Ali Imran Amjad

Autologous hematopoietic stem cell transplantation may reverse renal failure in patients with multiple myeloma.

Approximately 20% of patients with multiple myeloma (MM) have renal failure at diagnosis, and about 5% are dialysis-dependent. Many of these patients are considered ineligible for autologous hematopoietic stem cell transplantation (auto-HSCT) because of a high risk of treatment-related toxicity. We evaluated the outcome of 46 patient with MM and renal failure, defined as serum creatinine >2 mg/dL sustained for >1 month before the start of preparative regimen. Patients received auto-HSCT at our institution between September 1997 and September 2006. Median serum creatinine and creatinine clearance (CrCl) at auto-HSCT were 2.9 mg/dL (range: 2.0-12.5) and 33 mL/min (range: 8.7-63), respectively. Ten patients (21%) were dialysis-dependent. Median follow-up in surviving patients was 34 months (range: 5-81). Complete (CR) and partial responses (PR) after auto-HSCT were seen in 9 (22%) and 22 (53%) of the 41 evaluable patients, with an overall response rate of 75%. Two patients (4%) died within 100 days of auto-HSCT. Grade 2-4 nonhematologic adverse events were seen in 18 patients (39%) and included cardiac arrythmias, pulmonary edema, and hyperbilirubinemia. Significant improvement in renal function, defined as an increase in flomerular filtration rate (GFR) by 25% above baseline, was seen in 15 patients (32%). Kaplan-Meier estimates of 3-year progression-free survival (PFS) and overall survival (OS) were 36% and 64%, respectively. In conclusion, auto HSCT can be offered to patients with MM and renal failure with acceptable toxicity and with a significant improvement in renal function in approximately one-third of the transplanted patients. In this analysis, a melphalan (Mel) dose of 200 mg/m(2) was not associated with an increase in toxicity or nonrelapse (Mel) mortality (NRM).

Predictors of prolonged survival after allogeneic hematopoietic stem cell transplantation for multiple myeloma.

A total of 149 patients with multiple myeloma (MM) who received allogeneic hematopoietic stem cell transplantation (allo‐HCT) with myeloablative (MAC; n = 38) or reduced‐intensity conditioning (RIC; n = 110) regimens at MD Anderson Cancer Center were evaluated. Of the total, 120 (81%) patients had relapsed or had refractory disease. Median age of MM patients was 50 (28–70) years with a followup time of 28.5 (3–164) months. The 100‐day and 5‐year treatment related mortality (TRM) rates were 17% and 47%, respectively. TRM was significantly lower with RIC regimens (13%) vs. 29% for MAC at 100 days (P = 0.012). The cumulative incidence of Grade II–IV acute graft‐versus‐host disease (GVHD) was 35% and chronic GVHD was 46%. PFS and OS at 5 years were 15% and 21%, respectively. In multivariate analysis, allo‐HCT for primary remission consolidation was associated with longer PFS (HR 0.35; 95% CI, 0.18–0.67) and OS (HR 0.29; 95% CI 0.15–0.55), while absence of high‐risk cytogenetics was associated with longer PFS only (HR 0.59; 95% CI 0.37–0.95). We observe that TRM has decreased with the use of RIC regimens, and long‐term disease control can be expected in a subset of MM patients undergoing allo‐HCT. Further studies should be conducted in carefully designed clinical trials in this patient population. Am. J. Hematol., 2012.

Outcome of Allogeneic Hematopoietic Stem Cell Transplantation in Patients with Low Left Ventricular Ejection Fraction

A high risk of regimen-related toxicity with allogeneic hematopoietic stem cell transplantation (allo-HSCT) limits this potentially curative treatment for patients with a left ventricular ejection fraction (LVEF) of > or =50%. We evaluated the frequency of cardiac complications and 100-day nonrelapse mortality (NRM) in 56 patients with a LVEF of < or =45%, who received allo HCT at our institution. The results were retrospectively compared with a matched control group with LVEF of > or =50%, which received an allogeneic stem cell transplantation (allo-SCT). After a median follow-up of 29 months in the study group, grade > or =2 cardiac complications were seen in 7 of 56 (12.5%) patients and cumulative incidence of 100-day NRM was 12.5% with no deaths from cardiac causes. In contrast, after a median follow-up of 49 months in the control group, grade >2 cardiac complications were seen in 19 of 161 patients (11.8%; P = 1.00) and cumulative incidence of 100-day NRM was 14.9% (P = .82). The presence of at least 1 of the 7 pretransplant cardiac risk factors (past history of smoking, hypertension, hyperlipidemia, coronary artery disease, arrhythmia, prior myocardial infarction, and congestive heart failure) was associated with a higher cardiac complication rate in the study group (P = .03). In conclusion, selected patients with a LVEF of < or =45% can safely receive allo-HCT without a significant increase in cardiac toxicity or NRM.

Broccoli-Derived Sulforaphane and Chemoprevention of Prostate Cancer: From Bench to Bedside.

Sulforaphane (SFN) is a metabolic byproduct of cruciferous vegetables and is the biologically active phytochemical found in high concentrations in broccoli. It has been studied extensively for its anticancer efficacy and the underlying mechanisms using cell culture and preclinical models. The immediate precursor of SFN is glucoraphanin, a glucosinolate which requires metabolic conversion to SFN. SFN and other notable isothiocyanates (ITCs), including phenethyl isothiocyanate and benzyl isothiocyanate found in various cruciferous vegetables, have also been implicated to have a chemopreventive role for breast, colon, and prostate cancer. In vitro and in vivo anticancer activity of this class of compounds summarizing the past two decades of basic science research has previously been reviewed by us and the others. The present review aims to focus specifically on SFN and its chemopreventive and antineoplastic activity against prostate cancer. Particular emphasis in this communication is placed on the current status of clinical research and prospects for future clinical trials with the overall objective to better understand the clinical utility of this promising chemopreventive nutraceutical in the context of mechanisms of prostate carcinogenesis.

CXCR4 Is a Novel Target of Cancer Chemopreventative Isothiocyanates in Prostate Cancer Cells

Isothiocyanates (ITCs) derived from cruciferous vegetables, including phenethyl isothiocyanate (PEITC) and sulforaphane (SFN), exhibit in vivo activity against prostate cancer in a xenograft and transgenic mouse model, and thus are appealing for chemoprevention of this disease. Watercress constituent PEITC and SFN-rich broccoli sprout extract are under clinical investigations but the molecular mechanisms underlying their cancer chemopreventive effects are not fully understood. The present study demonstrates that chemokine receptor CXCR4 is a novel target of ITCs in prostate cancer cells. Exposure of prostate cancer cells (LNCaP, 22Rv1, C4-2, and PC-3) to pharmacologically applicable concentrations of PEITC, benzyl isothiocyanate (BITC), and SFN (2.5 and 5 μmol/L) resulted in downregulation of CXCR4 expression. None of the ITCs affected secretion of CXCR4 ligand (stromal-derived factor-1). In vivo inhibition of PC-3 xenograft growth upon PEITC treatment was associated with a significant decrease in CXCR4 protein level. A similar trend was discernible in the tumors from SFN-treated TRAMP mice compared with those of control mice, but the difference was not significant. Stable overexpression of CXCR4 in PC-3 cells conferred significant protection against wound healing, cell migration, and cell viability inhibition by ITCs. Inhibition of cell migration resulting from PEITC and BITC exposure was significantly augmented by RNAi of CXCR4. This study demonstrates, for the first time, that cancer chemopreventive ITCs suppress CXCR4 expression in prostate cancer cells in vitro as well as in vivo. These results suggest that CXCR4 downregulation may be an important pharmacodynamic biomarker of cancer chemopreventative ITCs in prostate adenocarcinoma. Cancer Prev Res; 8(5); 365–74. ©2015 AACR.

Renal Medullary Carcinoma: Case Report of an Aggressive Malignancy with Near-Complete Response to Dose-Dense Methotrexate, Vinblastine, Doxorubicin, and Cisplatin Chemotherapy

Renal medullary carcinoma (RMC) is a rare but aggressive malignancy affecting young individuals with sickle cell trait. Renal medullary carcinoma commonly presents with advanced or metastatic disease and is associated with a rapidly progressive clinical course and an extremely short overall survival measured in weeks to few months. Due to the rarity of RMC, there is no proven effective therapy and patients are often treated with platinum-based chemotherapy. We report near-complete radiological and pathological response in a patient treated with dose-dense MVAC (methotrexate, vinblastine, doxorubicin, and cisplatin) chemotherapy. The patient underwent consolidation nephrectomy and retroperitoneal lymph node dissection and had a 16-month progression-free survival, one of the longest reported in patients with RMC.

Breast Mass and Lytic Bone Lesions: A Rare Presentation of Non-Hodgkin’s Lymphoma Arising in the Breast

Background. Primary breast lymphoma is a rare malignancy representing less than 1% of all tumors presenting in the breast. Case Presentation. A 55-year-old woman presented with altered mental status due to severe hypercalcemia and was found to have a large breast mass with lytic bone lesions in the calvarium of the skull. Biopsy of the mass revealed diffuse large B-cell lymphoma. Staging workup did not reveal any visceral organ or distant lymph node involvement. The patients bone marrow biopsy was positive for involvement with lymphoma. Interestingly, the patient also had a non quantifiable IgA kappa monoclonal protein in the serum. Conclusion. Here, we describe a common presentation in medical oncology, that is, a patient presenting as a clinically advanced breast tumor with hypercalcemia from lytic bone lesions. However, diagnostic workup led to the diagnosis of another common malignancy in an uncommon location, namely, diffuse large B-cell lymphoma arising in the breast.

Abstract 1906: CXCR4 is a novel target of cancer chemopreventative isothiocyanates in prostate cancer cells

Proceedings: AACR 106th Annual Meeting 2015; April 18-22, 2015; Philadelphia, PA Isothiocyanates (ITCs) derived from cruciferous vegetables, including phenethyl isothiocyanate (PEITC) and sulforaphane (SFN), exhibit in vivo activity against prostate cancer in xenograft and transgenic mouse models, and thus are appealing for chemoprevention of this disease. Watercress constituent PEITC and SFN-rich broccoli sprout extract are under clinical investigation but the molecular mechanisms underlying their cancer chemopreventive effects are not fully understood. The present study demonstrates that chemokine receptor CXCR4 is a novel target of ITCs in prostate cancer cells. Exposure of prostate cancer cells (LNCaP, 22Rv1, C4-2, and PC-3) to pharmacologically applicable concentrations of PEITC, benzyl isothiocyanate (BITC), and SFN (2.5 and 5 μmol/L) resulted in downregulation of CXCR4 expression. None of the isothiocyanates affected secretion of CXCR4 ligand (stromal-derived factor-1). In vivo inhibition of PC-3 xenograft growth upon PEITC treatment was associated with a significant decrease in CXCR4 protein level. A similar trend was discernible in the tumors from SFN-treated TRAMP mice compared with those of control mice, but the difference was not significant. Stable overexpression of CXCR4 in PC-3 cells conferred significant protection against wound healing, cell migration, and cell viability inhibition by ITCs. Inhibition of cell migration resulting from PEITC and BITC exposure was significantly augmented by RNA interference of CXCR4. This study demonstrates, for the first time, that cancer chemopreventive ITCs suppress CXCR4 expression in prostate cancer cells in vitro as well as in vivo. These results suggest that CXCR4 downregulation may be an important pharmacodynamic biomarker of cancer chemopreventative ITCs in prostate adenocarcinoma. Citation Format: Ali I. Amjad, Kozue Sakao, Avani R. Vyas, Sreenivasa R. Chinni, Rahul Parikh, Shivendra V. Singh. CXCR4 is a novel target of cancer chemopreventative isothiocyanates in prostate cancer cells. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1906. doi:10.1158/1538-7445.AM2015-1906