Laura A. Lambert

Irreversible Conduction Block in Isolated Nerve by High Concentrations of Local Anesthetics

Background:Delivery of large doses of local anesthetics for spinal anesthesia by repeated injections or continuous infusion could expose the cauda equina to concentrations of drug that may be neurotoxic per se. We studied this possible neurotoxic effect by assessing recovery from conduction blockade of de-sheathed peripheral nerves after exposure to some of the local anesthetic solutions commonly used for spinal anesthesia. Methods:The reversibility of conduction blockade was studied in desheathed bullfrog sciatic nerves, using the sucrose-gap method for recording compound action potentials, before and during exposure to local anesthetics and during drug washout. The nerves were exposed for 15 min to 5% or 1.5% lidocaine, with or without 7.5% dextrose; 0.5% tetracaine; or 0.75% bupivacaine (the latter two without dextrose). Some nerves were also bathed in 7.5% dextrose (without local anesthetic) or in 0.06% tetracaine, which in this preparation is equipotent to 5% lidocaine. After 15 min in the drug, the nerves were washed for 2–3 h and soaked in Ringers solution overnight. Nerves exposed only to Ringers solution served as controls. We also studied neuronal uptake and washout of radio-labeled lidocaine. Results:Exposure of nerves to 5% lidocaine, with or without 7.5% dextrose, or to 0.5% tetracaine resulted in irreversible total conduction blockade, whereas 1.5% lidocaine or 0.75% bupivacaine caused 25–50% residual block after the 2–3-h wash. Nerves exposed to Ringers solution, 7.5% dextrose or 0.06% tetracaine had 0–10% residual block after 2–3 h wash. The action potential of all nerves declined after overnight soak to between 30–60% of the control value, except for those nerves exposed to 5% lidocaine or 0.5% tetracaine, which showed no activity. Exposure to 5% lidocaine for periods of only 4–5 min produced total, irreversible loss of conduction. The uptake by and washout of radiolabeled lidocaine from the nerves indicate that the maximum amount of residual drug after 2–4 min of exposure to 5% lidocaine and a 3-h wash should cause at most only 50% conduction block. Conclusions:Solutions of 5% lidocaine and 0.5% tetracaine that have been associated with clinical cases of cauda equina syndrome after continuous spinal anesthesia caused irreversible conduction block in desheathed amphibian nerve. Whether these in vitro actions also occur in mammalian nerves in vivo is an important, clinically relevant question now under investigation in our laboratory.

Validation of a breast cancer nomogram for predicting nonsentinel lymph node metastases after a positive sentinel node biopsy

BackgroundAlthough completion lymph node dissection (CLND) is the standard of care for breast cancer patients with sentinel lymph node (SLN) metastases, the SLN is the only node with tumor in 40% to 60% of cases. To assist with decision-making regarding CLND, investigators at Memorial Sloan-Kettering Cancer Center devised and validated a nomogram for predicting the likelihood of non-SLN metastases. To assess the generalizable use of this nomogram, validation analysis was performed by using an external database.MethodsEight clinicopathologic variables for 200 consecutive breast cancer patients at the University of Texas M. D. Anderson Cancer Center with SLN metastases and CLND were entered into the nomogram. The accuracy of the nomogram to predict non-SLN metastases was assessed by the receiver operating characteristic (ROC) curve and linear regression analysis. The accuracy of the nomogram with touch-imprint cytology (TIC) as a substitute variable for frozen section was also evaluated.ResultsThe linear correlation coefficient of the nomogram-predicted probabilities correlated with the observed incidence of non-SLN metastases for all patients (.97). The accuracy of the nomogram as measured by the area under the ROC curve was .71. When applied solely to patients who had TIC assessment of the SLN, the area under the ROC curve was .74.ConclusionsThis study validated the Memorial Sloan-Kettering Cancer Center breast cancer nomogram by using an external database. TIC seems to be an acceptable substitute for frozen section as a nomogram variable. The nomogram may help predict an individual’s risk of non-SLN metastases and assist in patient decision making regarding the benefit of CLND.

Autophagy: A Novel Mechanism of Synergistic Cytotoxicity between Doxorubicin and Roscovitine in a Sarcoma Model

Doxorubicin is a genotoxic chemotherapy agent used in treatment of a wide variety of cancers. Significant clinical side effects, including cardiac toxicity and myelosuppression, severely limit the therapeutic index of this commonly used agent and methods which improve doxorubicin efficacy could benefit many patients. Because doxorubicin cytotoxicity is cell cycle specific, the cell cycle is a rational target to enhance its efficacy. We examined the direct, cyclin-dependent kinase inhibitor roscovitine as a means of enhancing doxorubicin cytotoxicity. This study showed synergistic cytotoxicity between doxorubicin and roscovitine in three sarcoma cell lines: SW-982 (synovial sarcoma), U2OS-LC3-GFP (osteosarcoma), and SK-LMS-1 (uterine leiomyosarcoma), but not the fibroblast cell line WI38. The combined treatment of doxorubicin and roscovitine was associated with a prolonged G(2)-M cell cycle arrest in the three sarcoma cell lines. Using three different methods for detecting apoptosis, our results revealed that apoptotic cell death did not account for the synergistic cytotoxicity between doxorubicin and roscovitine. However, morphologic changes observed by light microscopy and increased cytoplasmic LC3-GFP puncta in U20S-LC3-GFP cells after the combined treatment suggested the induction of autophagy. Induction of autophagy was also shown in SW-982 and SK-LMS-1 cells treated with both doxorubicin and roscovitine by acridine orange staining. These results suggest a novel role of autophagy in the enhanced cytotoxicity by cell cycle inhibition after genotoxic injury in tumor cells. Further investigation of this enhanced cytotoxicity as a treatment strategy for sarcomas is warranted.

Modern systemic chemotherapy in surgically unresectable neoplasms of appendiceal origin: a single-institution experience.

Appendiceal neoplasms include tumors ranging from benign‐appearing cells with widespread mucin deposits to aggressive poorly differentiated signet ring cell adenocarcinomas. Traditionally, these tumors are treated with cytoreductive surgery followed by hyperthermic intraperitoneal chemotherapy. For some patients, cytoreductive surgery is not an option, and minimal published data exist in the management and outcome of these patients. A retrospective analysis was conducted to determine the benefit of modern systemic chemotherapy in patients with disseminated appendiceal neoplasm who were not considered optimal candidates for cytoreductive surgery.

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Equipotent Generation of Protective Antitumor Immunity by Various Methods of Dendritic Cell Loading With Whole Cell Tumor Antigens.

Multiple clinically applicable methods have been used to induce dendritic cells (DCs) to express whole cell tumor antigens, including pulsing DCs with tumor lysate, and mixing DCs with apoptotic or live tumor cells. Herein we demonstrate, using two different tumor systems, that these methods are equipotent inducers of systemic antitumor immunity. Furthermore, tumor lysate pulsed DC vaccines generate more potent antitumor immunity than immunization with irradiated tumor cells plus the classic adjuvant, Corynebacterium parvum.

Systemic chemotherapy and surgical cytoreduction for poorly differentiated and signet ring cell adenocarcinomas of the appendix

BACKGROUND Poorly differentiated and signet ring cell adenocarcinomas of the appendix represent a subset with aggressive tumor biology and poor outcomes with few studies evaluating the impact of systemic chemotherapy and cytoreductive surgery (CRS). PATIENTS AND METHODS A retrospective chart review of patients with either poorly differentiated and signet ring cell appendiceal adenocarcinomas was completed from 1992 to 2010. RESULTS One hundred forty-two patients were identified. Seventy-eight patients with metastatic disease received chemotherapy. Radiographic response was 44%, median progression-free survival (PFS) was 6.9 months, and median overall survival (OS) was 1.7 years. In multivariate analysis, response to chemotherapy [hazard ratio (HR) 0.5; P = 0.02] predicted improved PFS, and complete CRS (HR 0.3; P = 0.004) predicted improved OS. Patients who underwent complete CRS (n = 26) had a median relapse-free survival (RFS) of 1.2 years and a median OS of 4.2 years. In multivariate analysis for this subset, complete cytoreduction score of 0 was significantly correlated with improved RFS (HR 0.07; P = 0.01) and OS (HR 0.02; P = 0.01). CONCLUSIONS Systemic chemotherapy appears to be a viable treatment option for patients with metastatic poorly differentiated and signet ring cell appendiceal adenocarcinomas. Complete CRS is associated with improved RFS and OS, though part of this benefit likely reflects the selection of good tumor biology.BACKGROUND Poorly differentiated and signet ring cell adenocarcinomas of the appendix represent a subset with aggressive tumor biology and poor outcomes with few studies evaluating the impact of systemic chemotherapy and cytoreductive surgery (CRS). PATIENTS AND METHODS A retrospective chart review of patients with either poorly differentiated and signet ring cell appendiceal adenocarcinomas was completed from 1992 to 2010. RESULTS One hundred forty-two patients were identified. Seventy-eight patients with metastatic disease received chemotherapy. Radiographic response was 44%, median progression-free survival (PFS) was 6.9 months, and median overall survival (OS) was 1.7 years. In multivariate analysis, response to chemotherapy [hazard ratio (HR) 0.5; P = 0.02] predicted improved PFS, and complete CRS (HR 0.3; P = 0.004) predicted improved OS. Patients who underwent complete CRS (n = 26) had a median relapse-free survival (RFS) of 1.2 years and a median OS of 4.2 years. In multivariate analysis for this subset, complete cytoreduction score of 0 was significantly correlated with improved RFS (HR 0.07; P = 0.01) and OS (HR 0.02; P = 0.01). CONCLUSIONS Systemic chemotherapy appears to be a viable treatment option for patients with metastatic poorly differentiated and signet ring cell appendiceal adenocarcinomas. Complete CRS is associated with improved RFS and OS, though part of this benefit likely reflects the selection of good tumor biology.

Surgery and Radiotherapy for Retroperitoneal and Abdominal Sarcoma: Both Necessary and Sufficient

OBJECTIVE To evaluate the effect of surgical resection and radiotherapy (RT) in retroperitoneal or abdominal sarcoma. DESIGN Retrospective cohort. SETTING Surveillance, Epidemiology, and End Results, 1988-2005. PATIENTS Patients 18 years or older with initial diagnosis of primary retroperitoneal and nonvisceral abdominal sarcoma. MAIN OUTCOME MEASURES Survival for 2 years after diagnosis. Kaplan-Meier survival was stratified based on surgery and RT status. Cox proportional hazards model was used to assess adjusted effects of surgery and RT on survival in patients with locoregional disease. RESULTS Of 1901 patients with locoregional disease, 1547 (81.8%) underwent resection; 447 (23.5%) received RT. Overall, patients who received both surgery and RT demonstrated improved survival compared with patients who underwent either therapy alone; patients undergoing monotherapy in turn had more favorable survival compared with patients who received neither therapy (P < .001, log rank). Cox analysis demonstrated that surgical resection (hazard ratio [HR], 0.24; 95% confidence interval [CI], 0.21-0.29; P < .001) and RT (0.78; 0.63-0.95; P = .01) independently predicted improved survival in locoregional disease only. In adjusted analyses stratified for American Joint Commission on Cancer (AJCC) stage, for stage I disease (n = 694), RT provided an additional benefit (HR, 0.49; 95% CI, 0.25-0.96; P = .04) independent of that from resection (0.35; 0.21-0.58; P < .001). For stage II/III (n = 552), resection remained protective (HR, 0.24; 95% CI, 0.18-0.32; P < .001); however, RT was no longer associated with a significant benefit (0.78; 0.58-1.06; P = .11). CONCLUSIONS In a national cohort of retroperitoneal and abdominal sarcomas, surgical resection was associated with significant survival benefits for AJCC disease stages I to III. Radiotherapy provided additional benefit for patients with stage I disease. Resection should be offered to reasonable surgical candidates with nonmetastatic retroperitoneal/abdominal sarcomas; radiotherapy may most benefit patients with early-stage disease.

Rational Follow-Up After Curative Cancer Resection

Cancer recurrence after complete resection of the primary tumor is dreaded by patients and physicians alike. Intensive follow-up after curative resection is considered a marker of good practice and frequently perceived as an antidote against recurrence by patients and families. In the United States, there is abiding faith in frequent imaging and blood tests as the best tools for the job. Thoughtful practice, clinical guidelines, retrospective reviews of prospectively gathered data, and clinical trials of follow-up have focused on the number, frequency, and sequence of modalities. A different perspective on which to predicate follow-up of patients with curatively treated cancer is to consider whether meaningful treatment options exist for recurrence. In cancers for which there are meaningful treatment options, it is reasonable to expect that moreintensive follow-up may improve survival. This commentary discusses this perspective in the context of the established literature in patients with colorectal and breast cancers, two cancers considered to have effective treatments for metastatic and recurrent disease as compared with non–small-cell lung cancer (NSCLC) and pancreatic cancer, which do not.

Increased risk of mucinous neoplasm of the appendix in adults undergoing interval appendectomy

IMPORTANCE The role of interval appendectomy after conservative management of perforated appendicitis remains controversial. Determining the etiology of perforated appendicitis is one reason to perform interval appendectomies. OBJECTIVE To determine whether adult patients undergoing interval appendectomy experience an increased rate of neoplasms. DESIGN Retrospective study. SETTING A single tertiary care institution. PARTICIPANTS All patients 18 years or older who underwent appendectomy for presumed appendicitis from January 1, 2006, through December 31, 2010. EXPOSURES Appendectomy for presumed appendicitis. MAIN OUTCOMES AND MEASURES Underlying neoplasm as the cause of presentation for presumed appendicitis. Demographic data, clinicopathologic characteristics, interval resection rate, and complication data were collected and analyzed. RESULTS During the study period, 376 patients underwent appendectomies. Interval appendectomy was performed in 17 patients (4.5%). Neoplasms were identified in 14 patients (3.7%); 5 of those tumors occurred in patients who had undergone interval appendectomy (29.4%). Nine neoplasms were mucinous tumors (64.3%), including all neoplasms associated with interval appendectomies. The mean age of all patients with appendiceal tumors was 49 years (range, 35-74 years). CONCLUSIONS AND RELEVANCE Mucinous neoplasms of the appendix were found in 5 of 17 patients (29.4%) undergoing interval appendectomy. Interval appendectomies should be considered in all adult patients, especially those 40 years or older, to determine the underlying cause of appendicitis. A multi-institutional study to determine the generalizability of these findings is warranted.