cell carcinoma (mRCC): Results from the international mRCC database consortium (IMDC).

4577 Background: In mRCC, ipilimumab and nivolumab (ipi-nivo) is a 1L treatment option. Recent data have also shown efficacy of 1L IO-VEGF (IOVE) inhibitor combinations. Comparative data between these two strategies are limited and the efficacy of subsequent therapies remains unknown. Methods: Using the IMDC dataset, patients (pts) treated with any 1L IOVE combination were compared to those treated with ipi-nivo. Multivariable Cox regression analysis was performed to control for imbalances in IMDC risk factors. Results: 188 pts received 1L IO combination therapy: 113 treated with IOVE combinations and 75 with ipi-nivo. Baseline characteristics and IMDC risk factors were comparable between groups. When comparing IOVE combinations vs ipi-nivo, 1L response rate (RR) was 33% vs 40% (p=0.39), time to treatment failure (TTF) was 14.3 (95% CI 9.2-16.1) vs 10.2 months (95% CI 6.7-15.1, p=0.23), and median overall survival (OS) was not reached (NR) (95% CI 22.3-NR) vs NR (95% CI 35.1-NR, p=0.17). When adjusted for IMDC risk factors, the hazard ratio (HR) for TTF was 0.71 (95% CI 0.46-1.12, p=0.14) and the HR for death was 1.74 (95% CI 0.82-3.68, p=0.14). Second-line (2L) treatments were varied. In pts receiving subsequent VEGF-based therapy, 2L RR was lower in the IOVE (n=20) versus ipi-nivo (n=20) cohort (15% vs 45%; p=0.04), though 2L TTF was not significantly different (3.7 vs 5.4 months, p=0.40, n=55). The use of IO post IOVE was uncommon and 3/5 pts had PD as best response; 2/5 had PR/SD but their 1L IOVE exposure was short at <3 months. Conclusions: There does not appear to be a superior 1L IO combination strategy in mRCC, as lOVE combinations and ipi-nivo have comparable 1L RR, TTF and OS. Most pts received VEGF-based therapy in the 2L. In this group, 2L RR was greater in pts who received ipi-nivo, though there was no difference in 2L TTF. [Table: see text]

Overall Survival with Palbociclib and Fulvestrant in Advanced Breast Cancer

BackgroundThe cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitor palbociclib, in combination with fulvestrant therapy, prolongs progression-free survival among patients with hormone-receptor–positive, human epidermal growth factor receptor 2 (HER2)–negative advanced breast cancer. We report the results of a prespecified analysis of overall survival.MethodsWe randomly assigned patients with hormone-receptor–positive, HER2-negative advanced breast cancer who had progression or relapse during previous endocrine therapy to receive palbociclib plus fulvestrant or placebo plus fulvestrant. We analyzed overall survival; the effect of palbociclib according to the prespecified stratification factors of presence or absence of sensitivity to endocrine therapy, presence or absence of visceral metastatic disease, and menopausal status; the efficacy of subsequent therapies after disease progression; and safety.ResultsAmong 521 patients who underwent randomization, the median overall survival was 34.9 months (95% confidence interval [CI], 28.8 to 40.0) in the palbociclib–fulvestrant group and 28.0 months (95% CI, 23.6 to 34.6) in the placebo–fulvestrant group (hazard ratio for death, 0.81; 95% CI, 0.64 to 1.03; P=0.09; absolute difference, 6.9 months). CDK4/6 inhibitor treatment after the completion of the trial regimen occurred in 16% of the patients in the placebo–fulvestrant group. Among 410 patients with sensitivity to previous endocrine therapy, the median overall survival was 39.7 months (95% CI, 34.8 to 45.7) in the palbociclib–fulvestrant group and 29.7 months (95% CI, 23.8 to 37.9) in the placebo–fulvestrant group (hazard ratio, 0.72; 95% CI, 0.55 to 0.94; absolute difference, 10.0 months). The median duration of subsequent therapy was similar in the two groups, and the median time to the receipt of chemotherapy was 17.6 months in the palbociclib–fulvestrant group, as compared with 8.8 months in the placebo–fulvestrant group (hazard ratio, 0.58; 95% CI, 0.47 to 0.73; P<0.001). No new safety signals were observed with 44.8 months of follow-up.ConclusionsAmong patients with hormone-receptor–positive, HER2-negative advanced breast cancer who had sensitivity to previous endocrine therapy, treatment with palbociclib–fulvestrant resulted in longer overall survival than treatment with placebo–fulvestrant. The differences in overall survival in the entire trial group were not significant. (Funded by Pfizer; PALOMA-3 ClinicalTrials.gov number, NCT01942135.)

Host mediated inflammatory influence on glioblastoma multiforme recurrence following high-dose ionizing radiation.

Despite optimal clinical treatment, glioblastoma multiforme (GBM) inevitably recurs. Standard treatment of GBM, exposes patients to radiation which kills tumor cells, but also modulates the molecular fingerprint of any surviving tumor cells and the cross-talk between those cells and the host. Considerable investigation of short-term (hours to days) post-irradiation tumor cell response has been undertaken, yet long-term responses (weeks to months) which are potentially even more informative of recurrence, have been largely overlooked. To better understand the potential of these processes to reshape tumor regrowth, molecular studies in conjunction with in silico modeling were used to examine short- and long-term growth dynamics. Despite survival of 2.55% and 0.009% following 8 or 16Gy, GBM cell populations in vitro showed a robust escape from cellular extinction and a return to pre-irradiated growth rates with no changes in long-term population doublings. In contrast, these same irradiated GBM cell populations injected in vivo elicited tumors which displayed significantly suppressed growth rates compared to their pre-irradiated counterparts. Transcriptome analysis days to weeks after irradiation revealed, 281 differentially expressed genes with a robust increase for cytokines, histones and C-C or C-X-C motif chemokines in irradiated cells. Strikingly, this same inflammatory signature in vivo for IL1A, CXCL1, IL6 and IL8 was increased in xenografts months after irradiation. Computational modeling of tumor cell dynamics indicated a host-mediated negative pressure on the surviving cells was a source of inhibition consistent with the findings resulting in suppressed tumor growth. Thus, tumor cells surviving irradiation may shift the landscape of population doubling through inflammatory mediators interacting with the host in a way that impacts tumor recurrence and affects the efficacy of subsequent therapies. Clues to more effective therapies may lie in the development and use of pre-clinical models of post-treatment response to target the source of inflammatory mediators that significantly alter cellular dynamics and molecular pathways in the early stages of tumor recurrence.

Is Early Hematopoietic Stem-Cell Transplantation Necessary in Mantle-Cell Lymphoma?

Is Early Hematopoietic Stem-Cell Transplantation Necessary in Mantle-Cell Lymphoma?

The outcome of chronic lymphocytic leukemia patients who relapsed after fludarabine, cyclophosphamide, and rituximab

There are minimal data about the efficacy of subsequent therapy in patients with relapse after FCR (fludarabine, cyclophosphamide, and rituximab) chemoimmunotherapy. We retrospectively analyzed the outcomes of 119 patients who relapsed after standard-dose FCR. The patient cohort consisted of patients who relapsed after FCR administered as first-line therapy (Group 1, n = 63) and patients relapsing after FCR administered in second/subsequent line; (Group 2, n = 56). Basic parameters (age, clinical stage, cytogenetics, molecular genetics) did not differ significantly between these subgroups. Likewise, median progression-free survival (PFS) was not considerably different after FCR (18.6 vs. 14.7 months). Subsequent therapy for relapsed disease included FCR retreatment, R-CHOP, alemtuzumab, or rituximab plus high-dose dexamethasone. Overall response rates for the two groups did not significantly differ (59% vs. 44%). Although PFS after subsequent therapy was relatively short, longer PFS was observed in Group 1 (13.3 vs. 5.9 months; P = 0.01), in patients with response duration ≥ 24 months after previous FCR (13 vs. 6.1 months; P < 0.01), and in patients who achieved complete remission after FCR (10.8 vs. 7.9 months in partial remission; P = 0.01). Newly detected 17p deletions were observed in 5/62 patients, and new p53 mutations in 6/34 FCR-treated patients. Our data indicate that the prognosis of patients who relapse after FCR remains poor regardless of the subsequent treatment regimen.

Abstract 2822: Ascorbic acid synergistically potentiates antimetastatic effect of natural products on 4T1 tumors.

Abstract Our main objective was to determine the differential response of female gulonolactone oxidase (Gulo) mice challenged with 4T1 to vitamin C deficient, subclinical vitamin C sufficient, or vitamin C combined with other additional natural products (EQC) diets against 4T1 secondary growth phase metastasis to lungs, kidneys, and liver. Live murine 4T1 cells (5x105) were administered subcutaneously to the right flank of female Gulo (-/-) mice (n=27) 35-40 weeks of age and 18 age matched female wild-type mice. Tumors were established for an additional 2 weeks on subclinical vitamin C (100mg/L in water) in the Gulo (-/-) group, or with regular food and water in the wild-type vitamin C-generating mice. Tumor measurements were taken and the Gulo (-/-) mice were distributed into 3 groups (n=9 in each) to ensure average tumor burden was equivalent before therapy. Mice were then maintained for an additional 2 weeks on either subclinical vitamin C in water, subclinical C water + vitamin C (equivalent to that provided by 0.5% EQC supplemented diet), and subclinical C water + 0.5% EQC supplemented diet. Wild-type mice received an additional 2 weeks of either regular murine diet or 0.5% EQC supplemented food and regular water. At the endpoint, serum was collected, lungs, livers, and kidneys were evaluated for metastatic burden, and tissues collected for histology. Tumors were also harvested, weighed, and sectioned for histology. EQC exhibited the strongest anti-metastatic effect upon the second growth phase in scorbutic Gulo (-/-) mice as well as wild type vitamin C generating mice. Gulo (-/-) mice maintained throughout the study on subclinical vitamin C presented with the worst outcomes, including novel renal involvement. Vitamin C in diet equivalent to that in 0.5% EQC afforded only protection against novel renal pathology, but the metastatic burden was similar to that in subclinical C group. 0.5% EQC abrogated the cases of moderate to severe metastasis in scorbutic Gulo (-/-) mice by 16% compared to subclinical vitamin C group. In wild-type mice, 0.5% EQC abrogated the cases of moderate to severe metastasis by 37%. This study demonstrates that 0.5% EQC is superior to vitamin C alone in reducing metastasis from a primary 4T1 tumor and that prior scurvy is deleterious upon host resistance to primary tumors and reduces the efficacy of subsequent therapy against metastasis. Prior endogenous vitamin C generation in wild-type mice before tumor inoculation and continuous vitamin C generation during therapy with 0.5% EQC suggests that vitamin C both enhances host resistance and synergistically potentiates the effect of additional therapy. Tumor mass itself was not related to metastatic burden, suggesting that differing biochemical composition of the stromal and tumor structures are responsible for a metastatic or non-metastatic tumor of equal size. Citation Format: John Cha, M. Waheed Roomi, Matthias Rath, Aleksandra Niedzwiecki. Ascorbic acid synergistically potentiates antimetastatic effect of natural products on 4T1 tumors. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2822. doi:10.1158/1538-7445.AM2013-2822

Ventricular arrhythmias in elderly patients. Evaluation and management.

In evaluating and managing ventricular arrhythmias in elderly patients, the clinician must first decide which patients are appropriate candidates for therapy. Arrhythmias can be categorized as to their potential for causing sudden cardiac death as benign, potentially malignant, or malignant by considering their type and the underlying structural cardiac disease present. Factors that may aggravate the arrhythmias should be identified and corrected. The ventricular arrhythmias should be well characterized using ambulatory monitoring or electrophysiologic studies to gauge the efficacy of subsequent therapy. If pharmacologic therapy is to be initiated, the most appropriate antiarrhythmic drug should be chosen with consideration of potential efficacy, potential adverse cardiovascular and systemic side effects, pharmacokinetics, and drug interactions. In selected patients with malignant ventricular arrhythmias, the failure of antiarrhythmic medication may lead the clinician to consider nonpharmacologic therapy such as surgical endocardial resection or the automatic implantable cardioverter-defibrillator.