Timothy Spiro

Aromatase Inhibitor-Related Musculoskeletal Symptoms: Is Preventing Osteoporosis the Key to Eliminating These Symptoms?

BACKGROUND Aromatase inhibitors (AIs) are an effective treatment for postmenopausal women with hormone receptor-positive breast cancer. However, patients receiving AIs report a higher incidence of musculoskeletal symptoms and bone fractures; the mechanism and risk factors for this correlation are not well studied. The aim of this study was to correlate these musculoskeletal symptoms and bone fractures in patients receiving AIs with bone mineral density (BMD), previous tamoxifen use, and administration of calcium/bisphosphonate (Ca/Bis). PATIENTS AND METHODS We reviewed charts of 856 patients with hormone receptor-positive nonmetastatic breast cancer seen at our institution between January 1999 and October 2007. A total of 316 patients met the inclusion criteria of treatment with one of the AIs for > or = 3 months and availability of a dualenergy X-ray absorptiometry (DEXA) during this treatment. Arthralgia, generalized bone pain and/or myalgia, bone fracture after beginning AIs, any tamoxifen treatment, and Ca/Bis therapy were recorded. RESULTS Our study demonstrates a significant association between symptoms and DEXA-BMD results (P < .001). Similarly, the group receiving tamoxifen before AIs had fewer patients with arthralgia or generalized bone pain/myalgia or bone fracture (P < .001). Furthermore, the group receiving AIs plus Ca/Bis had more patients without musculoskeletal symptoms and had fewer fractures. Finally, the group receiving steroidal AIs compared with nonsteroidal AIs had more patients with arthralgia or generalized bone pain and/or myalgia, and bone fractures (P < .001). CONCLUSION Patients on AIs who develop osteoporosis are at increased risk of musculoskeletal symptoms and bone fracture. Comedication with Ca/Bis reduces the likelihood for osteoporosis and musculoskeletal symptoms. Patients who received tamoxifen before AIs were less likely to develop AI-related musculoskeletal symptoms. We recommend that patients on AIs should be offered Ca/Bis to reduce the incidence of musculoskeletal symptoms and fracture, especially if patients are receiving steroidal AI and/or did not receive tamoxifen before AIs.

Phase I Clinical and Pharmacokinetic Study of Rebeccamycin Analog NSC 655649 Given Daily for Five Consecutive Days

PURPOSE Rebeccamycin analog (NSC 655649) is active against a variety of both solid and nonsolid tumor cell lines. We performed a phase I trial to determine the maximum-tolerated dose (MTD) of rebeccamycin analog when given on a daily x 5 schedule repeated every 3 weeks, characterize the toxicity profile using this schedule, observe patients for antitumor response, and determine the pharmacokinetics of the agent and pharmacodynamic interactions. PATIENTS AND METHODS Thirty assessable patients received a total of 153 cycles according to the following dose escalation schema: 60, 80, 106, 141, and 188 mg/m(2)/d x 5 days. RESULTS Grade 2 phlebitis occurred in all patients before the use of central venous access, placed at dose level 4 and higher. Dose-limiting toxicity (DLT), grade 4 neutropenia, occurred at 188 mg/m(2)/d x 5 days in both previously treated and chemotherapy-naive patients. Pharmacokinetic analysis revealed a three-compartmental model of drug elimination and a long terminal half-life (154 +/- 55 hours). The percentage drop in absolute neutrophil count correlates with the area under the curve infinity. The presence of a second peak during the elimination phase as well as a high concentration of NSC 655649 in biliary fluid compared with the corresponding plasma measurement (one patient) is suggestive of enterohepatic circulation. Two partial responses, two minor responses, and six prolonged (> 6 months) cases of stable disease were observed. Of these, three patients with gallbladder cancer and one patient with cholangiocarcinoma experienced either a minor response or a significant period of freedom from progression. CONCLUSION The recommended phase II dose for NSC 665649 on a daily x 5 every 3 weeks schedule is 141 and 165 mg/m(2)/d for patients with prior and no prior therapy, respectively, with DLT being neutropenia. During this phase I trial, encouraging antitumor activity was been observed.

The utility of 18-F-fluorodeoxyglucose positron emission tomography in evaluation of bone marrow involvement by non-Hodgkin lymphoma.

Purpose:In non-Hodgkin lymphomas (NHLs), the bone marrow (BM) involvement is a sign of extensive disease and the iliac crest BM biopsy (BMB) is the established method for the detection of BM infiltration. However, iliac crest BMB is associated with a high rate of false negative results. We assess the ability of 18-F-fluorodeoxyglucose positron emission tomography (18F-FDG PET) scan to ascertain the presence of BM involvement in NHL. Methods:After reviewing charts of histologically proven NHLs, 97 patients were eligible for our study. All patients were examined by whole-body 18F-FDG PET scan for initial staging, and all had unilateral posterior iliac crest BMB. BM involvement was established after the result of unilateral posterior iliac crest BMB and image-guided BMB after positive 18F-FDG PET scan in selected patients. Results:Our data demonstrate an overall sensitivity of 79% for the 18F-FDG PET scan detecting BM involvement in all patients and specificity of 91%. Further analysis revealed no significant difference in the ability of the 18F-FDG PET scan to detect BM involvement between the indolent-NHL and the aggressive/highly aggressive-NHL groups (sensitivity P = 0.23, specificity P = 0.64). Conclusion:18F-FDG PET scan shows potential to detect BM involvement in NHL. In particular, image-guided repeat BMB should be considered in patients with negative initial iliac crest BMB, whose 18F-FDG PET scan demonstrates BM involvement in a different site.

Immune thrombocytopenia in adults: an update.

Immune thrombocytopenia (ITP) in adults is a chronic disease resulting from increased platelet destruction and impaired platelet production. Splenectomy remains the most effective and durable treatment in cases that are refractory to first-line therapy, but its use has declined because of the availability of alternate medical therapy, the associated risk of infection, and concern for surgeryrelated complications. Rituximab (Rituxan) may be an effective alternative but carries the risk of immunosuppression. Management has changed in the last decade, with new drugs and with increased awareness of treatment side effects.

Primary Cardiac Sarcoma: 25-Year Cleveland Clinic Experience.

Background:Cardiac sarcomas are rare and have a poor prognosis. The median overall survival remains dismal and has been reported ranging from 6 months to a few years. Primary cardiac sarcoma is the most common malignant tumor comprising approximately 95% of all malignant tumors of the heart. Methods:We conducted a retrospective chart review in a single institution of patients diagnosed between March 1988 and April 2013. A total of 42 patients were identified. The following variables were studied: age at diagnosis, year of diagnosis, sex, stage, site of tumor involvement, tumor histology, grade, treatment modality, type of chemotherapy, and survival outcome. The overall median follow-up time was 49.5 months. Results:The most common histologic type was angiosarcoma. Overall estimated median survival (EMS) was 25 months. Tumors involving the left side of the heart and pericardium demonstrated better survival. Patients who received multimodality treatment (any combination of surgery, radiation therapy, and chemotherapy) had an EMS of 36.5 months compared with 14.1 months for patients treated with surgery, radiation therapy, or chemotherapy only (P=0.05). Conclusions:Cardiac sarcoma is a lethal tumor with an EMS of 25 months. The tumor histology could be a possible predictor of better survival. Although selection bias may have been present, multimodality therapy (surgery, radiation therapy, and chemotherapy) was associated with improved survival.

Pulmonary toxicities of biologics: a review.

With the advancement of research in cancer treatment more and more drugs are being introduced for the treatment of cancer. In this review study, we have tried to look at some of the relatively newly introduced drugs, commonly referred to as biologics. The aim of this study was to review the very rare but fatal pulmonary toxicities (mostly interstitial lung disease) caused by these drugs. The drugs that were reviewed are rituximab, cetuximab, bevacizumab, alemtuzumab, and trastuzumab. This review basically aims at presenting a basic introduction (mechanism of action and indications of use) of these drugs followed by a summary of the incidence, various clinical presentations, diagnosis, treatment options, and outcome of patients around the world who presented with pulmonary toxicities caused by these drugs.

A Clinical Review of Small-Cell Carcinoma of the Urinary Bladder

Small-cell carcinoma of the urinary bladder is a rare and aggressive type of bladder cancer that has a poor prognosis. The incidence has been gradually increasing because of the aging population. Owing to its rarity there are no available treatment guidelines. Several retrospective studies and 1 prospective study have provided some insight into therapy for this disease. A multimodal approach that includes chemotherapy, local radiation therapy, and definitive surgery in resectable cases appears to be an optimal management approach.

Targeted therapy for lung cancer.

Lung cancer is considered the number one killer among all cancers. Recent observations have altered the treatment paradigm for non-small-cell lung cancer (NSCLC). The discovery of activating mutations in the epidermal growth factor receptor and anaplastic lymphoma kinase positivity has made personalized treatment for NSCLC more feasible. Both erlotinib and crizotinib have been shown to be effective and safe for subgroup populations, and now personalized treatment for nonsquamous NSCLC has progressed even further. New tyrosine kinase inhibitors are being tested, resistant mutations are being studied, and new detection systems are being incorporated; all these developments will make the detection and treatment of the deadliest cancer more affordable, practical, and effective. The National Comprehensive Cancer Network has already incorporated these new developments into their guidelines for advanced nonsquamous NSCLC.

Pharmacokinetics of O6-benzylguanine (NSC637037) and its metabolite, 8-oxo-O6-benzylguanine.

O6‐Benzylguanine and its metabolite, 8‐oxo‐O6‐benzylguanine, are equally potent inhibitors of the DNA repair enzyme, O6‐alkylguanine‐DNA alkyltransferase. Pharmacokinetic values are derived from cancer patients participating in a phase I trial (10 or 20 mg/m2 of O6‐benzylguanine in a single bolus dose or 10 to 120 mg/m2 as a 60‐min constant infusion). A two‐compartment model fits the plasma concentration versus time profile of O6‐benzylguanine. O6‐Benzylguanine is eliminated rapidly from the plasma compartment in humans (t1/2α and t1/2β are 2 ± 2 min and 26 ± 15 min [mean ± SD, n = 7], respectively), and its plasma clearance (513 ± 148 mL/min/m2) is not dose dependent. Metabolite kinetics are evaluated using both a novel approach describing the relationship between O6‐benzylguanine and 8‐oxo‐O6‐benzylguanine and classical metabolite kinetics methods. With increasing doses of O6‐benzylguanine, the plasma clearance of 8‐oxo‐O6‐benzylguanine decreases, prolonging elimination of the metabolite. This effect is not altered by coadministration of BCNU. The urinary excretion of drug and metabolites is minimal.

Simultaneous determination of O6-benzylguanine and 8-oxo-O6-benzylguanine in human plasma by reversed-phase high-performance liquid chromatography

A high-performance liquid chromatographic assay for the quantification of O6-benzylguanine (O6BG) in human plasma was modified to include the metabolite, O6-benzyl-8-oxo-guanine (8-oxo-O6BG). O6-(p-Chlorobenzyl)guanine was used as the internal standard. Plasma samples were extracted with ethyl acetate and chromatographed on a C18 base-deactivated reversed-phase column. Separation was accomplished by gradient elution with mobile phases consisting of acetonitrile and phosphate buffer, pH 3.60. Eluted compounds were observed with diode array detection at 288 nm (O6BG) and 292 nm (8-oxo-O6BG). Standard curves were linear from 12.5 ng/ml to 1000 ng/ml, with an average regression coefficient of 0.999 (n=5) for both compounds. The lowest limit of quantitation was 25 ng/ml, with a signal-to-noise ratio of 8:1. The within-day relative standard deviations for O6BG quality control samples (n=18) with concentrations of 735 ng/ml, 305 ng/ml and 38 ng/ml were 2.4%, 4.2% and 5.3%, respectively. The within-day relative standard deviations for 8-oxo-O6BG quality control samples (n=18) at concentrations of 735 ng/ml, 420 ng/ml and 42 ng/ml were 2.2%, 4.0% and 7.1%, respectively. The day-to-day relative standard deviations for the same control specimens were 3.1%, 4.8% and 7.1% for O6BG, respectively, and 2.3%, 4.7% and 11.0% for 8-oxo-O6BG, respectively. This method was applied to plasma samples obtained from patients in a clinical trial of O6-benzylguanine. O6-Benzyl-8-oxo-guanine was identified in patient plasma specimens by liquid chromatography-electrospray mass spectrometry by comparison with spectral data acquired from reference material.