[Show abstract][Hide abstract] ABSTRACT: A 46-year-old female presents with a pelvic mass and is diagnosed as having a high-grade endometrial stromal sarcoma. During surgery, she is noted to have areas of intussusception of the small bowel secondary to large hamartomatous polyps. The patient had a previous history of small bowel obstruction secondary to what had been thought to be hyperplastic polyps but represented hamartomatous polyps on further review. Additional examination revealed the presence of subtle hyperpigmented macules on the fingers leading to a diagnosis of Peutz-Jeghers Syndrome (PJS). The diagnosis was confirmed by the presence of a germ-line STK11 mutation. Immunohistochemistry analysis of the tumor showed decreased expression of STK-11 as compared to one of the patient's hamartomatous polyps. Next generation sequencing of the tumor specimen failed to demonstrate a "second hit" somatic mutation in STK-11. This case represents the first case of endometrial stromal sarcoma associated with PJS and illustrates the importance of increased awareness of this condition among oncologists. PJS is associated with dysregulation of the mTOR pathway; treatment with an mTOR inhibitor was not effective in this case.
Hereditary Cancer in Clinical Practice 12/2015; 13(1):6. DOI:10.1186/s13053-015-0027-0 · 1.47 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Background:
A nomogram to predict disease-specific mortality (DSM) following surgery for soft tissue sarcoma (STS) has been developed by the Memorial Sloan Kettering Cancer Center (MSKCC). The goal of this study was to validate this nomogram by assessing discrimination and calibration at the population level using a national cancer database.
Retrospective review of the Surveillance, Epidemiology, and End Results cancer registries identified patients undergoing surgery for STS from 1988 to 2011. Data for patient age, tumor size, tumor grade, histologic subtype, sex, primary tumor location, and tumor depth were entered into the nomogram calculator for each patient. Discrimination was quantified using a concordance index. Calibration was assessed by comparing quintiles of nomogram-predicted probabilities of disease-specific mortality (DSM) with American Joint Committee on Cancer (AJCC) stage DSM.
Overall, 9237 patients were identified with complete information needed for the nomogram. With a mean follow-up of 45 months, the concordance index for nomogram-predicted DSM with actual DSM was 0.74 for the entire cohort. For low- and high-grade tumors, this was 0.71 and 0.66, respectively. Kaplan-Meier curves showed better calibration for nomogram-predicted DSM when compared with AJCC staging.
Our results validate the use of the MSKCC STS nomogram in the general population, with better predictive ability than AJCC staging. However, a concordance index of 0.74 suggests that further improvement in prognostication is needed, perhaps with biological markers or additional clinical variables.
Annals of Surgical Oncology 09/2015; DOI:10.1245/s10434-015-4849-9 · 3.93 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: We report a response to pazopanib in a 69-year-old man with heavily pre-treated metastatic extraosseous Ewing sarcoma in addition to molecular profiling of his tumor. To our knowledge, this case is the earliest to demonstrate activity of an oral multi-targeted kinase inhibitor in Ewing sarcoma. This case provides rationale for adding a Ewing sarcoma arm to SARC024, a phase II study of regorafenib, another multi-targeted kinase inhibitor, in patients with liposarcoma, osteosarcoma and Ewing and Ewing-like sarcomas (NCT02048371). This national multi-institutional study is ongoing.
[Show abstract][Hide abstract] ABSTRACT: Perineal leiomyosarcoma is an extremely rare and aggressive cancer with a high metastatic potential and no defined standard treatment. There are only a few (six) reported cases in the literature. We report the case of a 67-year-old woman with a perineal leiomyosarcoma arising at the same site of a previously resected superficial angiomyxoma. Initially, she was treated for a presumptive recurrence of angiomyxoma. As she did not respond to medical therapy, she underwent repeat surgical excision. Pathology revealed a high grade leiomyosarcoma, histologically strikingly distinct from the initial diagnosis. She received adjuvant local radiation therapy, and remains without evidence of recurrent disease 36 months after completion of all therapy. This is the first reported case of a high grade perineal leiomyosarcoma originating at the same site as a resected benign superficial angiomyxoma. Our case emphasizes the necessity of a prompt histological diagnosis in cases of presumed recurrent perineal angiomyxoma.
[Show abstract][Hide abstract] ABSTRACT: Background:
A phase I study to assess the maximum-tolerated dose (MTD), dose-limiting toxicity (DLT), pharmacokinetics (PK) and antitumor activity of vorinostat in combination with bortezomib in patients with advanced solid tumors.
Patients received vorinostat orally once daily on days 1-14 and bortezomib intravenously on days 1, 4, 8 and 11 of a 21-day cycle. Starting dose (level 1) was vorinostat (400 mg) and bortezomib (0.7 mg/m(2)). Bortezomib dosing was increased using a standard phase I dose-escalation schema. PKs were evaluated during cycle 1.
Twenty-three patients received 57 cycles of treatment on four dose levels ranging from bortezomib 0.7 mg/m(2) to 1.5 mg/m(2). The MTD was established at vorinostat 400 mg daily and bortezomib 1.3 mg/m(2). DLTs consisted of grade 3 fatigue in three patients (1 mg/m(2),1.3 mg/m(2) and 1.5 mg/m(2)) and grade 3 hyponatremia in one patient (1.5 mg/m(2)). The most common grade 1/2 toxicities included nausea (60.9%), fatigue (34.8%), diaphoresis (34.8%), anorexia (30.4%) and constipation (26.1%). Objective partial responses were observed in one patient with NSCLC and in one patient with treatment-refractory soft tissue sarcoma. Bortezomib did not affect the PKs of vorinostat; however, the Cmax and AUC of the acid metabolite were significantly increased on day 2 compared with day 1.
This combination was generally well-tolerated at doses that achieved clinical benefit. The MTD was established at vorinostat 400 mg daily × 14 days and bortezomib 1.3 mg/m(2) on days 1, 4, 8 and 11 of a 21-day cycle.
Investigational New Drugs 10/2013; 31(6). DOI:10.1007/s10637-013-0029-6 · 2.92 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Objective:
Angiosarcoma is an aggressive malignancy with endothelial differentiation and notoriously poor prognosis despite aggressive therapy. Limited data are available to guide management decisions. To address this limitation, we present a large retrospective analysis of angiosarcoma patients treated at a single institution over a 25-year period.
To identify factors that impact angiosarcoma outcomes, we reviewed demographic, tumor, and treatment characteristics of angiosarcoma patients evaluated at the University of Wisconsin Hospital between 1987 and 2012.
The cohort included 81 patients diagnosed at ages 19 to 90 years (median, 67 y). Fifty-five (68%) patients presented with localized disease, whereas 26 (32%) presented with metastases. The primary sites were visceral/deep soft tissue (42%), head and neck/cutaneous (37%), breast (16%), and limbs in the setting of Stewart-Treves (5%). The 5-year overall survival was 40% with a median of 16 months. By univariate analysis, significant adverse predictors of survival included metastases at presentation, visceral/deep soft tissue tumor location, tumor size > 5 cm, tumor necrosis, and the absence of surgical excision. A trend toward prolonged survival was observed with radiation therapy and for chemotherapy in patients with metastases. Age, sex, and prior radiation showed no correlation with survival.
Our large single institution series confirms the poor prognosis of angiosarcoma, supports a central role for surgical excision in management, and highlights the need for novel therapies particularly in patients who present with metastatic disease.
American journal of clinical oncology 02/2013; 37(5). DOI:10.1097/COC.0b013e31827e4e7b · 3.06 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: AIDS-related Kaposi's sarcoma (KS) is a low-grade vascular tumor that occurs in association with human herpesvirus 8 infection. Here we report the case of a 21-year-old male with recently diagnosed cutaneous KS who presented with rectal bleeding and anal pruritus. Initial endoscopic evaluation was nondiagnostic. CT imaging showed diffuse lymphadenopathy including perirectal involvement which was suspicious for metastatic KS. Echoendoscopy with needle biopsies and EchoBrush sampling of the lymph nodes revealed spindle cells confirming metastatic KS. Treatment was initiated with liposomal doxorubicin resulting in rapid improvement of the skin lesions. After treatment completion, repeat CT imaging showed improved lymphadenopathy. No further rectal bleeding or perianal pruritus was reported. Although the EchoBrush has previously been used to aid in the diagnosis of pancreatic lesions, this report describes a novel use of EchoBrush to diagnose KS from perirectal lymph nodes.
Case Reports in Gastroenterology 05/2011; 5(2):416-21. DOI:10.1159/000330480
[Show abstract][Hide abstract] ABSTRACT: The purpose of this study was to evaluate baseline RRM2 protein and gene expression in tumors of patients receiving 3-AP.
Tumor blocks from patients enrolled in phase I and II clinical studies using 3-AP, were evaluated for RRM2 gene and protein expression by quantitative real time polymerase chain reaction (Q-RTPCR) and automated quantitative analysis (AQUA).
Esophageal and gastric cancers overexpressed RRM2 protein when compared to prostate cancer (Z-score, 0.68 +/- 0.94 SD, vs 0.41 +/- 0.84 SD, respectively; p = 0.04). Esophageal and gastric cancers also overexpressed RRM2 mRNA when compared to prostate cancer (relative gene expression 2.56 +/- 1.49 SD, vs 0.29 +/- 0.20 SD, respectively; p = 0.02). Protein and gene expression were moderately associated (Spearman's rank correlation = 0.30; p = 0.12).
RRM2 gene and protein expression varies by tumor type.
Cancer Chemotherapy and Pharmacology 11/2008; 64(1):79-86. DOI:10.1007/s00280-008-0845-0 · 2.77 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Exisulind is an apoptotic agent with preclinical activity in non-small cell lung cancer (NSCLC). Vinorelbine is safe and effective in older patients with advanced NSCLC. We assessed these agents together as palliative treatment for older patients with advanced NSCLC.
Chemotherapy-naive patients >/=70-years-old with stage IIIB-IV NSCLC and a performance status (PS) </=2 were eligible. Primary endpoints were the maximum tolerated dose (phase I) and time-to-progression (phase II) of oral exisulind with 25 mg/m/wk of intravenous vinorelbine on a 28-day cycle. Patients with clinical benefit after 6 cycles of this combination received exisulind alone.
Fourteen phase I patients (median PS 1; median age 78 years) were enrolled. Dose-limiting toxicities included grade 3 constipation (one patient), grade 3 febrile neutropenia (one patient) and grade 3 diarrhea (one patient). The maximum tolerated dose of oral exisulind with 25 mg/m/wk of intravenous vinorelbine was 125 mg twice daily. Thirty phase II patients (median PS 1; median age 78 years) were enrolled. Grade >/=3 neutropenia occurred in 14/30 patients. Two patients experienced neutropenic fever. There were no complete responses, one partial response and 12 patients with stable disease as their best response. The objective response rate was 4.0% (95% CI: 0.1-20.4%). Phase II median time-to-progression was 4.7 months (95% CI: 3.1-9.3 months) and median OS was 9.6 months (95% CI: 6.6-19.1 months).
This combination is safe, seems to have activity in the elderly with advanced NSCLC and a PS </=2, and warrants further investigation.
Journal of thoracic oncology: official publication of the International Association for the Study of Lung Cancer 10/2008; 3(9):1018-25. DOI:10.1097/JTO.0b013e3181834fa1 · 5.28 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: To define dose limiting toxicities (DLTs) and the maximum tolerated dose (MTD) of capecitabine with fixed-dose rate (FDR) gemcitabine.
Eligible adults (advanced solid tumor; performance status <or=2) received capecitabine 500 mg/m(2) PO BID days 1-14 and FDR gemcitabine (400-1,000 mg/m(2) escalated by 200 mg/m(2) increments) at 10 mg/m(2)/min days 1 and 8 on a 21-day cycle. A traditional 3 + 3 cohort design was used to determine the MTD.
Thirty patients (median age 59 years) were enrolled. The predominant grade >or=3 toxicity was myelosuppression, particularly neutropenia. At dose level 4 (1,000 mg/m(2) gemcitabine), two out of five evaluable patients had a DLT (grade 4 neutropenia >or=7 days). At dose level 3 (800 mg/m(2) gemcitabine), one patient had a DLT (grade 3 neutropenia >or=7 days) among six evaluable patients. Therefore, the MTD and recommended phase II dose was designated as capecitabine 500 mg/m(2) PO BID days 1-14 with 800 mg/m(2) FDR gemcitabine days 1 and 8 infused at 10 mg/m(2) per min on a 21-day cycle. Partial responses occurred in pretreated patients with esophageal, renal cell and bladder carcinomas.
This regimen was well tolerated and may deserve evaluation in advanced gastrointestinal and genitourinary carcinomas.
Cancer Chemotherapy and Pharmacology 10/2008; 64(1):45-51. DOI:10.1007/s00280-008-0844-1 · 2.77 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: 3-Aminopyridine-2-carboxaldehyde thiosemicarbazone (3-AP, Triapine) is a novel small molecule inhibitor of ribonucleotide reductase (RR) with clinical signs of activity in pancreatic cancer. Therefore, the Phase 2 Consortium (P2C) initiated a trial (two single stage studies with planned interim analysis) of 3-AP at 96 mg/m(2) intravenously days 1-4 and 15-18 of a 28-day cycle in both chemotherapy-naive and gemcitabine-refractory (GR) patients with advanced pancreatic cancer. The primary endpoint was survival at six months (chemotherapy-naive) and four months (GR). Secondary endpoints were toxicity, response, overall survival, time to progression and mechanistic studies. Fifteen patients were enrolled including one chemotherapy-naïve and 14 GR. The chemotherapy-naïve patient progressed during cycle 1 with grade 3 and 4 toxicities. Of 14 GR patients, seven received two cycles, six received one cycle and one received eight cycles. Progression precluded further treatment in 11 GR patients. Additionally, one died of an ileus in cycle 1 considered related to treatment and two stopped treatment due to toxicity. Five GR patients had grade 4 toxicities possibly related to 3-AP and six GR patients had grade 3 fatigue. Toxicities and lack of meaningful clinical benefit prompted early study closure. Four-month survival in GR patients was 21% (95% CI: 8-58%). Correlative studies confirmed that 3-AP increased the percentage of S-phase buccal mucosal cells, the presence of multidrug resistance gene polymorphisms appeared to predict leukopenia, and baseline pancreatic tumor RR M2 expression was low relative to other tumors treated with 3-AP. In conclusion, this regimen appears inactive against predominantly GR pancreatic cancer. RR M2 protein may not have a critical role in the malignant potential of pancreatic cancer.
Investigational New Drugs 09/2008; 26(4):369-79. DOI:10.1007/s10637-008-9123-6 · 2.92 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Perillyl alcohol (POH) is a naturally occurring lipid with preclinical activity against mammary carcinomas. We conducted a phase II multi-institutional study of oral POH administered four times daily in women with advanced treatment-refractory breast cancer.
Eligible women were treated with POH four times daily at 1,200-1,500 mg m(-2) dose(-1) on a 28-day cycle. Patients tolerating 1,200 mg m(-2) day(-1) four times daily after one cycle were dose-escalated to 1,500 mg/m(2). The primary endpoint was 1-year freedom-from-progression (FFP) rate. Secondary endpoints were response rate, tolerability and correlative evaluations.
Twenty-nine cycles of POH were administered to 14 women. Three patients were dose-escalated to 1,500 mg/m(2). Grade 1 and grade 2 gastrointestinal effects and fatigue were predominant toxicities. Of seven patients receiving up to one cycle, three stopped therapy due to intolerance. Only two patients received more than two cycles, with disease stabilization of 3 and 8 months. Thirteen patients were evaluable for response. One-year FFP rate was zero. No objective responses were seen. The median time to progression was 35 days (95% CI, 29-123 days). Median overall survival was 389 days (95% CI, 202-776 days). Pharmacokinetic parameters were similar to previous investigations. The ability to correlate plasma TGF-beta1 levels with outcome was limited by lack of clinical benefit and inter- and intra-patient variability.
Enrollment was suspended short of planned accrual because of lack of response and poor tolerance to POH. This regimen does not appear to provide benefit in advanced treatment-refractory breast carcinoma.
Cancer Chemotherapy and Pharmacology 07/2008; 62(1):149-57. DOI:10.1007/s00280-007-0585-6 · 2.77 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Docetaxel is standard of care for androgen-independent prostate cancer (AIPC). Doxercalciferol (1 alpha-hydroxyvitamin D2) had modest activity in phase I/II trials. Preclinical data support combining vitamin D analogues with docetaxel to treat AIPC.
Chemotherapy-naive men with metastatic AIPC were randomized 1:1 to receive, on a 4-week cycle, docetaxel (35 mg/m2 i.v., days 1, 8, and 15) with or without doxercalciferol (10 microg orally, days 1-28). The primary end point was prostate-specific antigen (PSA) response. Secondary end points were progression-free survival, overall survival, objective response, and toxicity. Survival was analyzed as intent to treat.
Seventy patients were randomized. Median follow-up was 17.6 months (range, 3.3-45.2). PSA response rate was 46.7% [95% confidence interval (95% CI), 30-64] in the doxercalciferol arm and 39.4% (95% CI, 25-56) with placebo (P = 0.560). Median progression-free survival in the doxercalciferol arm was 6.17 months (95% CI, 4.20-10.7) versus 6.20 months (95% CI, 4.83-9.07) with placebo (P = 0.764). Median overall survival in the doxercalciferol arm was 17.8 months (95% CI, 14.9-23.6) versus 16.4 months (95% CI, 11.9-23.8) with placebo (P = 0.383). Twenty-four patients in the doxercalciferol arm and 23 in the placebo arm were evaluable for objective response. No complete responses were observed. Partial objective response rate was 12.5% with doxercalciferol versus 8.7% with placebo (P = 0.672). Rate of grade > or =3 toxicity was 46% with doxercalciferol versus 42% with placebo (P = 0.785).
Daily doxercalciferol with weekly docetaxel did not enhance PSA response rate or survival. Toxicity was similar between arms. Despite the disappointing results of this study, other vitamin D analogues remain under active investigation.
Clinical Cancer Research 05/2008; 14(8):2437-43. DOI:10.1158/1078-0432.CCR-07-4274 · 8.72 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Animal models suggest that growth hormone participates in hepatocarcinogenesis.
To correlate the effect of octreotide long-acting release (LAR) on insulin-like growth factor-I (IGF-I) and -II (IGF-II) with response and survival in patients with unresectable and metastatic hepatocellular carcinoma.
We conducted a phase II, single-institution trial of octreotide-LAR (30 mg intramuscularly every 4 weeks) in 15 patients while monitoring serum IGF-I and -II levels.
Patients (median CLIP score 2, Okuda stage II, and ECOG performance status 1) were treated for a median of 2.0 cycles. No responses occurred. Median overall survival was 116 days (range, 27-937 days) and median progression-free survival was 60 days (range, 27-444 days). One patient had prolonged stable disease (16 months). There were no grade 4 and four grade 3 toxicities: abdominal cramping, elevated creatinine, diarrhea, and dyspnea. Median serum IGF-I decreased from baseline (42.2 ng/mL; range, 14.2-109 ng/mL) to day 29 (27.9 ng/mL; range, 5.7-71.1 ng/mL), and median serum IGF-II decreased from baseline (25,000 ng/mL; range, 12,400-93,600 ng/mL) to day 29 (18,400 ng/mL; range, 4,061-79,400 ng/mL; 2-sided P<.006 and P<.04, respectively; Wilcoxon signed rank test). This suppression did not correlate with clinical activity. Baseline serum IGF-I >30 ng/mL was associated with greater progression-free survival and overall survival (P=.0005 and P=.0173, respectively; 2-sided log-rank test).
Octreotide-LAR lowered serum IGF-I and -II levels; however, this lowering did not correlate with clinical activity. There were no responses, and progression-free survival and overall survival were similar to historical patients not on treatment. Baseline serum IGF-I predicted prognosis.
Clinical advances in hematology & oncology: H&O 02/2008; 6(1):44-54.
[Show abstract][Hide abstract] ABSTRACT: The mechanisms underlying prostate carcinogenesis are not firmly elucidated. An exciting area of research in this regard asks whether prostate cancer results from the consequences of lifelong exposure of prostate tissue to oxidative stress. This article reviews the laboratory-based literature on oxidative stress and its possible role in prostate carcinogenesis. The progression of clinical studies focusing on the relationship between antioxidant supplementation and risk of developing prostate cancer are discussed, along with the patent literature since 2003 involving novel antioxidant technology applicable to prostate cancer prevention and treatment. In particular, recently published in vitro experiments with a novel alpha-tocopherol analogue, 2,2,5,7,8-pentamethyl-6-chromonal, which characterised its unique spectrum of antioxidant and antiandrogen properties in prostate cancer cell lines, is discussed. In addition, recent patent applications and supporting findings from the literature surrounding: i) cisplatin tocopherol compounds; ii) coix seed soft capsules with vitamin E; iii) vitamin E succinate (alpha-tocopheryl succinate); iv) lycopene preparations with other carotenoids; v) compounds of the ginger family; vi) novel aryl-carbaldehyde oxime derivatives; vii) novel phenyl quinoline derivatives; and viii) resveratrol, its derivatives and preparations thereof are discussed as they relate to prostate cancer chemoprevention and treatment.