Matias E. Valsecchi

Sentinel Lymph Node Biopsy for Melanoma: American Society of Clinical Oncology and Society of Surgical Oncology Joint Clinical Practice Guideline

PURPOSE The American Society of Clinical Oncology (ASCO) and Society of Surgical Oncology (SSO) sought to provide an evidence-based guideline on the use of lymphatic mapping and sentinel lymph node (SLN) biopsy in staging patients with newly diagnosed melanoma. METHODS A comprehensive systematic review of the literature published from January 1990 through August 2011 was completed using MEDLINE and EMBASE. Abstracts from ASCO and SSO annual meetings were included in the evidence review. An Expert Panel was convened to review the evidence and develop guideline recommendations. RESULTS Seventy-three studies met full eligibility criteria. The evidence review demonstrated that SLN biopsy is an acceptable method for lymph node staging of most patients with newly diagnosed melanoma. RECOMMENDATIONS SLN biopsy is recommended for patients with intermediate-thickness melanomas (Breslow thickness, 1 to 4 mm) of any anatomic site; use of SLN biopsy in this population provides accurate staging. Although there are few studies focusing on patients with thick melanomas (T4; Breslow thickness, > 4 mm), SLN biopsy may be recommended for staging purposes and to facilitate regional disease control. There is insufficient evidence to support routine SLN biopsy for patients with thin melanomas (T1; Breslow thickness, < 1 mm), although it may be considered in selected patients with high-risk features when staging benefits outweigh risks of the procedure. Completion lymph node dissection (CLND) is recommended for all patients with a positive SLN biopsy and achieves good regional disease control. Whether CLND after a positive SLN biopsy improves survival is the subject of the ongoing Multicenter Selective Lymphadenectomy Trial II.

Lymphatic Mapping and Sentinel Lymph Node Biopsy in Patients With Melanoma: A Meta-Analysis

PURPOSE To perform a meta-analysis of all published studies of sentinel lymph node (SLN) biopsy for staging patients with melanoma. METHODS Published literature in all languages between 1990 and 2009 was critically appraised. Primary outcomes evaluated included the proportion successfully mapped (PSM) and test performance including false-negative rate (FNR), post-test probability negative (PTPN), and positive predictive value in the same nodal basin recurrence. RESULTS A total of 71 studies including 25,240 patients met full eligibility criteria. The average PSM was 98.1% (95% CI, 97.3% to 98.6%) and increased with the year of publication, female sex, ulceration, age, and the quality score of the studies. The FNR ranged from 0.0% to 34.0%, averaging 12.5% overall (95% CI, 11% to 14.2%). FNR increased with the length of follow-up (P = .002) but decreased with greater PSM (P = .001). PTPN averaged 3.4% (95% CI, 3.0% to 3.8%), which also increased in studies with longer follow-up, younger age, female sex, deeper Breslow thickness, and with tumor ulceration while decreasing with greater PSM (P < .001). Approximately 20% of the patients with a positive SLN had additional lymph nodes in the complete lymph node dissection and 7.5% of the patients with positive SLN developed recurrence in the same nodal basin which was greater in studies that also reported higher FNR (P = .01). CONCLUSION The estimated risk of nodal recurrence after a negative SLN biopsy was ≤ 5% supporting the use of this technology for staging patients with melanoma.

Reduced risk of breast cancer recurrence in patients using ACE inhibitors, ARBs, and/or statins.

Background: Epidemiologic and biochemical evidence suggest a role of statins and angiotensin-converting enzyme (ACE) inhibitors or angiotensin-receptor blockers (ARBs) as anti-neoplastic agents. This study was designed to evaluate the association between the use of these agents and the risk of breast cancer recurrence. Methods: We reviewed the medical records of patients treated for stage II/III breast cancer between 1999 and 2005. Statin and ACE-inhibitors/ARB users were defined as patients who took these medications for at least 6 months in no evidence of disease (NED) stage after the initial diagnosis. The primary outcome was disease-free survival and the secondary was overall survival. The Kaplan–Meier and Cox proportional hazard models were used. Results: A total of 703 patients were included. The median and maximal of follow up was 55 and 118 months, respectively. A total of 168 patients used ACE-inhibitors/ARBs, 156 patients used statins, and 81 used both. Univariate analysis showed significant reduction in breast cancer recurrence among patients who used ACE-inhibitors/ARBs (hazard ratio (HR) = 0.57; 95% CI: 0.37–0.89; p = .013) or statins (HR = 0.43; 95% CI: 0.26–0.70; p < .001). After adjusting for multiple variables, the use of ACE-inhibitors/ARBs (HR = 0.49; 95% CI: 0.31–0.76; p = .002) and statins (HR = 0.40; 95% CI: 0.24–0.67; p < .001) remained significant and an additive effect was found on those who used both drugs (HR = 0.30 95% CI: 0.15–0.61; p = .001). No association was found regarding overall survival. Conclusions: The use of ACE-inhibitors/ARBs, statins, and the combination of both were all associated with a reduced risk of breast cancer recurrence. This observation should prompt further exploration.

Sentinel Node Biopsy for Head and Neck Melanoma A Systematic Review

Objective. This systematic review was conducted to examine the test performance of sentinel node biopsy in head and neck melanoma, including the identification rate and false-negative rate. Data Sources. PubMed, EMBASE, ASCO, and SSO database searches were conducted to identify studies fulfilling the following inclusion criteria: sentinel node biopsy was performed, lesions were located on the head and neck, and recurrence data for both metastatic and nonmetastatic patients were reported. Review Methods. Dual-blind data extraction was conducted. Primary outcomes included identification rate and test performance based on completion neck dissection or nodal recurrence. Results. A total of 3442 patients from 32 studies published between 1990 and 2009 were reviewed. Seventy-eight percent of studies were retrospective and 22% were prospective. Trials varied from 9 to 755 patients (median 55). Mean Breslow depth was 2.53 mm. Median sentinel node biopsy identification rate was 95.2%. More than 1 basin was reported in 33.1% of patients. A median of 2.56 sentinel nodes per patient were excised. Sentinel node biopsy was positive in 15% of patients. Subsequent completion neck dissection was performed in almost all of these patients and revealed additional positive nodes in 13.67%. Median follow-up was 31 months. Across all studies, predictive value positive for nodal recurrence was 13.1% and posttest probability negative was 5%. Median false-negative rate for nodal recurrence was 20.4%. Conclusion. Sentinel node biopsy of head and neck melanoma is associated with an increased false-negative rate compared with studies of non–head and neck lesions. Positive sentinel node status is highly predictive of recurrence.

Dose-related Effect of Statins in Venous Thrombosis Risk Reduction

BACKGROUND Atherosclerosis and venous thromboembolism share similar pathophysiology based on common inflammatory mediators. The dose-related effect of statin therapy in venous thromboembolism remains controversial. This study investigated whether the use of antiplatelet therapy and statins decrease the occurrence of venous thromboembolism in patients with atherosclerosis. METHODS We conducted a retrospective cohort study reviewing 1795 consecutive patients with atherosclerosis admitted to a teaching hospital between 2005 and 2010. Patients who had been treated with anticoagulation therapy were excluded. Patients who either used statins for <2 months or never used them were allocated to the nonuser group. RESULTS The final analysis included 1100 patients. The overall incidence of venous thromboembolism was 9.7%. Among statin users, 6.3% (54/861) developed venous thromboembolism, compared with 22.2% (53/239) in the nonuser group (hazard ratio [HR] 0.24; P <.001). After controlling for confounding factors, statin use was still associated with a lower risk of developing venous thromboembolism (HR 0.29; P <.001). High-dose statin use (average 50.9 mg/day) (HR 0.25; P <.001) lowered the risk of venous thromboembolism compared with standard-dose statins (average 22.2 mg/day) (HR 0.38; P <.001). Dual antiplatelet therapy with aspirin and clopidogrel decreased occurrence of venous thromboembolism (HR 0.19; P <.001). Interestingly, combined statins and antiplatelet therapy further reduced the occurrence of venous thromboembolism (HR 0.16; P <.001). CONCLUSIONS The use of statins and antiplatelet therapy is associated with a significant reduction in the occurrence of venous thromboembolism with a dose-related response of statins.

RB-pathway Disruption is Associated with Improved Response to Neoadjuvant Chemotherapy in Breast Cancer

Purpose: We sought to determine whether dysregulation of the retinoblastoma (RB) tumor suppressor pathway was associated with improved response to neoadjuvant chemotherapy in breast cancer. Experimental Design: An RB-loss signature was used to analyze the association between pathway status and pathologic complete response in gene expression datasets encompassing three different neoadjuvant regimens. Parallel immunohistochemical analysis of the RB pathway was conducted on pretreatment biopsies to determine the association with pathologic response to neoadjuvant chemotherapy. Results: An RB-loss gene expression signature was associated with increased pathologic complete response in datasets from breast cancer patients treated with 5-fluorouracil/adriamycin/cytoxan (FAC; P < 0.001), T/FAC (P < 0.001), and Taxane/Adriaymcin (P < 0.001) neoadjuvant therapy encompassing approximately 1,000 patients. The association with improved response to neoadjuvant chemotherapy was true in both estrogen receptor (ER)–positive and ER-negative breast cancer. Elevated expression of p16ink4a is associated with the RB-loss signature (R = 0.493–0.5982), and correspondingly p16ink4a mRNA levels were strongly associated with pathologic complete response in the same datasets analyzed. In an independent cohort, immunohistochemical analyses of RB and p16ink4a revealed an association of RB loss (P = 0.0018) or elevated p16ink4a (P = 0.0253) with pathologic complete response. In addition, by Miller–Payne and clinicopathologic scoring analyses, RB-deficient tumors experienced an overall improved response to neoadjuvant chemotherapy. Conclusion: Disruption of the RB pathway as measured by several independent methods was associated with improved response to neoadjuvant chemotherapy. The RB-pathway status was relevant for pathologic response in both ER-positive and ER-negative breast cancer with similar results observed with multiple chemotherapy regimens. Combined, these data indicate that RB status is associated with the response to neoadjuvant chemotherapy in breast cancer and could be used to inform treatment. Clin Cancer Res; 18(18); 5110–22. ©2012 AACR.

Reverse Warburg Effect in a Patient With Aggressive B-Cell Lymphoma: Is Lactic Acidosis a Paraneoplastic Syndrome?

Chicago, IL; June 2011. 92. Mancias JD, Kimmelman AC. Targeting autophagy addiction in cancer. Oncotarget. 2011;

Is there a role for the quantification of RRM1 and ERCC1 expression in pancreatic ductal adenocarcinoma

BackgroundRRM1 and ERCC1 overexpression has been extensively investigated as potential predictive markers of tumor sensitivity to conventional chemotherapy agents, most thoroughly in lung cancer. However, data in pancreatic cancer are scarce.MethodsWe investigated the mRNA and protein expression of ERCC1 and RRM1 by RT-PCR and immunohistochemistry (IHC) in formalin-fixed, paraffin-embedded pancreatic ductal carcinoma (PDA) tissues. The primary outcome investigated was the association between RRM1 and ERCC1 expression and overall survival (OS) or disease-free survival (DFS).ResultsA total of 94 patients with resected PDA were included in this study. Most of them (87%) received gemcitabine based chemotherapy. Data for OS analysis was available in all cases but only 68% had enough information to estimate DFS. IHC analysis revealed information for 99% (93/94) and 100% of the cases for RRM1 and ERCC1 expression respectively. However, PCR data interpretation was possible in only 49 (52%) and 79 (84%) cases respectively. There was no significant association between high or low expression of either RRM1 or ERCC1, detected by IHC and OS (14.4 vs. 19.9 months; P = 0.5 and 17.1 vs. 19.9; P = 0.83 respectively) or PCR and OS (48.0 vs. 24.1 months; P = 0.21 and 22.0 vs. 16.0 months; P = 0.39 respectively). Similar results were obtained for DFS.ConclusionsRRM1 and ERCC1 expression does not seem to have a clear predictive or prognostic value in pancreatic cancer. Our data raise some questions regarding the real clinical and practical significance of analyzing these molecules as predictors of outcomes.

Recent treatment advances and novel therapies in pancreas cancer: a review.

PurposeOver the last couple of years, we have witnessed the availability of a wide variety of different therapeutic agents and the identification of effective combinations of existing ones that have transformed the way we approach and treat pancreatic cancer. Proof of this are the recent validations that combinations of conventional chemotherapy drugs, the FOLFIRINOX regimen and gemcitabine plus nab-paclitaxel, significantly improves clinical outcomes in patients with metastatic disease. However, deeper and more sophisticated understanding of the biology of this cancer as well as the ability to develop better and perhaps more precise drugs predict that the landscape may be changing even more.Methodology and ResultsIn this review, we will summarize the most recent treatment advances including FOLFIRINOX, gemcitabine plus nab-paclitaxel and discuss novel approaches such as immune-mediated therapies, drugs that disrupt the tumor-stromal compartment, PARP inhibitors for BRCA pathway-deficient pancreatic cancer and new generations of conventional chemotherapeutics, which are in early phases of clinical development and have shown promising early results. We will also discuss some examples of drugs that failed, despite very good preliminary data, in order to appraise the lessons learned from these negative clinical trials. Lastly, we will comment on ongoing adjuvant and neoadjuvant trials.ConclusionWe hope that at least some of these will result in positive trials and add to our armamentarium for treating this challenging malignancy.

Somatostatin receptor scintigraphy in patients with metastatic uveal melanoma.

As uveal melanoma originates in the neural crest, we aimed to explore whether somatostatin receptor (SSTR) expression is present and plays any role in these patients. Heavily pretreated metastatic uveal melanoma patients were tested with somatostatin receptor scintigraphy (SRS). Planar images of the whole body complemented by single-photon emission computed tomography on suspected sites were acquired between 4 and 24 h after an intravenous administration of 185–222 MBq (5–6 mCi) of 111indium-octeotride. SSTR expression in metastatic tissues was confirmed by immunohistochemistry. In seven patients, sandostatin LAR was used with therapeutic intention. Thirty white patients were tested. All had extensive metastatic disease and the median number of previous treatments was three. SRS was found to be positive in 14 (46%) of the patients, but was not related to sex, type of previous treatments, tumor site, or histological type. In 10 patients, sufficient tumor specimens were available to perform immunohistochemical staining for SSTR. All cases with positive SSTR-2A staining were also positive by SRS. Two of the seven patients who received sandostatin LAR died within a month after receiving the first dose, whereas another two (28.5%) had stable disease for more than 5 months. The median time to progression after starting sandostatin was 2.1 months (range: 0.2–5.5 months). Approximately 50% of the uveal melanoma patients with extensive metastatic disease were positive for SSR, which was consistent with immunohistochemical staining for SSTR-2A. Therapeutic approaches targeting SSTR might be beneficial in patients with metastatic uveal melanoma.