Vijaya Gottumukkala

Transport properties of pancreatic cancer describe gemcitabine delivery and response

BACKGROUND The therapeutic resistance of pancreatic ductal adenocarcinoma (PDAC) is partly ascribed to ineffective delivery of chemotherapy to cancer cells. We hypothesized that physical properties at vascular, extracellular, and cellular scales influence delivery of and response to gemcitabine-based therapy. METHODS We developed a method to measure mass transport properties during routine contrast-enhanced CT scans of individual human PDAC tumors. Additionally, we evaluated gemcitabine infusion during PDAC resection in 12 patients, measuring gemcitabine incorporation into tumor DNA and correlating its uptake with human equilibrative nucleoside transporter (hENT1) levels, stromal reaction, and CT-derived mass transport properties. We also studied associations between CT-derived transport properties and clinical outcomes in patients who received preoperative gemcitabine-based chemoradiotherapy for resectable PDAC. RESULTS Transport modeling of 176 CT scans illustrated striking differences in transport properties between normal pancreas and tumor, with a wide array of enhancement profiles. Reflecting the interpatient differences in contrast enhancement, resected tumors exhibited dramatic differences in gemcitabine DNA incorporation, despite similar intravascular pharmacokinetics. Gemcitabine incorporation into tumor DNA was inversely related to CT-derived transport parameters and PDAC stromal score, after accounting for hENT1 levels. Moreover, stromal score directly correlated with CT-derived parameters. Among 110 patients who received preoperative gemcitabine-based chemoradiotherapy, CT-derived parameters correlated with pathological response and survival. CONCLUSION Gemcitabine incorporation into tumor DNA is highly variable and correlates with multiscale transport properties that can be derived from routine CT scans. Furthermore, pretherapy CT-derived properties correlate with clinically relevant endpoints. TRIAL REGISTRATION Clinicaltrials.gov NCT01276613. FUNDING Lustgarten Foundation (989161), Department of Defense (W81XWH-09-1-0212), NIH (U54CA151668, KCA088084).

Two-surgeon technique of parenchymal transection contributes to reduced transfusion rate in patients undergoing major hepatectomy: Analysis of 1,557 consecutive liver resections

BACKGROUND Blood transfusions are an independent risk factor for adverse outcomes after hepatectomy. In-hospital transfusions are still reported in one third of patients in major series. Data on factors affecting blood transfusions in large series of liver resection are limited. The aim of this study was to evaluate factors predictive of blood transfusion in hepatectomies performed at a tertiary referral center. METHODS Records of 1,477 patients who underwent 1,557 liver resections between 1998 and 2007 were reviewed. Multivariate analysis of risk factors for red cell transfusion was performed. RESULTS Median intra-operative blood loss was 250 cc, and 30-day peri-operative red cell transfusion rate was 27%. On multivariate analysis, factors that significantly predicted increased red cell transfusion rates were female sex, pre-operative hematocrit<30%, platelet count<100,000/mm3, simultaneous resection of other organs, major hepatic resection, use of the Pringle maneuver, and tumors>10 cm. Parenchymal transection technique was an independent risk factor for perioperative red cell transfusion; the usage of the 2-surgeon technique (combined saline-linked cautery and ultrasonic dissection) was associated with a lower transfusion rate than other techniques, including ultrasonic dissection alone, finger fracture, and stapling (P<.001). CONCLUSION Although most factors that affect the red cell transfusion rate for liver resection are patient- or tumor-related, the parenchymal transection technique is under the surgeons control. The decrease in transfusion rate associated with the use of the 2-surgeon technique emphasizes the important role of the hepatobiliary surgeon in determining outcomes after liver resection.

A retrospective analysis of the effect of intraoperative opioid dose on cancer recurrence after non-small cell lung cancer resection

Preclinical studies have demonstrated that opioid receptor agonists increase the rate of non‐small cell lung cancer (NSCLC) growth and metastasis. Following institutional review board approval, we retrieved data on 901 patients who underwent surgery for NSCLC at MD Anderson Cancer Center. Comprehensive demographics, intraoperative data, and recurrence‐free survival (RFS) and overall survival (OS) at 3 and 5 years were obtained. Cox proportional analyses were conducted to assess the association between intraoperative opioid exposure and RFS and OS. The median intraoperative fentanyl equivalents dosage was 10.15 μg/kg. The multivariate analysis by stage indicated that a trend toward significance for opioid consumption as a risk factor in stage I patients (P = 0.053). No effect was found on RFS for stage II or III patients. Alternatively, opioid consumption was a risk factor for OS for stage I patients (P = 0.036), whereas no effect was noted for stage II or III patients. Intraoperative opioid use is associated with decreased OS in stage I but not stage II–III NSCLC patients. Until randomized controlled studies explore this association further, opioids should continue to be a key component of balanced anesthesia.

A call for new standard of care in perioperative gynecologic oncology practice: Impact of enhanced recovery after surgery (ERAS) programs

Enhanced recovery after surgery (ERAS) programs aim to hasten functional recovery and improve postoperative outcomes. However, there is a paucity of data on ERAS programs in gynecologic surgery. We reviewed the published literature on ERAS programs in colorectal surgery, general gynecologic surgery, and gynecologic oncology surgery to evaluate the impact of such programs on outcomes, and to identify key elements in establishing a successful ERAS program. ERAS programs are associated with shorter length of hospital stay, a reduction in overall health care costs, and improvements in patient satisfaction. We suggest an ERAS program for gynecologic oncology practice involving preoperative, intraoperative, and postoperative strategies including; preadmission counseling, avoidance of preoperative bowel preparation, use of opioid-sparing multimodal perioperative analgesia (including loco-regional analgesia), intraoperative goal-directed fluid therapy (GDT), and use of minimally invasive surgical techniques with avoidance of routine use of nasogastric tube, drains and/or catheters. Postoperatively, it is important to encourage early feeding, early mobilization, timely removal of tubes and drains, if present, and function oriented multimodal analgesia regimens. Successful implementation of an ERAS program requires a multidisciplinary team effort and active participation of the patient in their goal-oriented functional recovery program. However, future outcome studies should evaluate the efficacy of an intervention within the pathway, include objective measures of symptom burden and control, study measures of functional recovery, and quantify outcomes of the program in relation to the rates of adherence to the key elements of care in gynecologic oncology such as oncologic outcomes and return to intended oncologic therapy (RIOT).

Patient-Reported Outcomes Accurately Measure the Value of an Enhanced Recovery Program in Liver Surgery

BACKGROUND Enhanced recovery (ER) pathways have become increasingly integrated into surgical practice. Studies that compare ER and traditional pathways often focus on outcomes confined to inpatient hospitalization and rarely assess a patients functional recovery. The aim of this study was to compare functional outcomes for patients treated on an Enhanced Recovery in Liver Surgery (ERLS) pathway vs a traditional pathway. STUDY DESIGN One hundred and eighteen hepatectomy patients rated symptom severity and life interference using the validated MD Anderson Symptom Inventory preoperatively and postoperatively at every outpatient visit until 31 days after surgery. The ERLS protocol included patient education, narcotic-sparing anesthesia and analgesia, diet advancement, restrictive fluid administration, early ambulation, and avoidance of drains and tubes. RESULTS Seventy-five ERLS pathway patients were clinically comparable with 43 patients simultaneously treated on a traditional pathway. The ERLS patients reported lower immediate postoperative pain scores and experienced fewer complications and decreased length of stay. As measured by symptom burden on life interference, ERLS patients were more likely to return to baseline functional status in a shorter time interval. The only independent predictor of faster return to baseline interference levels was treatment on an ERLS pathway (p = 0.021; odds ratio = 2.62). In addition, ERLS pathway patients were more likely to return to intended oncologic therapy (95% vs 87%) at a shorter time interval compared to patients on the traditional pathway (44.7 vs 60.2 days). CONCLUSIONS In oncologic liver surgery, enhanced recoverys primary mechanism of action is reduction in life interference by postoperative surgical symptoms, allowing patients to return sooner to normal function and adjuvant cancer therapies.

Effects of postoperative epidural analgesia on recurrence-free and overall survival in patients with nonsmall cell lung cancer ☆

STUDY OBJECTIVE To determine whether postoperative epidural analgesia is associated with better recurrence-free survival and overall survival after lung cancer surgery. DESIGN Retrospective study. SETTING Academic hospital. MEASUREMENTS Data of patients with stage 1, stage 2, and stage 3 nonsmall cell lung cancer, who underwent tumor resection surgery, were studied. Patient data were grouped into three different postoperative pain management interventions: intravenous patient-controlled analgesia, patient-controlled epidural analgesia, and their combination. Univariate and multicovariate Cox proportional hazards models were applied to assess the effects of covariates of interest on overall survival and recurrence-free survival. MAIN RESULTS The type of postoperative analgesia used for patients who underwent surgery for nonsmall cell lung cancer did not affect recurrence-free survival or overall survival. However, certain variables, including age ≥ 65 years, male gender, body mass index ≥ 25 kg/m(2), ASA physical status 4, and the need for preoperative blood transfusions, pneumonectomy, and postoperative radiation, were associated with decreased recurrence-free survival and overall survival. CONCLUSIONS The type of postoperative analgesia used after surgery for nonsmall cell lung cancer is not associated with better 2-year or 5-year recurrence-free survival or overall survival rates.

The Impact of Paravertebral Block Analgesia on Breast Cancer Survival after Surgery

Background and Objectives The impact of regional anesthesia on breast cancer recurrence is controversial. We tested the hypothesis that the use of paravertebral block (PVB) analgesia during breast cancer surgery prolongs the recurrence-free survival (RFS) and overall survival (OS) of women with breast cancer. Methods Seven hundred ninety-two women with nonmetastatic breast cancer were included in this retrospective study. Patients were divided based on the administration of PVB analgesia for mastectomy surgeries. One hundred ninety-eight (25%) were given a PVB, the remainder were treated with opioid-based analgesia. Propensity score matching was developed using several variables. Univariate and multivariate analyses were used to assess the impact of PVB analgesia on RFS and OS. Results The median follow-up times for RFS and OS were 5.8 and 6 years, respectively. In the propensity score matching model, a total of 396 women were included in each group of treatment (non-PVB group, n = 198 vs PVB group, n = 198). As expected, the fentanyl consumption was significantly lower in PVB (122.8 ± 77.85 &mgr;g) patients than non-PVB subjects (402.23 ± 343.8 &mgr;g). Other variables were not statistically significant. After adjusting for several important covariates, the analysis indicated that the use of PVB is not associated with a significant change in RFS [1.60 (0.81–3.16), P = 0.172] or OS [1.28 (0.55–3.01)] survival. Discussion This retrospective study does not support the hypothesis that the use of regional analgesia is associated with longer survival after surgery for breast cancer.

Innate immune function after breast, lung, and colorectal cancer surgery

BACKGROUND The cytotoxic activity and count of natural killer (NK) cells appear to be reduced after surgery; however, it is unknown whether the magnitude of this immune suppression is similar among different types of oncological surgery. In this study, we compared the innate immune function of patients undergoing three different oncological surgeries. METHODS We compared the number and function of NK cells obtained from patients who had undergone mastectomies (n = 17), thoracotomies (n = 21), or liver resections for cancer (n = 22). Cytotoxicity assays were performed to measure the function of NK cells. We also determined the plasma concentrations of interleukins (IL) 2 and 4, interferon-γ, granzyme B, perforin, soluble major histocompatibility complex class I-related chain A, and epinephrine, both before and 24 h after surgery. Differences in immunologic parameters were compared preoperatively and postoperatively and by type of surgery. P values <0.05 were considered statistically significant. RESULTS The preoperative NK cell count differed statistically (P < 0.006) among all three types of surgeries; however, within surgery postoperative counts and changes compared with baseline did not. The postoperative function of NK cells was similar among types of surgeries, but was significantly reduced compared with preoperative levels (mastectomy P < 0.0001, thoracotomy P = 0.001, and liver resections P = 0.002). We observed a significant increase in the postoperative plasma concentrations of epinephrine, whereas the concentrations of major histocompatibility class I polypeptide-related sequence A and the IL-2 and/or IL-4 ratio remained unchanged before and after surgery. CONCLUSIONS The magnitude of innate immune suppression is similar among different oncological procedures. More studies are needed to better understand this complex phenomenon.

Intra-tumoral heterogeneity of gemcitabine delivery and mass transport in human pancreatic cancer

There is substantial heterogeneity in the clinical behavior of pancreatic cancer and in its response to therapy. Some of this variation may be due to differences in delivery of cytotoxic therapies between patients and within individual tumors. Indeed, in 12 patients with resectable pancreatic cancer, we previously demonstrated wide inter-patient variability in the delivery of gemcitabine as well as in the mass transport properties of tumors as measured by computed tomography (CT) scans. However, the variability of drug delivery and transport properties within pancreatic tumors is currently unknown. Here, we analyzed regional measurements of gemcitabine DNA incorporation in the tumors of the same 12 patients to understand the degree of intra-tumoral heterogeneity of drug delivery. We also developed a volumetric segmentation approach to measure mass transport properties from the CT scans of these patients and tested inter-observer agreement with this new methodology. Our results demonstrate significant heterogeneity of gemcitabine delivery within individual pancreatic tumors and across the patient cohort, with gemcitabine DNA incorporation in the inner portion of the tumors ranging from 38 to 74% of the total. Similarly, the CT-derived mass transport properties of the tumors had a high degree of heterogeneity, ranging from minimal difference to almost 200% difference between inner and outer portions of the tumor. Our quantitative method to derive transport properties from CT scans demonstrated less than 5% difference in gemcitabine prediction at the average CT-derived transport value across observers. These data illustrate significant inter-patient and intra-tumoral heterogeneity in the delivery of gemcitabine, and highlight how this variability can be reproducibly accounted for using principles of mass transport. With further validation as a biophysical marker, transport properties of tumors may be useful in patient selection for therapy and prediction of therapeutic outcome.

Advances in hepatectomy technique: Toward zero transfusions in the modern era of liver surgery

BACKGROUND Perioperative blood transfusions suppress immunity and increase hospital costs. Despite multiple improvements in perioperative care, rates of transfusion during/after hepatectomy are reported to range from 25 to 50%. The purpose of this study was to determine the current risk factors for perihepatectomy transfusion by assessing the impact of recent technical advances in liver surgery on transfusion rates. METHODS Using our prospectively maintained hepatobiliary tumor database from a high-volume center, a modern cohort of 2,249 hepatectomies (2004-2013) were identified. Patient and operative characteristics were compared between 2 time periods, 2004-2008 (n = 1,139) and 2009-2013 (n = 1,110). Throughout the study interval, transfusions were given based on clinical assessment and not triggered by laboratory thresholds. RESULTS Compared with the early cohort, the recent cohort had more patients with an American Society of Anesthesiologists score of ≥ 3 (79 vs 74%), preoperative chemotherapy (73 vs 68%), and a lesser median preoperative hemoglobin (12.9 vs 13.1 mg/dL) and platelet (215,000 vs 243,000) values (all P < .001). Despite these adverse risk factors, with an increasing use of the 2-surgeon resection technique (63 vs 50%), estimated blood loss (309 vs 394 mL), transfusion rates (6 vs 15%), and duration of stay (7.0 vs 8.4 days) were decreased (all P < .001) with no change in overall morbidity or mortality. Multivariate analysis of the recent cohort determined that the independent risk factors associated with transfusion were preoperative anemia and >350 mL of blood loss. The only independent factor associated with less transfusion was use of the 2-surgeon technique for hepatic parenchymal transection. CONCLUSION With the exception of patients with moderate to severe preoperative anemia requiring major hepatectomy, recent technical advances have decreased significantly the need for transfusion in liver surgery.