Mallika Sachdev Dhawan

Morphometric Analysis of the Ventral Nerve Roots and Retroperitoneal Vessels With Respect to the Minimally Invasive Lateral Approach in Normal and Deformed Spines

Study Design. A morphometric analysis, using magnetic resonance imaging (MRI) studies of the lumbar spine. Objective. To identify the anatomic position of the ventral root and the retroperitoneal vessels in relation to the vertebral body in normally aligned and deformed spines. Summary of Background Data. The lateral approach to the lumbar spine is a relatively new method for performing interbody fusions. In contrast to the standard open anterior approach with direct vision of the operative field, the lateral approach uses expandable retractors that are positioned under fluoroscopic guidance. Risks of this technique include injury to the exiting nerve root and retroperitoneal vessels. Methods. One hundred lumbar spine MRI studies were reviewed from patients treated for various spinal pathologies. The measured intervertebral segments were divided into 3 groups: group 1 (n = 247), normally aligned vertebrae and disc spaces; group 2 (n = 18), degenerative spondylolisthetic segments; and group 3 (n = 19), segments from the apex of degenerative lumbar scoliosis. Axial MR images were used to measure: the vertebral endplate anterior-posterior (AP) diameter, the overlap between the ventral root and the posterior margin of the vertebra, and the overlap between the retroperitoneal large vessels and the anterior edge of the vertebra. Results. The overlap between the adjacent neuro-vascular structures and the vertebral body endplate gradually increased from L1–L2 to L4–L5. The maximal overlap, at the L4–L5 level reached 87% resulting in a relatively narrow corridor for performing the operative procedure. Alteration in the anatomic location of the nerve root and the retroperitoneal vessels, in Group 3 (scoliosis) further decreased the safe corridor. Conclusion. The safe corridor for performing the discectomy and inserting the intervertebral cage narrows from L1–L2 to the L4–L5 level. This corridor is further narrowed with rotatory deformity of the spine. Using the preoperative MRI to assess the relative position of the adjacent neuro-vascular structures in relation to the lower vertebra’s endplate at each level is recommended.

Suppression of the Nitric Oxide Pathway in Metastatic Renal Cell Carcinoma Patients Receiving Vascular Endothelial Growth Factor–Signaling Inhibitors

Therapies that target the vascular endothelial growth factor (VEGF) pathway cause hypertension, but the mechanism remains unknown. This cross-sectional study tested the hypothesis that VEGF inhibition causes hypertension by suppressing VEGF-mediated vasodilatory pathways. Urine was collected from 80 patients with metastatic renal cell carcinoma from 2002 to 2009, 40 at baseline and 40 while on VEGF inhibitors. Measured urinary biomarkers include albumin, metabolites of the nitric oxide (NO) pathway and its downstream effector cGMP, and prostaglandin pathway biomarkers prostaglandin E2, 6-keto prostaglandin F1&agr;, and cAMP, all normalized to urinary creatinine. The mean age in both groups was 61.8 years, 76% were men, and urinary albumin was higher in patients receiving VEGF inhibitors (median: 18.4 versus 4.6 mg/g; P=0.009). cGMP/creatinine was suppressed in patients on VEGF inhibitors (0.28 versus 0.39 pmol/&mgr;g; P=0.01), with a trend toward suppression of nitrate/creatinine (0.46 versus 0.62 &mgr;mol/mg; P=0.09). Both comparisons were strengthened when patients on bevacizumab were excluded, and only those receiving small molecule tyrosine kinase inhibitors were analyzed (cGMP/creatinine: P=0.003; nitrate/creatinine: P=0.01). Prostaglandin E2, 6-keto prostaglandin F1&agr;, and cAMP did not differ between groups. These results suggest that hypertension induced by VEGF inhibitors is mediated by suppression of NO production. Prospective studies are needed to explore whether these biomarkers may be useful predictors of efficacy in patients receiving VEGF-targeted therapies.

Incidence and prevention of intervertebral cage overhang with minimally invasive lateral approach fusions.

Study Design. Radiographic review. Objective. To evaluate the incidence and degree of cage overhang in minimally invasive spinal (MIS) fusions, when using either the direct lateral interbody fusion (DLIF) or extreme lateral interbody fusion (XLIF) techniques. Summary of Background Data. Among the difficulties surgeons face during a MIS lateral interbody fusion is to assess the proper placement of the cage without the use of direct visualization. Determining the proper length of the cage using AP view fluoroscopy can be misleading. As the axial profile of the vertebral body is oval, inserting the cage anterior or posterior to the maximal width point requires adjustment of the cages length. Methods. The incidence and degree of cage overhang were measured using magnetic resonance imaging (MRI) and computed tomography (CT) studies from patients that underwent a MIS lateral interbody fusion. To determine the adjustment needed when the cage is inserted at various sagittal sites, the coronal spans of normal vertebral endplates were measured. Results. Forty-five percent of the cages were placed in the central portion, 34% were located in the anterior 1/3, and 7% were located in the posterior 1/3 of the disc space. Of the anterior positioned cages, 45% were found to be overhanging outside of the boundaries of the intervertebral disc space. The average measured lateral protrusion was 7.8 ± 3.6 mm, and anterior protrusion was 9.8 ± 3.3 mm. The vertebral body width measured 41.7 ± 6 mm at the anterior 1/3, 50 ± 4 mm at the mid, and 49 ± 1 mm at the posterior 1/3. Compared with the midvertebral width, the vertebral body width at the anterior 1/3 was decreased by 16.5% ± 0.9% (P < 0.05). Conclusion. The risk of placing an excessively long cage, when the insertion site is located in the anterior 1/3 of the disc, is relatively high, when performing MIS lateral approach interbody fusions. When using an anterior entry point for the insertion of the cage, choosing a 15% shorter cage length compared with that measured on the AP should prevent anterolateral protrusion of the cage.

Differential toxicity in patients with and without DNA repair mutations: Phase I Study of Carboplatin and Talazoparib in advanced solid tumors

Purpose: The PARP inhibitor (PARPi) talazoparib may potentiate activity of chemotherapy and toxicity in cells vulnerable to DNA damage. Experimental Design: This phase I study evaluated the safety, tolerability, pharmacokinetics, and efficacy of talazoparib and carboplatin. Pharmacokinetic modeling explored associations between DNA vulnerability and hematologic toxicity. Results: Twenty-four patients (eight males; 16 females) with solid tumors were enrolled in four cohorts at 0.75 and 1 mg daily talazoparib and weekly carboplatin (AUC 1 and 1.5, every 2 weeks or every 3 weeks), including 14 patients (58%) with prior platinum treatment. Dose-limiting toxicities included grade 3 fatigue and grade 4 thrombocytopenia; the MTD was not reached. Grade 3/4 toxicities included fatigue (13%), neutropenia (63%), thrombocytopenia (29%), and anemia (38%). After cycle 2s dose, delays/reductions were required in all patients. One complete and two partial responses occurred in germline BRCA1/2 (gBRCA1/2) patients. Four patients showed stable disease beyond 4 months, three of which had known mutations in DNA repair pathways. Pharmacokinetic toxicity modeling suggests that after three cycles of carboplatin AUC 1.5 every 3 weeks and talazoparib 1 mg daily, neutrophil counts decreased 78% [confidence interval (CI), 87–68] from baseline in gBRCA carriers and 63% (CI, 72–55) in noncarriers (P < 0.001). Pharmacokinetic toxicity modeling suggests an intermittent, pulse dosing schedule of PARP inhibition, differentiated by gBRCA mutation status, may improve the benefit/risk ratio of combination therapy. Conclusions: Carboplatin and talazoparib showed efficacy in DNA damage mutation carriers, but hematologic toxicity was more pronounced in gBRCA carriers. Carboplatin is best combined with intermittent talazoparib dosing differentiated by germline and somatic DNA damage mutation carriers. Clin Cancer Res; 23(21); 6400–10. ©2017 AACR.

Heterogeneous drug penetrance of veliparib and carboplatin measured in triple negative breast tumors

BackgroundPoly(ADP-ribose) polymerase inhibitors (PARPi), coupled to a DNA damaging agent is a promising approach to treating triple negative breast cancer (TNBC). However, not all patients respond; we hypothesize that non-response in some patients may be due to insufficient drug penetration. As a first step to testing this hypothesis, we quantified and visualized veliparib and carboplatin penetration in mouse xenograft TNBCs and patient blood samples.MethodsMDA-MB-231, HCC70 or MDA-MB-436 human TNBC cells were implanted in 41 beige SCID mice. Low dose (20 mg/kg) or high dose (60 mg/kg) veliparib was given three times daily for three days, with carboplatin (60 mg/kg) administered twice. In addition, blood samples were analyzed from 19 patients from a phase 1 study of carboplatin + PARPi talazoparib. Veliparib and carboplatin was quantified using liquid chromatography–mass spectrometry (LC-MS). Veliparib tissue penetration was visualized using matrix-assisted laser desorption/ionization mass spectrometric imaging (MALDI-MSI) and platinum adducts (covalent nuclear DNA-binding) were quantified using inductively coupled plasma–mass spectrometry (ICP-MS). Pharmacokinetic modeling and Pearson’s correlation were used to explore associations between concentrations in plasma, tumor cells and peripheral blood mononuclear cells (PBMCs).ResultsVeliparib penetration in xenograft tumors was highly heterogeneous between and within tumors. Only 35% (CI 95% 26–44%), 74% (40–97%) and 46% (9–37%) of veliparib observed in plasma penetrated into MDA-MB-231, HCC70 and MDA-MB-436 cell-based xenografts, respectively. Within tumors, penetration heterogeneity was larger with the 60 mg/kg compared to the 20 mg/kg dose (RSD 155% versus 255%, P = 0.001). These tumor concentrations were predicted similar to clinical dosing levels, but predicted tumor concentrations were below half maximal concentration values as threshold of response. Xenograft veliparib concentrations correlated positively with platinum adduct formation (R2 = 0.657), but no PARPi–platinum interaction was observed in patients’ PBMCs. Platinum adduct formation was significantly higher in five gBRCA carriers (ratio of platinum in DNA in PBMCs/plasma 0.64% (IQR 0.60–1.16%) compared to nine non-carriers (ratio 0.29% (IQR 0.21–0.66%, P < 0.0001).ConclusionsPARPi/platinum tumor penetration can be measured by MALDI-MSI and ICP-MS in PBMCs and fresh frozen, OCT embedded core needle biopsies. Large variability in platinum adduct formation and spatial heterogeneity in veliparib distribution may lead to insufficient drug exposure in select cell populations.

A multicenter phase I study of cabazitaxel, mitoxantrone, and prednisone for chemotherapy-naïve patients with metastatic castration-resistant prostate cancer: A department of defense prostate cancer clinical trials consortium study.

BACKGROUND Cabazitaxel plus prednisone has significant activity in patients with chemotherapy-naïve and pretreated metastatic castration-resistant prostate cancer (mCRPC). Mitoxantrone has antitumor activity in mCRPC and nonoverlapping mechanism of action and toxicity profile. OBJECTIVE To establish the maximally tolerated dose of the combination of cabazitaxel, mitoxantrone, and prednisone. METHODS AND MATERIALS Patients with chemotherapy-naïve mCRPC were prospectively enrolled in a multicenter phase 1 trial. Cabazitaxel 20 and 25mg/m2 were each evaluated in combination with escalating doses of mitoxantrone (starting dose 4mg/m2), given with prednisone 5mg twice daily. RESULTS A total of 25 patients were enrolled, with median age of 67 (range: 51-78) and prostate-specific antigen of 66.8ng/ml (range: 3-791.2). There were 4 dose-limiting toxicities (febrile neutropenia, n = 3; sepsis, n = 1). The maximally tolerated dose was cabazitaxel 20mg/m2 plus mitoxantrone 12mg/m2. The most common treatment-related grade≥3 related adverse events included neutropenia (n = 8; 32%), febrile neutropenia (n = 5; 20%), and thrombocytopenia (n = 4; 16%). The median number of treatment cycles was 8 (range: 2 to 19+). Decline in prostate-specific antigen to≥50% from baseline was observed in 15 patients (60%). Objective responses were observed in 10/14 (71%) evaluable patients. The median radiographic progression-free survival was 14.5 months (95% CI: 8.0-not reached (NR)), and median overall survival was 23.3 months (95% CI: 14.3-NR). CONCLUSIONS The approved single-agent doses of mitoxantrone and cabazitaxel were safely combined. The combination led to durable tumor responses in most patients. Further study of the combination is warranted.

BRCAness and prostate cancer: diagnostic and therapeutic considerations

Background:Recent advances in genetic sequencing and recent studies focusing on the broader use of Poly ADP Ribose polymerase (PARP) inhibitors have led to an upsurge of interest in DNA repair mutations as they relate to prostate cancer.Methods:This review outlines ongoing studies and recent publications as they relate to the prevalence and detection of DNA repair mutations in metastatic prostate cancer. The detection of these mutations through multiple diagnostic approaches is discussed, including germline sequencing, somatic sequencing, cell-free DNA assays, and circulating tumor cell assays. The clinical course of patients with prostate cancer and DNA repair gene mutations is explored in addition to therapeutic strategies for this population.Conclusions:In men with metastatic prostate cancer, it is reasonable to obtain germline genetic sequencing as well as somatic tumor genomic sequencing to help guide further treatment decisions that may include PARP inhibitors or carboplatin in the future. In the future, in men with metastatic castrate resistant prostate cancer with progression on PARP inhibitors, cell-free DNA sequencing may help elucidate mechanisms of resistance, which include reversion mutations.

Utility of novel androgen receptor therapies in the real world: A nuanced approach

Abiraterone and enzalutamide are in widespread clinical use because of their favorable safety and efficacy. Nonetheless, even with newer agents, resistance develops overtime. In this review, we discuss mechanisms of resistance to these newer agents as well as novel therapeutic agents. We also review the literature to help clinicians decide which agent to begin with and when to stop or switch androgen receptor agents.

Abstract CT051: Carboplatin and talazoparib combination therapy results in differential efficacy and hematologic toxicity in BRCA-mutated patients

Background: Talazoparib is a novel PARP inhibitor (PARPi) in clinical development. Synergistic anti-tumor effects of PARPi and chemotherapy have been observed in preclinical models. This Phase 1 trial evaluates the tolerability, dose limiting toxicities (DLT) and efficacy of talazoparib in combination with carboplatin in patients with or without germ line DNA repair mutations. We hypothesize that talazoparib may overcome carboplatin resistance but induce greater toxicity in patients with DNA repair defects. Methods: Talazoparib and carboplatin pharmacokinetics (PK), safety and anti-tumor activity were evaluated in a 3+3 dose escalation design. Genetic testing, PK, pharmacodynamic effects (PD), biomarkers, and alternate dose modeling were evaluated to better understand the interaction of carboplatin and talazoparib. Results: 24 patients (median age 59y) were enrolled in 4 cohorts and treated with talazoparib 0.75 or 0.1 mg/day and carboplatin AUC 1 or 1.5 for 3/3 or 2/3 weeks. Tumor types included: breast (n = 11), prostate (n = 5), cholangiocarcinoma (n = 2), ovarian (n = 2), bladder (n = 1), adenoid cystic carcinoma (n = 1) and adenocarcinoma of unknown origin (n = 2). Germline mutations were noted in BRCA1 (n = 3), BRCA2 (n = 3), BRIP1 (n = 1), and MSH6 (n = 1) and germ line variants of uncertain significance in BRIP1 (n = 1) and BRCA2 (n = 1). Somatic mutations were found in BRCA2 (n = 1), BAP1 (n = 2) and PALB2 (n = 1). DLTs included fatigue and thrombocytopenia; other non-DLT grade 3/4 toxicities included fatigue (13%), neutropenia (33%), thrombocytopenia (33%), and anemia (58%). Post cycle 1 hematological toxicities required dose delays and reductions in almost all patients. One complete response occurred in a patient with germline BRCA1 (gBRCA1) breast cancer and a partial response (PR) in a gBRCA2 bladder cancer patient; 11 patients (pts) had stable disease (SD) for ?3 months. 5 pts had progressive disease (PD) and 6 pts are not yet evaluable. Of those with PD, 83% had prior platinum therapy, whereas in those with SD or disease response, 46% had prior platinum therapy. Effects of talazoparib/carboplatin on platelet (-11.4% vs. -1.1% P Conclusions: Mutation carriers in BRCA or other DNA repair genes responded better to this combination than non-carriers. Progression with prior platinum or PARPi did not exclude response or clinical benefit. Talazoparib and carboplatin showed significant hematologic toxicity in those with gBRCA or other germ line DNA repair mutations. Lower dosing frequencies of carboplatin when given with PARPi may be required in gBRCA mutation carriers. Citation Format: Mallika S. Dhawan, Rahul Aggarwal, Imke Bartelink, Jim Leng, Scott Thomas, Nela Pawlowska, Laurie Stevenson, Amy Jo Chien, Robin Kate Kelley, Pamela N. Munster. Carboplatin and talazoparib combination therapy results in differential efficacy and hematologic toxicity in BRCA-mutated patients. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr CT051.