Kettering Cancer Center Research Articles

Advances in the diagnosis and management of lymphoma

Advances in the diagnosis and management of lymphoma Zachary H Word1, Matthew J Matasar1,21Lymphoma Service, Department of Medicine, Memorial Sloan–Kettering Cancer Center, 2Department of Medicine, New York Presbyterian Hospital, New York, NY, USAAbstract: The lymphomas are a heterogeneous group of cancers that have played a prominent role in the history of oncology, being among the first cancers to respond to radiotherapy or systemic chemotherapy. Progressive improvement in the understanding of the biology and natural history of these diseases has led to changes in both classification and management. Because of the heterogeneity present among the lymphomas, accurate diagnosis and staging are essential prerequisites to their effective management. Lymphoma stage frequently informs treatment decisions, but in contrast with solid tumor malignancies carries limited prognostic value. This has led to the development of prognostic models in lymphoma, which use patient and disease characteristics to stratify patients by risk. Modern approaches to Hodgkin's lymphoma include chemotherapy only, combined-modality therapy with both chemotherapy and radiotherapy, and risk-adapted approaches that modify treatment based on initial response. Management of non-Hodgkin's lymphoma (NHL) varies widely depending upon histology. Use of rituximab, the anti-CD20 monoclonal antibody, is included in the management of most B cell lymphomas and has improved outcomes in these diseases. The T cell lymphomas are less common and generally less well understood than the B cell diseases, and their management has only recently become disease-specific. Though effective therapy is available for many types of lymphoma, relapse remains common in a number of subtypes, and management of relapsed and refractory disease remain research priorities.Keywords: lymphoma, diagnosis, treatment

Validation of Serum Amyloid α as an Independent Biomarker for Progression-Free and Overall Survival in Metastatic Renal Cell Cancer Patients

BackgroundWe recently identified apolipoprotein A2 (ApoA2) and serum amyloid α (SAA) as independent prognosticators in metastatic renal cell carcinoma (mRCC) patients, thereby improving the accuracy of the Memorial-Sloan Kettering Cancer Center (MSKCC) model. ObjectiveValidate these results prospectively in a separate cohort of mRCC patients treated with tyrosine kinase inhibitors (TKIs). Design, setting, and participantsFor training we used 114 interferon-treated mRCC patients (inclusion 2001–2006). For validation we studied 151 TKI-treated mRCC patients (inclusion 2003–2009). MeasurementsUsing Cox proportional hazards regression analysis, SAA and ApoA2 were associated with progression-free survival (PFS) and overall survival (OS). In 72 TKI-treated patients, SAA levels were analyzed longitudinally as a potential early marker for treatment effect. Results and limitationsBaseline ApoA2 and SAA levels significantly predicted PFS and OS in the training and validation cohorts. Multivariate analysis identified SAA in both separate patient sets as a robust and independent prognosticator for PFS and OS. In contrast to our previous findings, ApoA2 interacted with SAA in the validation cohort and did not contribute to a better predictive accuracy than SAA alone and was therefore excluded from further analysis. According to the tertiles of SAA levels, patients were categorized in three risk groups, demonstrating accurate risk prognostication. SAA as a single biomarker showed equal prognostic accuracy when compared with the multifactorial MSKCC risk mode. Using receiver operating characteristic analysis, SAA levels >71 ng/ml were designated as the optimal cut-off value in the training cohort, which was confirmed for its significant sensitivity and specificity in the validation cohort. Applying SAA >71 ng/ml as an additional risk factor significantly improved the predictive accuracy of the MSKCC model in both independent cohorts. Changes in SAA levels after 6–8 wk of TKI treatment had no value in predicting treatment outcome. ConclusionsSAA but not ApoA2 was shown to be a robust and independent prognosticator for PFS and OS in mRCC patients. When incorporated in the MSKCC model, SAA showed additional prognostic value for patient management.

History of the Clinical Endocrinology Branch of the National Institute of Diabetes and Digestive and Kidney Diseases: Impact on Understanding and Treatment of Diseases of the Thyroid Gland

History of the Clinical Endocrinology Branch of the National Institute of Diabetes and Digestive and Kidney Diseases: Impact on Understanding and Treatment of Diseases of the Thyroid Gland

Editorial introductions

Editorial introductions

Relapse pattern and prognostic factors for patients with primary central nervous system lymphoma

BackgroundPrimary central nervous system lymphoma (PCNSL) rarely relapses in extracranial sites, and no specialized guidelines for follow-up evaluation have been proposed.MethodsWe analyzed 65 patients with newly diagnosed PNCSL to evaluate the pattern of relapse and prognostic factors.ResultsOf the 65 patients analyzed, 55 had only parenchymal brain disease, and 10 had both intracranial and extracranial lesions. As a first-line treatment, 29 patients received chemotherapy only (CTx), 13 received chemotherapy followed by whole brain radiotherapy (CTx-WBRT), 18 received chemotherapy followed by autologous stem cell transplantation (CTx-ASCT), 2 received palliative WBRT, and 3 received best supportive care. The overall response rate to the initial treatment was 75.8%, with specific response rates of 62.1% to CTx, 84.6% to CTx-WBRT, and 100% to CTx-ASCT. The complete response (CR) rate was higher with CTx-ASCT than in the absence of ASCT (77.8% vs. 43.2%; P=0.025). After a median follow-up of 18.8 months, the median failure-free survival (FFS) and overall survival (OS) were 13.0 and 36.1 months, respectively. No systemic relapse without a CNS lesion was noted. Multivariate analysis showed that ASCT was predictive of better FFS but not of OS. Age and the Memorial-Sloan Kettering Cancer Center prognostic score were predictive of survival.ConclusionWe observed no systemic relapse without a CNS lesion, suggesting that regular systematic evaluation of extracranial sites may not always be necessary. Age was prognostic of survival irrespective of treatment scheme. ASCT may improve CR rate and FFS.

Molecular classification of prostate cancer using curated expression signatures

High Gleason score is currently the best prognostic indicator for poor prognosis in prostate cancer. However, a significant number of patients with low Gleason scores develop aggressive disease as well. In an effort to understand molecular signatures associated with poor outcome in prostate cancer, we analyzed a microarray dataset characterizing 281 prostate cancers from a Swedish watchful-waiting cohort. Patients were classified on the basis of their mRNA microarray signature profiles indicating embryonic stem cell expression patterns (stemness), inactivation of the tumor suppressors p53 and PTEN, activation of several oncogenic pathways, and the TMPRSS2-ERG fusion. Unsupervised clustering identified a subset of tumors manifesting stem-like signatures together with p53 and PTEN inactivation, which had very poor survival outcome, a second group with intermediate survival outcome, characterized by the TMPRSS2-ERG fusion, and three groups with benign outcome. The stratification was validated on a second independent dataset of 150 tumor and metastatic samples from a clinical cohort at Memorial Sloan-Kettering Cancer Center. This classification is independent of Gleason score and therefore provides useful unique molecular profiles for prostate cancer prognosis, helping to predict poor outcome in patients with low or average Gleason scores.

In Vitro Culture Reveals Microenvironment-Dependent Growth, Heterogeneity and Hierarchical Structure of Primary Human Pediatric Pre-B Cell Acute Lymphoblastic Leukemia (pre-B ALL) Cells

Abstract 1483In Vitro culture reveals microenvironment-dependent growth, heterogeneity and hierarchical structure of primary human pediatric pre-B cell acute lymphoblastic leukemia (pre-B ALL) cells.J.-H. Shieh1, P. Steinherz2, J Shieh3 and M. A.S. Moore1. 1Moore Laboratory. Cell Biology Program and 2Leukemia and Lymphoma Studies, Department of Pediatrics, Memorial-Sloan Kettering Cancer Center, New York, NY. 3Department of Biology, Brandeis Univ., Waltham, MAPre-B cell acute lymphoblastic leukemia (pre-B ALL) is the most common leukemia in children. Although this pediatric pre-B ALLs are treatable, no in vitro nor in vivo models are available to investigate their pathophysiology other than a number of established cell lines that grow in the absence of any cytokine dependence or stromal interaction. To address this issue, we systemically evaluated the effects of various tissue culture parameters to the growth of primary pre-B ALL cells. A serum-free MS-5 cells (a murine bone marrow stromal cell line) co-culture system is capable of expanding the pre-B ALL CD34+CD19+ cells and supporting their differentiation to CD34−CD19+ B cells. This expansion requires a contact between the stromal cells and the pre-B ALL cells, and is inhibited by fetal bovine serum and IL-6 in a dose-dependent manner. c-Kit ligand and Flt3 ligand can reverse the IL-6 inhibition. Expansion of individual CD34+CD19+ cells revealed a hierarchical structure with respect to CD34 antigen expression and an heterogeneity in cell proliferation. When the pre-B ALL cells were sorted into CD34dim and CD34bright populations, the CD34dim cells were capable of a faster proliferation but gradually lost their CD34 antigen. In contrast, the CD34bright cells were more slowly proliferating and retained their CD34 antigen. We transduced the B-ALL cells with a fusion gene expressing green fluorescent protein (GFP) and luciferase (GFP-Lu-pre-B ALL). These GFP-Lu-pre-B ALL cells display the similar in vitro characteristics and in vivo xenograftment to NOD/SCID IL2R gamma null (NSG) mice as the non-transduced pre-B ALL cells. One hundred, 103, 104 or 105 GFP-LU-pre-B ALL CD34+ cells were i.v. transplanted to NSG mice. Both 104 and 105 cells resulted in the engraftment of the leukemia cells in limbs and cranium as judged by imaging after 6 weeks, and 103 cells engrafted after 13 weeks. When the 105 cells-transplanted mice were sacrificed after 14 weeks, the harvested peripheral blood, spleen (3–4×108cells/spleen) and bone marrow (5−10×106 cells/femur) displayed 2–3%, 51–55% and 75–81% of human CD34+CD19+ cells, respectively. Human CD34−CD19+ cells were 1–2%, 12–13% and 15–21%, respectively. Therefore, our stromal culture system supports leukemic stem cell/leukemia initiating cell proliferation and closely recapitulates the growth of primary human pre-B ALL cells in their niche in vivo, and reveals the heterogeneity and hierarchical structure of human pre-B ALL cells. The in vitro stromal co-culture system combined with the xenograft model of GFP-Lu-pre-B ALL cells provides powerful tools to dissect the pathophysiology of human pre-B ALL, and to screen new drugs for pre-B ALL therapy. Disclosures:No relevant conflicts of interest to declare.

MO-D-BRA-01: Leibel Memorial Symposium: Advanced IMRT Planning and Delivery and Future Directions

Steven Leibel MD was an inspiring leader in radiation oncology who died prematurely, and this symposium honors his memory and his collegial relationships with medical physicists at Memorial‐Sloan Kettering Cancer Center, Stanford University, UCSF and the American Board of Radiology. Dr. Leibel was a major innovative force in development and application of Intensity‐Modulated Radiation Therapy(IMRT), and his vision and energy were instrumental in national and international adoption of this practice‐changing technology in radiation therapy. In this memorial symposium, three distinguished medical physicists will examine the current state of IMRT and provide their vision for its future, including considerations of biologically‐adaptive IMRT,tumormodeling integrated into IMRT, and advanced technical IMRT features. Specific issues to be addressed include: 1. Advanced IMRT planning, including a review of novel optimization techniques and delivery strategies. 2. Commissioning, routine quality assurance and safety considerations for clinical use of advanced IMRT planning and delivery techniques. 3. Future directions in advanced IMRT planning and delivery, including the incorporation of biological considerations, tumormodeling and normal tissue response in optimization.

Profile of Charles L. Sawyers

Charles Sawyers is a rock star in his own right. Last year, Sawyers, chair of the Human Oncology and Pathogenesis Program at Memorial Sloan–Kettering Cancer Center and a member of the National Academy of Sciences, posed with singer Debbie Harry of the rock band Blondie to promote cancer research in a campaign sponsored by the Geoffrey Beene Cancer Research Center. The unlikely assemblage of rock star and researcher shined the spotlight on pioneering efforts in translational cancer research. Few physicians deserve that spotlight more than Sawyers, who co-discovered the targeted cancer drug, Gleevec, forging a path to cancer treatment that has now become increasingly common. Charles L. Sawyers. Born to physicians who served as a source of inspiration, Sawyers grew up in a Nashville, Tennessee household where medicine was the order of the day. A standout in school, Sawyers excelled in science and mathematics. However, he headed toward college without the conviction that his professional path was predestined. “Although I was heavily exposed to medicine through my parents, my uncles, and my grandfather—all physicians, I never felt like I was part of a lineage,” he says. So, when it came time to choose a field of study at college, Sawyers decided that the humanities could help widen his worldview. He majored in history at Princeton University, focusing on the history of science. At Princeton, Sawyers’ interest in the scientific method was sparked by the writings of legendary science historian Thomas Kuhn, whose storied opus, The Structure of Scientific Revolutions, has inspired generations of researchers pursuing science. Sawyers’ scientific temperament took shape when, in 1981, he enrolled in the Johns Hopkins School of Medicine. There, Sawyers attended lectures in molecular biology with the eagerness of a budding physician intrigued by basic science. “When I learned that the clinical presentation of some diseases could be narrowed down to single-nucleotide mutations, I was awestruck,” he says. Awe gave way to passion as Sawyers pored over volumes of basic biology literature, soon surpassing peers who had undergraduate degrees in science. Toward the end of medical school, his cousin, a physician, recommended Sawyers move across the country to complete his medical residency at the University of California in San Francisco (USCF).

Immunotherapies in Clinical Trials: Do They Demand Different Evaluation Tools?

M elanoma patients and immunotherapy researchers alike had cause to celebrate in late March when the U.S. Food and Drug Administration approved ipilimumab (Yervoy) to treat metastatic melanoma. For patients, the drug is a much-needed alternative to the commonly used dacarbazine (DTIC-Dome), the first agent shown to prolong overall survival. For immunotherapy researchers, the drug, which works by binding to a receptor on the surface of T lymphocytes and releasing the brakes on the immune system, represents one more piece of evidence that they can recruit a patient’s immune system to fight cancer. Despite ipilimumab’s success, a key question in the fi eld remains how best to measure disease re sponse in patients treated with immunotherapies. No one will argue with the statistically signifi cant increase in overall survival that occurred in the pivotal ipilimumab trial (10 months in patients treated with ipilimumab with or without an experimental vaccine vs. 6.5 months for patients treated with the experimental vaccine alone). However, many researchers are concerned that response and progressionfree survival criteria developed in the era of cytotoxic therapies are inappropriate measures for immunotherapeutic agents and may lead to premature closures of trials and, perhaps, loss of active therapies. Last fall, an international group of academic and industry researchers, the Cancer Immunotherapy Consortium (CIC), proposed modifi ed criteria for measuring response to drugs that work through the immune system. Many cancer researchers see value in amended criteria and are currently testing them prospectively, but not everyone is convinced they are necessary. “The unique kinetics we see with immunotherapies really challenge the endpoints that we usually use for cancer clinical trials,” said Jedd Wolchok, M.D., Ph.D. , a medical oncologist at Memorial Sloan – Kettering Cancer Center in New York and an associate director of the CIC. “The surrogate endpoints that we’ve become so dependent on—response rate and progressionfree survival—just don’t tell the whole story.”

Prognostic Factors for Renal Cell Carcinoma With Bone Metastasis: Who Are the Long-Term Survivors?

Renal cell carcinoma is sometimes associated with bone metastasis. Several risk factors have been reported but some are still controversial. Also, the significance of laboratory tests has not been fully examined for such cases. We collected data on 94 renal cell carcinoma cases with bone metastasis treated at 3 tertiary referral centers. Clinicopathological parameters and outcome data were analyzed to search for predictors of overall survival retrospectively. The log rank test and the Cox proportional hazard model were used for univariate and multivariate analyses, respectively. There were 64 males with a median age of 63.9 years. Histological diagnosis showed clear cell renal cell carcinoma in 63 patients, nonclear cell renal cell carcinoma in 7 and unclassified cancer in 6. Sarcomatoid differentiation was found in 17 cases. Metastasis was detected synchronously in 37 patients or metachronously at a median interval of 33.1 months. Multivariate analysis identified sarcomatoid differentiation (p = 0.001), vertebral bone involvement (p = 0.003), extraosseous metastasis (p = 0.021), alkaline phosphatase increased to 1.5 times the upper limit of normal (p = 0.0003) and C-reactive protein increased to greater than 0.3 mg/dl (p = 0.018) as significant risk factors. Cases were classified into 3 groups based on the number of risk factors, including low risk-28 with 0 or 1 risk factor, intermediate risk-26 with 2 risk factors and high risk-40 with 3 to 5 risk factors. This grouping clearly separated survival among these groups (each p <0.001). It also confirmed the usefulness of the Memorial-Sloan Kettering Cancer Center classification system. Our risk classification incorporating 5 risk factors enables accurate prediction of survival, which can be helpful to make clinical decisions in cases of renal cell carcinoma with bone metastasis.

Measuring the Importance of PSA Velocity

A lthough controversial, the prostate-specific antigen (PSA) test is still widely used to determine whether a man should undergo a biopsy for prostate cancer. In recent years, PSA velocity, or how quickly the PSA level increases, is also being used to decide when to biopsy men for prostate cancer. Even though both the American Urological Associ ation and the National Comprehensive Cancer Network (NCCN) have made PSA velocity part of their clinical guidelines, clinicians remain divided on its relevancy, and a recent study brings that debate to the fore. In this issue of the Journal, Andrew Vickers, Ph.D. , an associate attending research methodologist at Memorial Sloan – Kettering Cancer Center in New York, and colleagues use data from the large, randomized Prostate Cancer Prevention Trial (PCPT) to test PSA velocity’s diagnostic accuracy. The team concludes that using PSA velocity, as the NCCN guidelines state, would lead to many unnecessary biopsies and should therefore be removed from the guidelines. But some experts argue that this study is just one piece in a much larger body of literature that still favors PSA velocity. The one thing both sides agree on is that not only scientific data but also personal opinion influences what makes it into clinical practice guidelines, putting the onus on physicians to use their own judgment on a case-by-case basis. Challenge Current Guidelines Clinical practice guidelines have become more common since the 1990s as the medical community has put more emphasis on management algorithms. Yet exactly what constitutes adequate evidence to support including a given approach or technique is a matter of discussion. The current NCCN guidelines state that physicians should use PSA velocity as part of early prostate cancer detection methods, specifi cally men who have a PSA below 4 ng/mL but whose PSA is rising more than 0.35 ng/mL per year should undergo a biopsy, even without other indications. In support of this approach, the guidelines cite a 2006 article in the Journal by H. Ballentine Carter, M.D. , professor of urology and oncology at Johns Hopkins Medicine in Baltimore, and colleagues ( see J. Natl. Cancer Inst. 2006;98:1521 – 7). In that study, investigators showed that in a cohort of 980 men, individuals with a PSA velocity higher than 0.35 ng/mL per year, measured 10 – 15 years before prostate cancer diagnosis, had a 4.7-fold – increased relative risk of cancerspecifi c death compared with men whose PSA velocity was 0.35 ng/mL per year or lower. According to Vickers, the 2006 study does not support the NCCN guideline. “What Carter’s data say is that PSA velocity predicts advanced cancer 10 – 15 years later,” Vickers said. “That does not address the question of whether you should biopsy a man now.” To address that question, Vickers and colleagues decided to test the NCCN guidelines by applying them to data from the PCPT — a randomized, placebo-controlled trial to test fi nasteride’s (Proscar’s) ability to prevent prostate cancer. All men in the trial had done multiple PSA tests and had undergone a biopsy at the end of the study, regardless of their PSA score. Using these data, Vickers and his colleagues calculated PSA velocity and estimated its sensitivity and specifi city for prostate cancer detection. Of the 5,519 men in the placebo arm, PSA velocity usage would have led to 548 (almost 10% of the study population) additional biopsies, 433 (79%) of which would have been negative. Moreover, had the team added PSA velocity to existing clinical factors, including digital rectal exam, age, family history, prior biopsy, and PSA to predict prostate cancer, the predictive accuracy of the model would have increased only slightly (the area under the curve increased by just 0.007). From these fi ndings, Vickers concluded that the guidelines should be changed and all references to PSA velocity should be removed. “We are evaluating exactly what the guidelines say, and when we do that we end up with a very large number of unnecessary biopsies,” he said. “There are real implications of these guidelines — people getting biopsies and a lot of anxiety.”

NSCLC Drug Targets Acquire New Visibility

F or researchers studying drug targets in non – small-cell lung cancer (NSCLC), 2010 was a very good year. The National Comprehensive Cancer Network recommended, for the fi rst time, that oncologists test their NSCLC patients for EGFR mutations and treat those testing positive with erlotinib (Tarceva). In June, the American Society of Clinical Oncology annual meeting featured a phase I/II trial of a newer targeted NSCLC drug, crizotinib, which the New England Journal of Medicine later published. And in October, at the annual meeting of the European Society for Medical Oncology (ESMO), sessions focused on major trials with erlotinib and gefi tinib (Iressa), both targeted at EGFR mutations, as well as newer agents targeting MET, HER2, and other genes with mutated versions that appear to drive the development of NSCLC. The reports allowed researchers to savor progress and pronounce hope for targeted therapies in NSCLC, a cancer that has not responded markedly to traditional chemotherapies. “At this point we’ve found driver mutations in over half of lung cancer patients,” said Mark Kris, M.D ., of Memorial Sloan – Kettering Cancer Center in New York. “Even for those in whom we don’t fi nd a driver mutation, at least we know not to subject our patients to drugs that don’t work.”

Erratum: Comparative risk‐adjusted mortality outcomes after primary surgery, radiotherapy, or androgen‐deprivation therapy for localized prostate cancer

NIH Public Access Author Manuscript Cancer. Author manuscript; available in PMC 2011 November 15. NIH-PA Author Manuscript Published in final edited form as: Cancer. 2010 November 15; 116(22): 5226–5234. doi:10.1002/cncr.25456. Comparative risk-adjusted mortality outcomes following primary surgery, radiation therapy, or androgen deprivation therapy for localized prostate cancer Matthew R. Cooperberg, MD, MPH (1),† , Andrew J. Vickers, PhD (2) , Jeanette M. Broering, RN, MS, MPH (1) , Peter R. Carroll, MD, MPH (1) , and the CaPSURE Investigators (1) Department of Urology, UCSF Helen Diller Family Comprehensive Cancer Center, San Francisco, CA Department of Epidemiology and Biostatistics, Memorial-Sloan Kettering Cancer Center, New York, NY NIH-PA Author Manuscript Abstract Purpose—No adequate randomized trials comparing active treatment modalities for localized prostate cancer have been reported. We analyzed risk-adjusted cancer-specific mortality outcomes among men undergoing radical prostatectomy, external-beam radiation therapy, or primary androgen deprivation therapy. Methods—The CaPSURE registry comprises men from 40 urologic practice sites followed prospectively under uniform protocols, regardless of treatment. 7538 men with localized disease were analyzed. Prostate cancer risk was assessed using the Kattan preoperative nomogram and the Cancer of the Prostate Risk Assessment (CAPRA) score, both well-validated instruments calculated from clinical data at the time of diagnosis. A parametric survival model was constructed to compare outcomes across treatments, adjusting for risk and age. NIH-PA Author Manuscript Results—226 men died of prostate cancer during followup. Adjusting for age and risk, the hazard ratio for cancer-specific mortality relative to prostatectomy was 2.21 (1.50–3.24) for radiation, and 3.22 (2.16–4.81) for androgen deprivation. Absolute differences between prostatectomy and radiation therapy were small for men at low risk, but increased substantially for men at intermediate and high risk. These results were robust to a variety of different analytic techniques including competing risks regression analysis, adjustment by CAPRA rather than Kattan score, and examination of overall survival as the endpoint. Conclusions—Prostatectomy for localized prostate cancer was associated with a significant and substantial reduction in mortality relative to radiation or androgen deprivation monotherapy. Although not a randomized study, given the multiple adjustments and sensitivity analyses it is unlikely that unmeasured confounding would account for the large observed differences in survival. Keywords prostate neoplasms; comparative effectiveness; surgery; radiation; hormonal therapy; CaPSURE To whom correspondence should be addressed: University of California, San Francisco, Box 1695, 1600 Divisadero St, A-607, San Francisco, CA 94143-1695, tel (415) 885-3660, fax (415) 885-7443, mcooperberg@urology.ucsf.edu.

The Prognostic Significance of Capsular Incision Into Tumor During Radical Prostatectomy

BackgroundThe prognostic significance of capsular incision (CapI) into tumor during radical prostatectomy (RP) with otherwise organ-confined disease remains uncertain. ObjectiveTo evaluate the impact of CapI into tumor on oncologic outcome. Design, setting, and participantsA retrospective review of 8110 consecutive patients with prostate cancer treated at Ottawa Hospital and at Memorial Sloan–Kettering Cancer Center, both tertiary academic centers, between 1985 and 2008. InterventionAll patients underwent an open, laparoscopic or robotic RP. MeasurementsPatients were divided into four pathologic categories: group 1 (CapI group), positive surgical margins (PSMs) without extraprostatic extension (EPE); group 2, negative surgical margins (NSMs) without EPE; group 3, NSM with EPE; group 4, PSMs with EPE. Estimates of recurrence-free survival were generated with the Kaplan-Meier method. Recurrence was defined as a prostate-specific antigen (PSA) >0.2 ng/ml and rising. Cox proportional hazards regression was used to estimate the hazard ratio (HR) for recurrence controlling for pretreatment PSA, RP date, RP Gleason sum, seminal vesicle invasion, and lymph node involvement. Pathologic categories were defined in the model by including the variables EPE and surgical margins (SMs) as well as their interaction. Results and limitationsMedian follow-up was 37.3 mo. The 5-yr recurrence-free probability after RP for the CapI group was 77% (95% confidence interval [CI], 72–83). This was not only inferior to patients with NSMs and no EPE (log rank p<0.0001) but also to those with NSMs and EPE (log rank p=0.0002). In multivariate analysis the interaction between EPE and SM was not significant (p=0.26). In the adjusted model excluding the interaction term, patients with EPE had an increased risk for recurrence (HR: 1.80; 95% CI, 1.49–2.17; p<0.0001) as did those with positive margins (HR: 1.81; 95% CI, 1.51–2.15; p<0.0001). This was a retrospective study. ConclusionsCapI into tumor has a significant impact on patient outcome following RP. Patients, who otherwise would have organ-confined disease, will now have a higher probability of recurrence than those with completely resected extraprostatic disease.

High Number of Successful Mobilizations Associated with the Use of Plerixafor and Colony Stimulating Factors In Patients with Multiple Myeloma (MM) and Lymphoma Treated at Memorial Sloan-Kettering Cancer Center

AbstractAbstract 2263 Background:Autologous stem cell transplantation (ASCT) remains the only curative option for many lymphoma patients and it is an integral component of treatment for patients with multiple myeloma (MM). Stem cell mobilization has most commonly been performed using either chemotherapy and colony-stimulating factors or colony stimulating factors alone. This approach was challenged by the inability to collect enough CD 34 cell count to perform an ASCT. Plerixafor (Mozobil ®) previously known as AMD3100, a selective antagonist of CXCR4, has recently been approved for ASCT mobilization in combination with granulocyte- colony stimulating factor (G-CSF) for both multiple myeloma and lymphoma patients and is effective for patients who failed to mobilize enough CD34 cells with other modalities. Patients and Methods:This retrospective study examines all adult patients with MM and lymphoma who received plerixafor as a mobilization agent for ASCT at Memorial Sloan- Kettering Cancer Center between January 1st, 2009 and August 1st, 2010. Patient's information was obtained from the pharmacy data base and electronic medical records. Data included demographics, diagnosis, first line mobilization regimen, second and third line regimens, doses of plerixafor received, number of pheresis sessions and CD34 cells per kg collected per each session. The primary objective was to determine how many patients failed stem cell collection following mobilization at our center. Results:Fifty-six adult patients with lymphoma (N=23) and MM (N=33) were identified. Patients were excluded if they were treated for a pediatric malignancy or an alternate diagnosis. The average number of pheresis and CD34 cells/kg collected in each group are shown Table 1. Forty-three percent (10/23) patients with lymphoma received plerixafor and G-CSF as the first line option for mobilization and 57% (13/23) received plerixafor and G-CSF after failing other regimens. A total of 5 (22%) patients with lymphoma failed collection following mobilization with plerixafor, 1 as a primary mobilization failure and 4 having failed other mobilization strategies. Thirty-nine percent (13/33) of patients with MM received plerixafor and G-CSF as the first line option for mobilization and 61% (20/33)after failing other regimens, including cyclophosphamide (N=15) and G-CSF alone (N=5). Among the patients mobilized with plerixafor, 6% (2/33) failed collection, 1 who received plerixafor and G-CSF for primary mobilization and only 1 after failing other regimens.Table 1:Number of Pheresis required and CD 34 cells /kg collectedPlerixafor + GCSF as front linePlerixafor + G-CSF after failureAverage Number of PheresisAverage CD34 cells/kg collectedAverage Number of PheresisAverage CD34 cells/kg collectedMM2 (range 1–3)8.7 × 1063 (range 1–4)4.9 × 106Lymphoma3.5 (range 1–4)4.7 × 1063 (range 1–4)3.8 × 106 Conclusion:In lymphoma and MM patients plerixafor in combination with G-CSF is effective for stem cell mobilization and in this study we report higher success rates than in previously published data. The few number of failures with plerixafor plus G-CSF given as a primary mobilization regimen, supports its use in this setting and is attractive considering that it can reduce patient's exposure to chemotherapy. Disclosures:Matasar: Genzyme Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees.

Phase‐II trial of combination treatment of interferon‐α, cimetidine, cyclooxygenase‐2 inhibitor and renin‐angiotensin‐system inhibitor (I‐CCA therapy) for advanced renal cell carcinoma

We have recently reported favorable responses to a combination treatment comprising cimetidine, a cyclooxygenase-2 inhibitor and a renin-angiotensin-system inhibitor in metastatic renal cell carcinoma (RCC). In view of the potential synergistic effects of these three agents and interferon-α (I-CCA therapy), we conducted a phase-II trial to examine the efficacy and toxicity of I-CCA as first-line treatment. Fifty-one patients with advanced RCC received natural interferon-α (3-6 million U thrice/week) and cimetidine (800 mg), cyclooxygenase-2 inhibitor meloxicam (10 mg), and renin-angiotensin-system inhibitor candesartan (4 mg) or perindopril (4 mg) orally daily. Memorial Sloan-Kettering Cancer Center prognostic categories were favorable, intermediate and poor in 10 (20%), 31 (61%) and 10 (20%) patients, respectively. The primary end-point was the objective response rate (ORR) and the secondary end-points included clinical benefit, progression-free survival (PFS), overall survival (OS) and safety. Median follow-up was 19 months. Complete response (CR) was observed in four patients (8%) and partial response in seven (14%), yielding an ORR of 22%. None of the four patients who achieved CR relapsed during the 16- to 81-month follow up. The ORR were 17% in the favorable- or intermediate-risk group and 40% in the poor-risk group. The other 24 patients (45%) had stable disease for at least 6 months, resulting in a clinical benefit rate of 67%. The median PFS and OS were 12 and 30 months, respectively. Grade 3/4 toxicities were never observed. The I-CCA therapy, providing favorable responses and low toxicity profiles, is worthy of further consideration as a first-line therapy for metastatic RCC.

Reply to Dr. Wiwanitkit’s letter to the editor

We are grateful to Dr. Wiwanitkit for his positive review of our recent publication. Dr. Wiwanitkit noted that there are many other systems that can be used to classify cholangiocarcinoma and that additional comparative assessments using these systems will provide useful data that can help us identify the best classification system. We believe that a useful classification contains three categories, including local tumor extension, lymph node metastasis, and distant metastasis in patients with extrahepatic cholangiocarcinoma as well as other gastrointestinal malignancies. The Bismuth–Corlette and modified Memorial Sloan–Kettering Cancer Center classifications [1, 2] both consider local tumor extension, but these two classifications are not commonly used to estimate patient prognosis or evaluate treatment results. The TNM staging of the International Union Against Cancer (UICC) and the classification system of the Japanese Society of Biliary Surgery (JSBS) include these three categories. The JSBS classification was revised five times, and the sixth edition has been revised by reacting to and drawing from the UICC-TNM classification. In order to generate the best classification system, we believe that it is eminently important to compare these two classifications and identify important aspects in these systems. In the near future, these two classifications may become similar and be integrated to generate an improved classification system that will greatly help surgeons assess patients with extrahepatic cholangiocarcinoma.

Evidence-Based Surgical Practice in Academic Medical Centers: Consistently Anecdotal?

IntroductionRandomized trials, meta-analyses, and guidelines form the basis of clinical decision making. We queried a small sample of surgeons at three academic medical centers to determine whether key elements of surgical practice were concordant with available evidence. Materials and MethodsA French Society of Digestive Surgery (FSDS) questionnaire was submitted to general surgery trainees and faculty at the University of South Florida and University of Chicago and to surgical oncology fellows at the Memorial Sloan–Kettering Cancer Center. Participants were asked to respond “never,” “rarely,” “often,” or “always” to 13 questions involving different aspects of gastrointestinal surgery. For each question, a correct evidence-based answer was available from published studies. Results and DiscussionOne hundred ten surgeons (79% of eligible participants) completed the survey. Only 60% of the answers were concordant with existing data. The percentages of correct answers did not differ significantly according to institution or level of experience of participants. The low frequency of correct responses in our subjects paralleled the findings from the 2004 FSDS study. Variability in the quality of evidence and ambiguity in the survey questions may have influenced the responses, but evidence-based medicine does not appear to uniformly influence clinical decision making.

Predicting the Risk of Perioperative Transfusion for Patients Undergoing Elective Hepatectomy

To develop 2 instruments that predict the probability of perioperative red blood cell transfusion in patients undergoing elective liver resection for primary and secondary tumors. Hepatic resection is the most effective treatment for several benign and malign conditions, but may be accompanied by substantial blood loss and the need for perioperative transfusions. While blood conservation strategies such as autologous blood donation, acute normovolemic hemodilution, or cell saver systems are available, they are economically efficient only if directed toward patients with a high risk of transfusion. Using preoperative data from 1204 consecutive patients who underwent liver resection between 1995 and 2000 at Memorial Sloan- Kettering Cancer Center, we modeled the probability of perioperative red blood cell transfusion. We used the resulting model, validated on an independent dataset (n = 555 patients), to develop 2 prediction instruments, a nomogram and a transfusion score, which can be easily implemented into clinical practice. The planned number of liver segments resected, concomitant extrahepatic organ resection, a diagnosis of primary liver malignancy, as well as preoperative hemoglobin and platelets levels predicted the probability of perioperative red blood cell transfusion. The predictions of the model appeared accurate and with good discriminatory abilities, generating an area under the receiver operating characteristic curve of 0.71. Preoperative factors can be combined into risk profiles to predict the likelihood of transfusion during or after elective liver resection. These predictions, easy to calculate in the frame of a nomogram or of a transfusion score, can be used to identify patients who are at high risk for red cell transfusions and therefore most likely to benefit from blood conservation techniques.