DNA bulges are biologically consequential defects that can arise from template-primer misalignmen... more DNA bulges are biologically consequential defects that can arise from template-primer misalignments during replication and pose challenges to the cellular DNA repair machinery. Calorimetric and spectroscopic characterizations of defectcontaining duplexes reveal systematic patterns of sequence-context dependent bulge-induced destabilizations. These distinguishing energetic signatures are manifest in three coupled characteristics, namely: the magnitude of the bulgeinduced duplex destabilization (""G Bulge); the thermodynamic origins of ""G Bulge (i.e. enthalpic versus entropic); and, the cooperativity of the duplex melting transition (i.e. two-state versus non-two state). We find moderately destabilized duplexes undergo two-state dissociation and exhibit ""G Bulge values consistent with localized, nearest neighbor perturbations arising from unfavorable entropic contributions. Conversely, strongly destabilized duplexes melt in a non-twostate manner and exhibit ""G Bulge values consistent with perturbations exceeding nearest-neighbor expectations that are enthalpic in origin. Significantly, our data reveal an intriguing correlation in which the energetic impact of a single bulge base centered in one strand portends the impact of the corresponding complementary bulge base embedded in the opposite strand. We discuss potential correlations between these bulge-specific differential energetic profiles and their overall biological implications in terms of DNA recognition, repair and replication.
www.urotodayinternationaljournal.com Volume 2 December 2009 Outcome of Patients with Abnormal Upp... more www.urotodayinternationaljournal.com Volume 2 December 2009 Outcome of Patients with Abnormal Upper Tract Cytology and Negative Initial Workup UroToday International Journal ® UIJ INTRODUCTION: Patients with pathologically confirmed upper tract transitional cell carcinoma (TCC) currently undergo surveillance according to well described protocols. The literature offers little guidance for monitoring patients with abnormal upper tract cytology without prior upper tract TCC. The purpose of the present study was to assess the risk of upper tract TCC based on cytology and determine a reasonable observation strategy for this abnormal finding. METHODS: The authors performed a 10-year retrospective cohort study of 204 patients (366 renal units) within the New England Veterans Administration Healthcare System. Upper tract cytology was collected: (1) as a consequence of lateralizing hematuria during cystoscopy in 2 patients; (2) following abnormal upper tract imaging in 27 patients; (3) from ...
INTRODUCTION AND OBJECTIVE:Alternatives to radical cystectomy (RC) are critically needed for the ... more INTRODUCTION AND OBJECTIVE:Alternatives to radical cystectomy (RC) are critically needed for the treatment of high-risk BCG-unresponsive NMIBC. Vicinium is a recombinant fusion protein comprised of...
Level 1 evidence supports use of neoadjuvant platinum chemotherapy (NAC) for muscle invasive blad... more Level 1 evidence supports use of neoadjuvant platinum chemotherapy (NAC) for muscle invasive bladder cancer, but little is known about prospective efficacy and safety of NAC in HG UTUC. This multisite phase II trial investigated NAC prior to nephroureterectomy and lymph node dissection (NU). METHODS: Patients (pts) with HG UTUC planned for NU were eligible, with treatment arm of 4 NAC cycles assigned by baseline creatinine clearance (CrCl), CrCl >50 received accelerated (a)MVAC (methotrexate 30 mg/m2, vinblastine 3 mg/m2, doxorubicin 30 mg/m2, cisplatin 70 mg/m2 with pegfilgrastim q14 days). CrCl !30 and 50 received carboplatin AUC 5 D1 and gemcitabine 1000 mg/m2 days 1, 8 (GC). Primary endpoint was pathologic complete response (pCR) rate (ypT0N0). On each arm, a pCR rate of 18% was of interest vs. a null of 4%. Success was defined as at least 3 pCRs among 28 pts (10.7%). Accrual goal was 30 pts per arm. RESULTS: From April 2015-May 2017, 30 patients were enrolled to the aMVAC cohort. Six enrolled to the GC cohort which closed for poor accrual in January 2018. On aMVAC arm 1 pt had renal cell ca. 3/29 eligible pts (23 M 6F), median age 65(40-84), median PS 0, achieved ypT0N0 at NU (10.3%, 90% CI [2.9 e 24.6]). Including pt with clinical CR on preoperative imaging without lymph node dissection at NU (ypT0Nx), the pCR rate was 4/29 (14%, 90% CI [4.9 e 28.8]), (table). The median number of chemotherapy cycles was 4 (1-4), 79% of patients completed treatment. One pt on aMVAC arm with cycle 1 Gr4 sepsis deferred further NAC and NU. Grade 3-4 toxicity rate was 23% on aMVAC arm, no G5 events. CONCLUSIONS: aMVAC NAC demonstrated pre-defined activity with 14% pCR, above null 4%, with no new safety concerns in pts with HG UTUC and CrCl >50. Rate of ypT1 over 60% may be of clinical interest. Slow accrual in the CrCl 50 arm suggests novel trials are warranted. A follow up immunotherapy-chemotherapy combination trial in UTUC is planned through ECOG-ACRIN.
302 Background: Micropapillary bladder cancer (MPBC) is an aggressive variant of urothelial carci... more 302 Background: Micropapillary bladder cancer (MPBC) is an aggressive variant of urothelial carcinoma. We have previously published clinical risk stratification groups for patients with conventional urothelial carcinoma and sought to identify if these were valid in patients with this variant histology. Methods: An IRB approved review of 1910 patients in our radical cystectomy database revealed 106 patients with preoperative diagnosis of ≤cT4aN0M0 MPBC between December 1992 and January 2012 who underwent upfront radical cystectomy (RC, n = 74) or neoadjuvant chemotherapy (NAC) followed by RC (n = 32). To determine whether patients with MPBC can be risk stratified using traditional risk factors, a recursive partitioning analysis (RPA) was performed. Results: In multivariate analyses, hydronephrosis (HR=3.1; p=0.01), and extent of MPBC at transurethral resection (TUR) (HR=1.9; p=0.04) were associated with shortened OS. In the reduced model, clinical stage also achieved significance (HR...
To analyze survival in clinically localized, surgically resectable micropapillary bladder cancer ... more To analyze survival in clinically localized, surgically resectable micropapillary bladder cancer patients undergoing radical cystectomy with and without neoadjuvant chemotherapy and develop risk strata based on outcome data. A review of our database identified 103 patients with surgically resectable (≤cT4acN0cM0) micropapillary bladder cancer who underwent radical cystectomy. Survival estimates were calculated using Kaplan-Meier method and compared using log-rank tests. Classification and regression tree analysis was performed to identify risk groups for survival. For the entire cohort, estimated 5-year overall and disease-specific survival rates were 52% and 58%, respectively. Classification and regression tree analysis identified three risk subgroups: low-risk: cT1, no hydronephrosis; high-risk: ≥cT2, no hydronephrosis; and highest-risk: cTany with tumor-associated hydronephrosis. Five-year disease-specific survival for the low-, high-, and highest-risk groups were 92%, 51%, and 1...
The human Fc receptor, FcγRIIA, is known to mediate phagocytosis and endocytosis, yet the greates... more The human Fc receptor, FcγRIIA, is known to mediate phagocytosis and endocytosis, yet the greatest numbers of these receptors are expressed on the surface of non-phagocytic platelets, where they are involved in serotonin secretion. FcγRIIA harbors three tyrosine (Y) residues within its cytoplasmic domain. Y1 is upstream of both Y2 and Y3, which are contained within an immunoreceptor tyrosine-based activation motif (ITAM), required for many signaling events. We have demonstrated that the two ITAM tyrosines are required for phagocytic signaling and that mutation of a single ITAM tyrosine decreases but does not abolish phagocytic signaling. Furthermore, we have identified that the YMTL motif is required for endocytosis. These observations suggest that FcγRIIA utilizes different sequences for various signaling events. Therefore, we investigated the sequence requirements for another important FcγRIIA-mediated signaling event, serotonin secretion, using Rat Basophilic Leukemia (RBL-2H3) cells transfected with wildtype (WT) FcγRIIA or mutant FcγRIIA. Stimulation of cells expressing WT FcγRIIA induced release of serotonin at a level 7-fold greater than that in nonstimulated WT FcγRIIAtransfected cells or nontransfected RBL cells. Mutation of either ITAM tyrosine (Y2 or Y3) to phenylalanine was sufficient to abolish serotonin secretion. Further, while inhibition of Syk with piceatannol blocked phagocytosis as expected, it did not inhibit serotonin secretion. Additionally, inhibition of phosphoinositol-3-kinase (PI3K) with wortmannin only had a partial effect on serotonin signaling, despite the fact that the concentrations used completely abolished phagocytic signaling. These data suggest that the requirements for serotonin secretion differ from those for phagocytosis mediated by FcγRIIA.
DNA bulges are biologically consequential defects that can arise from template-primer misalignmen... more DNA bulges are biologically consequential defects that can arise from template-primer misalignments during replication and pose challenges to the cellular DNA repair machinery. Calorimetric and spectroscopic characterizations of defectcontaining duplexes reveal systematic patterns of sequence-context dependent bulge-induced destabilizations. These distinguishing energetic signatures are manifest in three coupled characteristics, namely: the magnitude of the bulgeinduced duplex destabilization (""G Bulge); the thermodynamic origins of ""G Bulge (i.e. enthalpic versus entropic); and, the cooperativity of the duplex melting transition (i.e. two-state versus non-two state). We find moderately destabilized duplexes undergo two-state dissociation and exhibit ""G Bulge values consistent with localized, nearest neighbor perturbations arising from unfavorable entropic contributions. Conversely, strongly destabilized duplexes melt in a non-twostate manner and exhibit ""G Bulge values consistent with perturbations exceeding nearest-neighbor expectations that are enthalpic in origin. Significantly, our data reveal an intriguing correlation in which the energetic impact of a single bulge base centered in one strand portends the impact of the corresponding complementary bulge base embedded in the opposite strand. We discuss potential correlations between these bulge-specific differential energetic profiles and their overall biological implications in terms of DNA recognition, repair and replication.
Penile pain is one of the most distressing, limiting, and difficult to treat manifestations of Pe... more Penile pain is one of the most distressing, limiting, and difficult to treat manifestations of Peyronie disease. The use of steroid injections for penile deformities associated with Peyronie disease has been ineffective. However, use of steroid injections in managing penile pain has been poorly investigated. The aim of this study was to examine the efficacy and safety of subcutaneous, nonintralesional steroid injections in patients with severe, disabling, and/or chronic penile pain associated with Peyronie disease. This was a single-institution retrospective study of 16 patients with severe, disabling, and/or chronic penile pain associated with Peyronie disease who underwent subcutaneous, nonintralesional injection of triamcinolone (50 mg) between 2004 and 2006. Preinjection and postinjection analog pain scales were used to assess treatment efficacy. All 16 patients (mean age, 47.6 6 11.1 years) had penile pain associated with erections for an average of 13.9 months (range, 3-36 months) prior to injections. Mean preinjection and postinjection penile pain scores were 6.6 6 2.1 and 0.5 6 0.5, respectively. On average, patients were pain free at follow-up visits within 10.6 6 7.6 weeks. The mean pain-free duration was 23.8 months (range, 3-52 months). The mean cumulative dose of triamcinolone was 75.0 mg (range, 50-200 mg), with a mean of 1.5 injections (range, 1-4 injections). All 16 patients had overall improvement in pain scores. There were no adverse events or geometric penile changes after injections. Subcutaneous, nonintralesional injections of triamcinolone is an effective, safe, and durable means of managing severe, disabling, and/or chronic penile pain in patients with Peyronie disease. Future studies are needed to validate these findings.
DNA bulges are biologically consequential defects that can arise from template-primer misalignmen... more DNA bulges are biologically consequential defects that can arise from template-primer misalignments during replication and pose challenges to the cellular DNA repair machinery. Calorimetric and spectroscopic characterizations of defectcontaining duplexes reveal systematic patterns of sequence-context dependent bulge-induced destabilizations. These distinguishing energetic signatures are manifest in three coupled characteristics, namely: the magnitude of the bulgeinduced duplex destabilization (""G Bulge); the thermodynamic origins of ""G Bulge (i.e. enthalpic versus entropic); and, the cooperativity of the duplex melting transition (i.e. two-state versus non-two state). We find moderately destabilized duplexes undergo two-state dissociation and exhibit ""G Bulge values consistent with localized, nearest neighbor perturbations arising from unfavorable entropic contributions. Conversely, strongly destabilized duplexes melt in a non-twostate manner and exhibit ""G Bulge values consistent with perturbations exceeding nearest-neighbor expectations that are enthalpic in origin. Significantly, our data reveal an intriguing correlation in which the energetic impact of a single bulge base centered in one strand portends the impact of the corresponding complementary bulge base embedded in the opposite strand. We discuss potential correlations between these bulge-specific differential energetic profiles and their overall biological implications in terms of DNA recognition, repair and replication.
www.urotodayinternationaljournal.com Volume 2 December 2009 Outcome of Patients with Abnormal Upp... more www.urotodayinternationaljournal.com Volume 2 December 2009 Outcome of Patients with Abnormal Upper Tract Cytology and Negative Initial Workup UroToday International Journal ® UIJ INTRODUCTION: Patients with pathologically confirmed upper tract transitional cell carcinoma (TCC) currently undergo surveillance according to well described protocols. The literature offers little guidance for monitoring patients with abnormal upper tract cytology without prior upper tract TCC. The purpose of the present study was to assess the risk of upper tract TCC based on cytology and determine a reasonable observation strategy for this abnormal finding. METHODS: The authors performed a 10-year retrospective cohort study of 204 patients (366 renal units) within the New England Veterans Administration Healthcare System. Upper tract cytology was collected: (1) as a consequence of lateralizing hematuria during cystoscopy in 2 patients; (2) following abnormal upper tract imaging in 27 patients; (3) from ...
INTRODUCTION AND OBJECTIVE:Alternatives to radical cystectomy (RC) are critically needed for the ... more INTRODUCTION AND OBJECTIVE:Alternatives to radical cystectomy (RC) are critically needed for the treatment of high-risk BCG-unresponsive NMIBC. Vicinium is a recombinant fusion protein comprised of...
Level 1 evidence supports use of neoadjuvant platinum chemotherapy (NAC) for muscle invasive blad... more Level 1 evidence supports use of neoadjuvant platinum chemotherapy (NAC) for muscle invasive bladder cancer, but little is known about prospective efficacy and safety of NAC in HG UTUC. This multisite phase II trial investigated NAC prior to nephroureterectomy and lymph node dissection (NU). METHODS: Patients (pts) with HG UTUC planned for NU were eligible, with treatment arm of 4 NAC cycles assigned by baseline creatinine clearance (CrCl), CrCl >50 received accelerated (a)MVAC (methotrexate 30 mg/m2, vinblastine 3 mg/m2, doxorubicin 30 mg/m2, cisplatin 70 mg/m2 with pegfilgrastim q14 days). CrCl !30 and 50 received carboplatin AUC 5 D1 and gemcitabine 1000 mg/m2 days 1, 8 (GC). Primary endpoint was pathologic complete response (pCR) rate (ypT0N0). On each arm, a pCR rate of 18% was of interest vs. a null of 4%. Success was defined as at least 3 pCRs among 28 pts (10.7%). Accrual goal was 30 pts per arm. RESULTS: From April 2015-May 2017, 30 patients were enrolled to the aMVAC cohort. Six enrolled to the GC cohort which closed for poor accrual in January 2018. On aMVAC arm 1 pt had renal cell ca. 3/29 eligible pts (23 M 6F), median age 65(40-84), median PS 0, achieved ypT0N0 at NU (10.3%, 90% CI [2.9 e 24.6]). Including pt with clinical CR on preoperative imaging without lymph node dissection at NU (ypT0Nx), the pCR rate was 4/29 (14%, 90% CI [4.9 e 28.8]), (table). The median number of chemotherapy cycles was 4 (1-4), 79% of patients completed treatment. One pt on aMVAC arm with cycle 1 Gr4 sepsis deferred further NAC and NU. Grade 3-4 toxicity rate was 23% on aMVAC arm, no G5 events. CONCLUSIONS: aMVAC NAC demonstrated pre-defined activity with 14% pCR, above null 4%, with no new safety concerns in pts with HG UTUC and CrCl >50. Rate of ypT1 over 60% may be of clinical interest. Slow accrual in the CrCl 50 arm suggests novel trials are warranted. A follow up immunotherapy-chemotherapy combination trial in UTUC is planned through ECOG-ACRIN.
302 Background: Micropapillary bladder cancer (MPBC) is an aggressive variant of urothelial carci... more 302 Background: Micropapillary bladder cancer (MPBC) is an aggressive variant of urothelial carcinoma. We have previously published clinical risk stratification groups for patients with conventional urothelial carcinoma and sought to identify if these were valid in patients with this variant histology. Methods: An IRB approved review of 1910 patients in our radical cystectomy database revealed 106 patients with preoperative diagnosis of ≤cT4aN0M0 MPBC between December 1992 and January 2012 who underwent upfront radical cystectomy (RC, n = 74) or neoadjuvant chemotherapy (NAC) followed by RC (n = 32). To determine whether patients with MPBC can be risk stratified using traditional risk factors, a recursive partitioning analysis (RPA) was performed. Results: In multivariate analyses, hydronephrosis (HR=3.1; p=0.01), and extent of MPBC at transurethral resection (TUR) (HR=1.9; p=0.04) were associated with shortened OS. In the reduced model, clinical stage also achieved significance (HR...
To analyze survival in clinically localized, surgically resectable micropapillary bladder cancer ... more To analyze survival in clinically localized, surgically resectable micropapillary bladder cancer patients undergoing radical cystectomy with and without neoadjuvant chemotherapy and develop risk strata based on outcome data. A review of our database identified 103 patients with surgically resectable (≤cT4acN0cM0) micropapillary bladder cancer who underwent radical cystectomy. Survival estimates were calculated using Kaplan-Meier method and compared using log-rank tests. Classification and regression tree analysis was performed to identify risk groups for survival. For the entire cohort, estimated 5-year overall and disease-specific survival rates were 52% and 58%, respectively. Classification and regression tree analysis identified three risk subgroups: low-risk: cT1, no hydronephrosis; high-risk: ≥cT2, no hydronephrosis; and highest-risk: cTany with tumor-associated hydronephrosis. Five-year disease-specific survival for the low-, high-, and highest-risk groups were 92%, 51%, and 1...
The human Fc receptor, FcγRIIA, is known to mediate phagocytosis and endocytosis, yet the greates... more The human Fc receptor, FcγRIIA, is known to mediate phagocytosis and endocytosis, yet the greatest numbers of these receptors are expressed on the surface of non-phagocytic platelets, where they are involved in serotonin secretion. FcγRIIA harbors three tyrosine (Y) residues within its cytoplasmic domain. Y1 is upstream of both Y2 and Y3, which are contained within an immunoreceptor tyrosine-based activation motif (ITAM), required for many signaling events. We have demonstrated that the two ITAM tyrosines are required for phagocytic signaling and that mutation of a single ITAM tyrosine decreases but does not abolish phagocytic signaling. Furthermore, we have identified that the YMTL motif is required for endocytosis. These observations suggest that FcγRIIA utilizes different sequences for various signaling events. Therefore, we investigated the sequence requirements for another important FcγRIIA-mediated signaling event, serotonin secretion, using Rat Basophilic Leukemia (RBL-2H3) cells transfected with wildtype (WT) FcγRIIA or mutant FcγRIIA. Stimulation of cells expressing WT FcγRIIA induced release of serotonin at a level 7-fold greater than that in nonstimulated WT FcγRIIAtransfected cells or nontransfected RBL cells. Mutation of either ITAM tyrosine (Y2 or Y3) to phenylalanine was sufficient to abolish serotonin secretion. Further, while inhibition of Syk with piceatannol blocked phagocytosis as expected, it did not inhibit serotonin secretion. Additionally, inhibition of phosphoinositol-3-kinase (PI3K) with wortmannin only had a partial effect on serotonin signaling, despite the fact that the concentrations used completely abolished phagocytic signaling. These data suggest that the requirements for serotonin secretion differ from those for phagocytosis mediated by FcγRIIA.
DNA bulges are biologically consequential defects that can arise from template-primer misalignmen... more DNA bulges are biologically consequential defects that can arise from template-primer misalignments during replication and pose challenges to the cellular DNA repair machinery. Calorimetric and spectroscopic characterizations of defectcontaining duplexes reveal systematic patterns of sequence-context dependent bulge-induced destabilizations. These distinguishing energetic signatures are manifest in three coupled characteristics, namely: the magnitude of the bulgeinduced duplex destabilization (""G Bulge); the thermodynamic origins of ""G Bulge (i.e. enthalpic versus entropic); and, the cooperativity of the duplex melting transition (i.e. two-state versus non-two state). We find moderately destabilized duplexes undergo two-state dissociation and exhibit ""G Bulge values consistent with localized, nearest neighbor perturbations arising from unfavorable entropic contributions. Conversely, strongly destabilized duplexes melt in a non-twostate manner and exhibit ""G Bulge values consistent with perturbations exceeding nearest-neighbor expectations that are enthalpic in origin. Significantly, our data reveal an intriguing correlation in which the energetic impact of a single bulge base centered in one strand portends the impact of the corresponding complementary bulge base embedded in the opposite strand. We discuss potential correlations between these bulge-specific differential energetic profiles and their overall biological implications in terms of DNA recognition, repair and replication.
Penile pain is one of the most distressing, limiting, and difficult to treat manifestations of Pe... more Penile pain is one of the most distressing, limiting, and difficult to treat manifestations of Peyronie disease. The use of steroid injections for penile deformities associated with Peyronie disease has been ineffective. However, use of steroid injections in managing penile pain has been poorly investigated. The aim of this study was to examine the efficacy and safety of subcutaneous, nonintralesional steroid injections in patients with severe, disabling, and/or chronic penile pain associated with Peyronie disease. This was a single-institution retrospective study of 16 patients with severe, disabling, and/or chronic penile pain associated with Peyronie disease who underwent subcutaneous, nonintralesional injection of triamcinolone (50 mg) between 2004 and 2006. Preinjection and postinjection analog pain scales were used to assess treatment efficacy. All 16 patients (mean age, 47.6 6 11.1 years) had penile pain associated with erections for an average of 13.9 months (range, 3-36 months) prior to injections. Mean preinjection and postinjection penile pain scores were 6.6 6 2.1 and 0.5 6 0.5, respectively. On average, patients were pain free at follow-up visits within 10.6 6 7.6 weeks. The mean pain-free duration was 23.8 months (range, 3-52 months). The mean cumulative dose of triamcinolone was 75.0 mg (range, 50-200 mg), with a mean of 1.5 injections (range, 1-4 injections). All 16 patients had overall improvement in pain scores. There were no adverse events or geometric penile changes after injections. Subcutaneous, nonintralesional injections of triamcinolone is an effective, safe, and durable means of managing severe, disabling, and/or chronic penile pain in patients with Peyronie disease. Future studies are needed to validate these findings.
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Papers by Rian Dickstein