Allan W. Silberman

Genomic landscape of liposarcoma

Liposarcoma (LPS) is the most common type of soft tissue sarcoma accounting for 20% of all adult sarcomas. Due to absence of clinically effective treatment options in inoperable situations and resistance to chemotherapeutics, a critical need exists to identify novel therapeutic targets. We analyzed LPS genomic landscape using SNP arrays, whole exome sequencing and targeted exome sequencing to uncover the genomic information for development of specific anti-cancer targets. SNP array analysis indicated known amplified genes (MDM2, CDK4, HMGA2) and important novel genes (UAP1, MIR557, LAMA4, CPM, IGF2, ERBB3, IGF1R). Carboxypeptidase M (CPM), recurrently amplified gene in well-differentiated/de-differentiated LPS was noted as a putative oncogene involved in the EGFR pathway. Notable deletions were found at chromosome 1p (RUNX3, ARID1A), chromosome 11q (ATM, CHEK1) and chromosome 13q14.2 (MIR15A, MIR16-1). Significantly and recurrently mutated genes (false discovery rate < 0.05) included PLEC (27%), MXRA5 (21%), FAT3 (24%), NF1 (20%), MDC1 (10%), TP53 (7%) and CHEK2 (6%). Further, in vitro and in vivo functional studies provided evidence for the tumor suppressor role for Neurofibromin 1 (NF1) gene in different subtypes of LPS. Pathway analysis of recurrent mutations demonstrated signaling through MAPK, JAK-STAT, Wnt, ErbB, axon guidance, apoptosis, DNA damage repair and cell cycle pathways were involved in liposarcomagenesis. Interestingly, we also found mutational and copy number heterogeneity within a primary LPS tumor signifying the importance of multi-region sequencing for cancer-genome guided therapy. In summary, these findings provide insight into the genomic complexity of LPS and highlight potential druggable pathways for targeted therapeutic approach.

Tumor aneuploidy in young patients with colorectal cancer

Background. Colorectal cancer in young patients (40 years of age of younger) often is considered to have a worse prognosis than in older patients. The authors studied tumor DNA status and stage of disease to determine whether tumors in younger patients behaved differently from tumors in older patients.

Adjuvant radiation trials for high-risk breast cancer patients: adequacy of lymphadenectomy.

Background: The recently published, widely publicized adjuvant radiation trials from Denmark and Canada concluded that the addition of postoperative radiotherapy (XRT) to modified radical mastectomy (MRM) and adjuvant chemotherapy reduces locoregional recurrences and prolongs survival in high-risk premenopausal patients with breast cancer. Our thesis is that adequate lymphadenectomies were not performed in either study. Consequently, the conclusion to these studies is not applicable to those patients who have undergone adequate surgery.Methods: To better assess adequate lymph node yield from an MRM, a retrospective review was performed on 215 consecutive patients treated surgically for invasive breast cancer. Data from this review were compared with the surgical data from the above-mentioned radiotherapy trials.Results: In a group of 131 patients who had MRM, the average number of nodes removed was 26 (median, 25), and 75.5% of the specimens had 20 or more lymph nodes. In 73 patients who underwent segmental mastectomy with axillary lymph node dissection, both the average and the median number of lymph nodes removed were 24, and 68.9% had 20 or more nodes. These data compare to the Danish radiation trial in which a median of 7 lymph nodes were removed (with 76% of the patients having 9 or fewer lymph nodes in the specimen) and to the Canadian radiation trial in which a median of 11 lymph nodes were removed. In addition, in our breast cancer patients with positive nodes (84 of 204; 41.2%), 45.2.% (38 of 84) had more than three positive nodes compared with 29.8% in the Danish study and 35% in the Canadian study.Conclusions: Our surgical data are sufficiently different from those of the Danish and Canadian studies to indicate that, in those studies, incomplete lymph node dissections were performed and that residual disease was left behind in the axilla in some or all of the patients. The addition of XRT in the setting of residual axillary disease may compensate for an inadequate operation and yield an acceptable oncological result; however, these studies did not provide an adequate comparison with a well-performed MRM without XRT. In the absence of documented benefit, XRT should not be routinely added if a complete lymph node dissection has been performed.

Thromboprophylaxis and Major Oncologic Surgery Performed With Epidural Analgesia

OBJECTIVE To evaluate clinical outcomes in patients with cancer undergoing major abdominal surgery who received preoperative indwelling epidural catheters (ECs) and no postoperative thromboprophylaxis. DESIGN Retrospective analysis of a prospective database. SETTING Tertiary referral medical center. PATIENTS Between January 1, 2009, and July 31, 2011, 119 patients, with a mean age of 64.5 years (range, 34-95 years), underwent major abdominal oncologic surgery with an indwelling EC. MAIN OUTCOME MEASURES Records of all patients were reviewed for age, duration of surgery, hospital length of stay, and clinical outcomes. All patients underwent lower extremity venous duplex ultrasonography prior to hospital discharge. RESULTS The average operative time was 338 minutes. Mean (SD) intensive care unit stay was 2.8 (1.4) days (range, 1-7 days). Patients ambulated by postoperative day 1 or 2. Most ECs were removed on postoperative day 4. There were no major complications from the EC. Fifty-two patients (44%) were treated with deep venous thrombosis prophylaxis on postoperative day 4 after removal of the EC. Lower extremity duplex studies showed 8 patients (6.7%) had an acute thrombus. One patient (0.8%) developed an asymptomatic proximal deep venous thrombosis and 7 patients (5.9%) developed distal superficial thrombi. No patient developed a pulmonary embolus. CONCLUSIONS Thromboembolic complications following major abdominal surgery for cancer may be reduced with the use of ECs. Epidural catheters may directly prevent deep venous thrombosis through sympathetic blockade, resulting in increased blood flow to the lower extremities. This effect may also be attributable to earlier ambulation. These results suggest that patients who have an EC and do not receive concurrent postoperative thromboprophylaxis do not have an increased risk for thromboembolic events.

Surgical Resection of Retroperitoneal Sarcomas: Analysis of Factors Determining Outcome.

INTRODUCTION Retroperitoneal sarcomas (RS) are rare malignant tumors characterized by high local recurrence rates and poor survival, Aggressive surgical resection may improve local recurrence rates and disease-specific survival (DSS), The aim of our study was to determine predictors of survival and local recurrence in primary RS. METHODS We performed a retrospective analysis and identified 68 patients who underwent surgical resection of a primary RS between 1985 and 2010, Clinical and pathologic variables were used to create univariate and multivariate models for both survival and recurrence. RESULTS 68 patients (37% male) with mean age 59 (range 25-84) underwent surgical resection for RS. Median tumor size was 12.0 cm (range 7.0-18.0 cm). 75% of tumors were intermediate/high grade, Incontinuity organ resection was performed in 29 (43%) patients. Seven patients (10%) underwent vascular resection with graft placement. Overall survival at 5, 10 and 15 years was 55%, 42%, and 33%, respectively. Grade (p<0.007), tumor size (p=0.048) and margin status (p<0.05) were found to significantly affect local recurrence. In a multivariate analysis, recurrent disease (p<0.001), age (p<0.003) and high/intermediate grade (p<0.001) significantly affected DSS. Incontinuity organ resection did not significantly affect recurrence (HR = 1.1, CI 0.63 - 1.85) or survival (HR = 1.4, CI 0.8 - 2.9). CONCLUSION Surgical resection of RS affords the best chance of survival. Incontinuity organ resection did not affect outcome on multivariate analysis; however, margin status did significantly affect recurrence and could not be achieved without aggressive resection of incontinuity organs.