David L Bartlett

NCI-Frederick, Фредерик, Maryland, United States

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Publications (350)

  • [Show abstract] [Hide abstract] ABSTRACT: Background Several studies suggest that young patients may derive less oncologic benefit from surgical resection of cancers compared with older patients. We hypothesized that young patients may have worse outcomes following cytoreductive surgery with hyperthermic intraperitoneal chemoperfusion (CRS/HIPEC) for peritoneal metastases. Methods Perioperative and oncologic outcomes in adolescent and young adults (AYA), defined as younger than age 40 years (n = 135), undergoing CRS/HIPEC between 2001 and 2015 were reviewed and compared with middle-aged adults, defined as aged 40–65 years (n = 684). ResultsThe two groups were similar with regards to perioperative characteristics except that AYA were more likely to be symptomatic at presentation (65.2 vs. 50.9%, p = 0.003), had lower Charleson comorbidity index (median 6 vs. 8, p < 0.001), were less likely to receive neoadjuvant chemotherapy (32.8 vs. 42.5%, p = 0.042), and had longer operative times (median 543 vs. 493 min, p = 0.010). Postoperative Clavien–Dindo grade 3–4 morbidity was lower in AYA (17 vs. 26%, p = 0.029), and they required fewer reoperations for complications (3.7 vs. 10.4%, p = 0.014). AYA had longer median overall survival (103.6 vs. 73.2 months, p = 0.053). In a multivariate Cox regression analysis, age was an independent predictor of improved overall survival [hazard ratio 0.705; 0.516–0.963, p = 0.028]. Conclusions Young patients with peritoneal metastases derive similar benefits from CRS/HIPEC as middle-aged patients. Young age should not be a deterrent to consideration of CRS/HIPEC for peritoneal metastases.
    Article · Dec 2016 · Annals of Surgical Oncology
  • [Show abstract] [Hide abstract] ABSTRACT: Introduction: The aim was to evaluate the impact of obesity on perioperative outcomes in patients undergoing robotic pancreaticoduodenectomy (RPD) compared to open pancreaticoduodenectomy (OPD). Methods: A retrospective review of all pancreaticoduodenectomies from 9/2011 to 4/2015 was performed. Obesity was defined as body mass index (BMI) > 30 kg/m(2). Results: Of 474 pancreaticoduodenectomies performed: RPD = 213 (45%) and OPD = 261 (55%). A total of 145 (31%) patients were obese (70 RPD, 75 OPD). Obese patients had increased EBL (p = 0.03), pancreatic fistula (B&C; p = 0.077), and wound infection (p = 0.068) compared to the non-obese. For obese patients, RPD had decreased OR time (p = 0.0003), EBL (p < 0.001), and wound infection (p = 0.001) with no difference in Clavien ≥3 complications, margins, LOS or 30-day mortality compared with OPD. In multivariate analysis, obesity was the strongest predictor of Clavien ≥3 (OR 1.6; p = 0.041) and wound infection if BMI > 35 (OR 2.6; p = 0.03). The robotic approach was protective of Clavien ≥3 (OR 0.6; p = 0.03) on univariate analysis and wound infection (OR 0.3; p < 0.001) and grade B/C pancreatic fistula (OR 0.34; p < 0.001) on multivariate analysis. Conclusions: Obese patients are at risk for increased postoperative complications regardless of approach. However, the robotic approach mitigates some of the increased complication rate, while preserving other perioperative outcomes.
    Article · Dec 2016 · HPB
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    [Show abstract] [Hide abstract] ABSTRACT: The impact of genomic profiling on the outcomes of patients with advanced gastrointestinal (GI) malignancies remains unknown. The primary objectives of the study were to investigate the clinical benefit of genomic-guided therapy, defined as complete response (CR), partial response (PR), or stable disease (SD) at 3 months, and its impact on progression-free survival (PFS) in patients with advanced GI malignancies. Clinical and genomic data of all consecutive GI tumor samples from April, 2013 to April, 2016 sequenced by FoundationOne were obtained and analyzed. A total of 101 samples from 97 patients were analyzed. Ninety-eight samples from 95 patients could be amplified making this approach feasible in 97% of the samples. After removing duplicates, 95 samples from 95 patients were included in the further analysis. Median time from specimen collection to reporting was 11 days. Genomic alteration-guided treatment recommendations were considered new and clinically relevant in 38% (36/95) of the patients. Rapid decline in functional status was noted in 25% (9/36) of these patients who could therefore not receive genomic-guided therapy. Genomic-guided therapy was utilized in 13 patients (13.7%) and 7 patients (7.4%) experienced clinical benefit (6 PR and 1 SD). Among these seven patients, median PFS was 10 months with some ongoing durable responses. Genomic profiling-guided therapy can lead to clinical benefit in a subset of patients with advanced GI malignancies. Attempting genomic profiling earlier in the course of treatment prior to functional decline may allow more patients to benefit from these therapies.
    Full-text available · Article · Dec 2016 · Cancer Medicine
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    [Show abstract] [Hide abstract] ABSTRACT: Background The currently-used modes of administration of immunotherapeutic agents result in their limited delivery to the lymph nodes and/or require repetitive ultrasound-guided nodal injections or microsurgical lymphatic injections, limiting their feasibility. Here, we report on the feasibility and safety of a new method of long-term repetitive intralymphatic (IL) infusion of immune cells, using implantable delivery ports. Methods Nine patients with stage IV recurrent colorectal cancer underwent complete resection and received autologous dendritic cells (DCs) loaded with killed autologous tumor cells, KLH and PADRE, for up to four monthly cycles. Leg lymphatic vessels were cannulated, connected to 6.6Fr low-profile implantable subcutaneous delivery ports, and used to infuse 12 doses of DC over each 72 h-long cycle (every 6 h), followed by heparin flushes of the cannula-port system (one 72 h-long cycle per month). The patients who opted for alternative route of vaccine administration (2 patients) or whose ports became non-functional between cycles, continued treatment via intranodal (one injection/cycle) or intradermal (four injections/cycle) routes. Results A total of nine lymphatic cannulations and implantations of subcutaneous delivery ports were attempted in seven patients, with a success rate of eight out of nine (89 %). The average patency of the IL delivery system was 7.5 (±3.2) weeks. All six patients with IL ports successfully completed at least one complete 72 h-long DC infusion cycle (12 injections). Five patients (56 %) completed two full IL cycles (24 IL injections). No patients received more than two IL cycles without replacement of the IL port, due to catheter occlusion and/or local side effects: cellulitis and hematoma. Intranodal and intradermal backup options were used in, respectively, one and two patients. Overall cohort survival was >28 (±25) months. One patient with aggressive recurrent carcinomatosis, who received DC vaccines by intranodal route is alive at > 90 months, without evidence of disease. Conclusions We conclude that an intermediate-duration IL delivery of multiple doses of immunotherapeutic factors using implantable delivery ports is feasible, highly-tolerable and can be reproducibly performed in cancer patients to administer immune cells, or potentially, other immune factors. However, long-term IL port placement (>7.5 weeks), is not a currently-feasible option. Trial registration NCT00558051, registered Nov. 13, 2007.
    Full-text available · Article · Dec 2016
  • [Show abstract] [Hide abstract] ABSTRACT: Background: Treatment with yttrium-90 (Y90) microspheres has emerged as a viable liver-directed therapy for patients with unresectable tumors and those outside transplantation criteria. A select number of patients demonstrate a favorable response and become candidates for surgical resection. Methods: Patients who underwent selective internal radiation therapy (SIRT) with Y90 microspheres at two institutions were reviewed. Patients who underwent liver resection were included in the study. The data gathered included demographics, tumor characteristics, response to Y90, surgical details, perioperative outcomes, and survival. Results: The inclusion criteria were met by 12 patients. The diagnoses included metastatic disease from colorectal adenocarcinoma (n = 6), neuroendocrine tumor (n = 1), and ocular melanoma (n = 1) in addition to hepatocellular carcinoma (n = 4). The median time from liver disease diagnosis to Y90 treatment was 5.5 months (range 2-92 months). The median time from Y90 treatment to surgery was 9.5 months (range 3-20 months). The surgical approach included right hepatectomy (n = 3), extended right hepatectomy (n = 5), extended left hepatectomy (n = 1), segmentectomy with ablation (n = 2), and segmentectomy with isolated liver perfusion (n = 1). The hospital stay was 7 days (range 4-31 days), and 67% of the patients were discharged home. The readmission rate was 42%. The 90-day morbidity and mortality rates were respectively 42 and 8%. At this writing, the median overall survival has not been reached at 25 months. Conclusion: Liver resection after Y90 SIRT is a challenging surgical procedure with high rates of perioperative morbidity and hospital readmission. However, for properly selected patients, potential exists for extending disease-free and overall survival in the current era of multimodal therapy for malignant liver disease.
    Article · Nov 2016 · Annals of Surgical Oncology
  • [Show abstract] [Hide abstract] ABSTRACT: Peritoneal metastasis in colorectal carcinoma is associated with a dismal prognosis; however, features that correlate with patterns of metastatic spread are not well characterized. We analyzed the clinicopathologic and molecular features of 166 patients with colorectal carcinomas stratified by metastases to the peritoneum or liver. Mucinous and signet ring cell differentiation were more frequently observed in colorectal carcinoma with peritoneal dissemination compared to colorectal carcinoma with liver metastasis (mucinous differentiation: 62% vs 23%, P < .001; signet ring cell differentiation: 21% vs 0%, P < .0001). The significant association of mucinous differentiation with peritoneal dissemination compared with liver metastasis was identified in patients with both synchronous and metachronous development of metastasis (P < .01). In contrast, colorectal carcinomas with liver metastasis were more frequently low-grade (90% vs 72%, P = .005) and associated with dirty necrosis (81% vs 56%, P = .001) compared with colorectal carcinomas with peritoneal dissemination. No significant differences were identified between colorectal carcinoma with peritoneal metastasis versus liver metastasis with respect to KRAS mutations, BRAF mutation, or high levels of microsatellite instability. Patients with tumors involving the peritoneum had a significantly worse overall survival in comparison to patients with liver metastasis lacking peritoneal involvement (P = .02). When including only those patients with peritoneal metastasis, the presence of any mucinous or signet ring cell differentiation was associated with a significantly worse overall survival (P = .006). Our findings indicate that mucinous and signet ring cell differentiation may be histologic features that are associated with an increased risk of peritoneal dissemination and poor overall survival in patients with peritoneal metastasis.
    Article · Aug 2016 · International Journal of Surgical Pathology
  • [Show abstract] [Hide abstract] ABSTRACT: Background Hepatic artery infusion (HAI) chemotherapy is an effective regional therapy for unresectable colorectal liver metastases (U-CRLM).1 ,2 One of its limitations is the need for a laparotomy, which can delay the use of systemic therapy.3 Here, we describe a purely robotic technique for placement of an HAI pump (Fig 1). Patient A 62-year-old male presented with a symptomatic ascending colon cancer and multiple bilobar unresectable liver metastases. He underwent laparoscopic right colectomy followed by six cycles of FOLFOXIRI and bevacizumab with stable disease by RECIST (Response Evaluation Criteria in Solid Tumors) criteria, and also underwent robotic HAI pump placement. Technique The patient was placed supine on a split-leg table, and four robotic and two laparoscopic assistant ports were placed as shown. Use of the robot allowed for precise dissection of the common hepatic artery (CHA) and gastroduodenal artery (GDA), as well as a portal lymphadenectomy. A standard cholecystectomy was performed and the GDA was dissected for a distance of 2–3 cm from its takeoff from the CHA. The robotic scissors were used to create a precise transverse GDA arteriotomy, and the HAI pump catheter tip was advanced to the CHA/GDA junction and secured with two silk ties. Finally, a methylene blue dye injection test was performed to ensure uniform distribution within the liver. Operative time was 147 min, estimated blood loss was 20 ml, and the postoperative course was uneventful. The first dose of HAI with floxuridine was administered on postoperative day 4 (day of discharge) and systemic chemotherapy was administered 2 weeks later. Conclusion The robotic platform allows for minimally invasive HAI pump placement. Fig. 1 Port placement for robotic-assisted hepatic artery infusion pump placement using the DaVinci Si platform. Illustration depicts a 12 mm periumbilical port for the robotic camera (upper green port), three 8 mm (purple) robotic working ports (the left MCL, right MCL, and right AAL for robotic arms R1, R2, and R3, respectively), and 12 mm (lower green) and 5 mm (red) laparoscopic assistant ports in the right and left lower quadrants, respectively. The pump pocket is created in the left lower quadrant just below the 5 mm (red) port site
    Article · Aug 2016 · Annals of Surgical Oncology
  • [Show abstract] [Hide abstract] ABSTRACT: Background: Hepatic artery infusion (HAI) chemotherapy can be combined with systemic chemotherapy for the treatment of isolated unresectable colorectal liver metastases (IU-CRLM) and intrahepatic cholangiocarcinoma (U-ICC). However, HAI pump placement requires a major laparotomy that may be associated with morbidity. We hypothesized that the computer-assisted robotic platform would be well suited for this procedure and report the first single institutional case series of robotic assisted HAI pump placement for primary and secondary malignancies of the liver. Methods: A retrospective review of patients who underwent robotic assisted HAI pump placement from January 2008 to January 2016. Peri-operative outcomes were evaluated. Results: A total of 24 consecutive patients underwent robotic assisted HAI pump placement. Median age was 61 years and 50% were females. Main indications were colorectal cancer = 17 (71%) and intrahepatic cholangiocarcinoma = 4 (17%). The majority (87.5%) of patients had bilobar disease with a median of 6 liver lesions. Concurrent procedures including ablation +/- resection and colectomies were performed in 58% of the patients. Median operative time was 282 min, with median blood loss of 100 ml and length of stay 6 days. Conversion to open was required in one (4%) case. Grade 3 or higher complications were seen in 13% of cases and pump related complications were seen in 21% of patients. All except one HAI pumps could be used for pump chemotherapy. CUSUM analysis of operative time indicated a learning curve of eight cases. Conclusion: Robotic assisted placement of HAI pump placement is safe, feasible, and obviates the need for major laparotomy. J. Surg. Oncol. © 2016 Wiley Periodicals, Inc.
    Article · Aug 2016 · Journal of Surgical Oncology
  • [Show abstract] [Hide abstract] ABSTRACT: Background: Morbidity and mortality of pancreatectomy has improved and chemotherapeutic options for pancreatic cancer (PC) are growing, yet there is reluctance to treat octogenarians. This study examined the reasons for failure to treat and analyzes outcomes in octogenarians with PC. Methods: Retrospective chart review 2005-2013. Demographics, tumor characteristics, treatment, reason for lack of treatment, Charlson comorbidity index (CCI), and survival were analyzed. Expected treatment for early-stage patients (I/II) included surgery ± chemotherapy ± radiation. Expected treatment for advanced stage patients (III/IV) was chemotherapy. Results: A total of 431 octogenarians were analyzed. Mean age was 84.0 ± 3.4, 59.6 % female, and 44.1 % received no treatment. Patients with operable tumors (I = 31 [7.2 %]/II = 214 [49.7 %]) had surgery 39.2 % of the time. Age was a predictor of not receiving surgery (odds ratio [OR] 0.78; 95 % confidence interval [CI] 0.70-0.86; p = 0.0001), whereas CCI was not. The most common reason for no surgery was contraindication despite similar CCI. Median overall survival for early-stage patients was better in the surgical group (15.8 vs. 5.5 months) than nonsurgical group (p < 0.0001). Advanced patients (III = 54 [12.5 %]/IV = 132 [30.6 %]) had similarly low treatment rates (n = 65 [34.9 %]). Survival for advanced disease was best for treated patients (6.9 vs. 1.8 months; p < 0.0001). CCI did not differ between those receiving chemotherapy and not, although age was significantly different (p < 0.0001). Conclusions: There is significant deviation from expected treatment for octogenarians with PC. While no correlation existed between CCI and treatment, age correlated with therapy for nearly all stages. Chronological age, not comorbidity, may drive recommendation for treatment in elderly patients.
    Article · Jul 2016 · Annals of Surgical Oncology
  • Carissa A Low · Dana H Bovbjerg · David L Bartlett
    Article · Jul 2016 · Journal of Clinical Oncology
  • [Show abstract] [Hide abstract] ABSTRACT: Background: In the era of effective modern systemic chemotherapy (CT), the role of hepatic arterial infusion of fluoxuridine (HAI-FUDR) in the treatment of isolated unresectable colorectal liver metastasis (IU-CRCLM) remains controversial. This study aimed to compare the overall survival (OS) of HAI-FUDR in combination with modern systemic CT versus modern systemic CT alone in patients with IU-CRCLM. Methods: This was a case-control study of IU-CRCLM patients who underwent HAI + modern systemic CT or modern systemic CT alone. Modern systemic CT was defined as the use of multidrug regimens containing oxaliplatin and/or irinotecan ± biologics. Results: Overall, 86 patients met the inclusion criteria (n = 40 for the HAI + CT group, and n = 46 for the CT-alone group). Both groups were similar in demographics, primary and stage IV tumor characteristics, and treatment-related variables (carcinoembryonic antigen, use of biologic agents, total number of lines of systemic CT administered) (all p > 0.05). Additionally, both groups were comparable with respect to liver tumor burden [median number of lesions (13.5 vs. 15), percentage of liver tumor replacement (37.5 vs. 40 %), and size of largest lesion] (all p > 0.05). Median OS in the HAI + CT group was 32.8 months compared with 15.3 months in the CT-alone group (p < 0.0001). Multivariate analysis revealed HAI + CT (hazard ratio 0.4, 95 % confidence interval 0.21-0.72; p = 0.003), Eastern Cooperative Oncology Group status, and receipt of increasing number of lines of systemic CT to be independent predictors of survival. Conclusions: In this case-control study of patients with IU-CRCLM, HAI in combination with CT was associated with improved OS when compared with modern systemic CT alone.
    Article · Jul 2016 · Annals of Surgical Oncology
  • Article · Jul 2016 · Cancer Research
  • [Show abstract] [Hide abstract] ABSTRACT: Background The impact of histopathologic features on oncologic outcomes for patients with peritoneal metastases from goblet cell carcinoid (GCC) undergoing multimodality therapy, including cytoreductive surgery with hyperthermic intraperitoneal chemoperfusion (CRS-HIPEC), is unknown. Methods This study prospectively analyzed 43 patients with GCC undergoing CRS-HIPEC between 2005 and 2013. Pathology slides were re-reviewed to classify GCC into histologic subtypes according to the Tang classification. Kaplan–Meier survival curves and multivariate Cox-regression models identified prognostic factors affecting oncologic outcomes. Results The 43 patients in this study underwent 50 CRS-HIPEC procedures for peritoneal metastases from GCC, and the majority received neoadjuvant and/or adjuvant systemic chemotherapy. The GCC demonstrated an aggressive phenotype with frequent lymph node and peritoneal metastases without systemic dissemination. The majority of the patients had Tang B GCC. The estimated median overall survival times after surgery for the patients with Tang A, B, and C GCC were respectively 59, 22, and 13 months. In a multivariate Cox-regression analysis, poor survival was associated with patients who had Tang B or C GCC, those undergoing incomplete macroscopic resection, and those with symptoms at the time of CRS-HIPEC. The patients with Tang A GCC demonstrated oncologic outcomes similar to those with intermediate-grade (American Joint Committee on Cancer [AJCC] grade 2) disseminated mucinous appendiceal neoplasms, whereas the patients with Tang B and C GCC demonstrated survival rates similar to or worse than those with high-grade (AJCC grade 3) disseminated mucinous appendiceal neoplasms. Conclusions Tang classification is an independent prognostic factor for poor survival after multimodality therapy for GCC. Patients with Tang C GCC demonstrate limited survival and are not ideal candidates for a surgical approach.
    Article · Jul 2016 · Annals of Surgical Oncology
  • [Show abstract] [Hide abstract] ABSTRACT: Objective: To evaluate and quantify surgical skill by grading surgical performance of the pancreaticojejunostomy from robotic pancreaticoduodenectomies (RPDs). We hypothesized that video grading of surgical performance would contribute to estimating risk of postoperative pancreatic fistula (POPF) after pancreaticoduodenectomy. Background: POPF majorly contributes to pancreaticoduodenectomy morbidity. Risk scores [Fistula Risk Score (FRS) and Braga] derived from patient variables are validated for predicting POPF. Birkmeyer et al showed assessment of surgical proficiency is an important component of outcomes. Methods: POPF was diagnosed using International Study Group definition. Technical performance of robotic pancreaticojejunostomy video was graded by 2 blinded surgeons using: (1) pancreaticojejunostomy step-by-step variables [PJ-specific variables (PJVs); max = 115]; and (2) the Objective Structured Assessment of Technical Skills (OSATS) score. Results: One hundred thirty-three pancreaticojejunostomies were analyzed. POPF was 18%. Higher FRS (P = 0.011) and Braga (P = 0.041) scores predicted POPF. Graders' subjective prediction did not correlate with FRS/Braga scores. Grader 1 scores (P = 0.043), but not grader 2 (P = 0.44), predicted POPF. PJV scores >105 were predictive of POPF (P = 0.039). Scoring only PJV duct-to-mucosa stitches (max = 50) was highly predictive of POPF (P = 0.0053). Higher OSATS scores were associated with a decreased rate of POPF (P = 0.022). On multivariate analysis, adding technical scoring to statistically significant patient variables (ie, gland texture) improves the model and can independently predict POPF. The strongest predictive model for POPF consisted of soft gland (odds ratio = 18.28, 95% confidence interval = 2.19-152.57) and low OSATS (odds ratio = 0.82, 95% confidence interval = 0.70-0.96). OSATS, modeled with FRS or Braga scores, independently predicted POPF. Conclusions: This is the first study to demonstrate that technical scoring of a surgeon's performance independently predicts patient outcomes in pancreatic surgery. Future studies should consider how to validate and incorporate technical metrics.
    Article · Jul 2016 · Annals of Surgery
  • [Show abstract] [Hide abstract] ABSTRACT: Background: Distal pancreatectomy with celiac axis resection (DP-CAR) is an option for T4 tumors of the pancreatic body. We examined the perioperative and oncologic outcomes of open and robotic DP-CAR at a high-volume pancreatic center. Methods: Retrospective review of all consecutive DP-CARs. Patient demographics, 90-day perioperative outcomes, and disease specific survival were collected. Results: 30 DP-CARs were performed (11 Robotic, 19 Open). Both groups had similar preoperative/tumor characteristics, and 27 of 28 PDA patients received neoadjuvant chemotherapy. Robotic DP-CAR was associated with decreased OT (316 vs. 476 min), reduced EBL (393 vs. 1736 ml) and lower rates of blood transfusion (0% vs. 54%) (all p < 0.05). No robotic DP-CAR required conversion. Both groups had similar rates of 90-day mortality, major morbidity, LOS, readmission, and receipt of adjuvant therapy. Similarly, both approaches were associated with high R0 resection rates (82% vs. 79%). At a median follow-up of 33 months, median overall survival for the PDA cohort was 35 months, with no difference in the robotic and open approach (33 and 40 months, p = 0.310). Conclusions: With a median survival approaching 3 years, DP-CAR represents an effective treatment for select patients with locally advanced pancreatic body cancer, regardless of approach.
    Article · Jul 2016 · HPB
  • Stephanie Downs-Canner · Zong Sheng Guo · Roshni Ravindranathan · [...] · David L. Bartlett
    [Show abstract] [Hide abstract] ABSTRACT: We have conducted a Phase I study of intravenous vvDD, a Western Reserve strain oncolytic vaccinia virus, on eleven patients with standard treatment-refractory advanced colorectal or other solid cancers. The primary endpoints were maximum tolerated dose and associated toxicity while secondary endpoints were pharmacokinetics, pharmacodynamics, immune responses and antitumor activity. No dose-limiting toxicities and treatment related severe adverse events were observed. The most common adverse events were grades 1/2 flu-like symptoms. Virus genomes were detectable in the blood 15-30 minutes after virus administration in a dose-dependent manner. There was evidence of a prolonged virus replication in tumor tissues in two patients, but no evidence of virus replication in non-tumor tissues, except a healed injury site and an oral thrush. Over 100-fold of anti-viral antibodies were induced in patients' sera. A strong induction of inflammatory and Th1, but not Th2 cytokines, suggested a potent Th1-mediated immunity against the virus and possibly the cancer. One patient showed a mixed response on PET-CT with resolution of some liver metastases, and another patient with cutaneous melanoma demonstrated clinical regression of some lesions. Given the confirmed safety, further trials evaluating intravenous vvDD in combination with therapeutic transgenes, immune checkpoint blockade or complement inhibitors, are warranted.Molecular Therapy (2016); doi:10.1038/mt.2016.101.
    Article · May 2016 · Molecular Therapy
  • [Show abstract] [Hide abstract] ABSTRACT: Background Robotic-assisted surgery has potential benefits over laparoscopy yet little has been published on the integration of this platform into complex surgical oncology. We describe the outcomes associated with integration of robotics into a large surgical oncology program, focusing on metrics of safety and efficiency. Methods A retrospective review of a prospectively maintained database of robotic procedures from July 2009 to October 2014 identifying trends in volume, operative time, complications, conversion to open, and 90-day mortality. Results Fourteen surgeons performed 1236 cases during the study period: thyroid (246), pancreas/duodenum (458), liver (157), stomach (56), colorectal (129), adrenal (38), cholecystectomy (102), and other (48). There were 38 conversions to open (3.1%), 230 complications (18.6%), and 13 mortalities (1.1%). From 2009 to 2014, operative volume increased (7 cases/month vs 24 cases/month; P < .001) and procedure time decreased (471 ± 166 vs 211 ± 140 minutes; P < .001) with statistically significant decreases for all years except 2014 when volume and time plateaued. Conversion to open decreased (12.1% vs 1.7%; P = .009) and complications decreased (48.5% vs 12.3%; P < .001) despite increasing complexity of cases performed. There were 13 deaths within 90 days (5/13 30-day mortality) and 2 (15.4%) were from palliative surgeries. Conclusions Implementation of a diverse robotic surgical oncology program utilizing multiple surgeons is safe and feasible. As operative volume increased, operative time, complications, and conversions to open decreased and plateaued at approximately 3 years. No unanticipated adverse events attributable to the introduction of this platform were observed.
    Article · Apr 2016 · Surgical Innovation
  • [Show abstract] [Hide abstract] ABSTRACT: Background The currently-used modes of administration of immunotherapeutic agents result in their limited delivery to the lymph nodes and/or require repetitive ultrasound-guided nodal injections or microsurgical lymphatic injections, limiting their feasibility. Here, we report on the feasibility and safety of a new method of long-term repetitive intralymphatic (IL) infusion of immune cells, using implantable delivery ports. Methods Nine patients with stage IV recurrent colorectal cancer underwent complete resection and received autologous dendritic cells (DCs) loaded with killed autologous tumor cells, KLH and PADRE, for up to four monthly cycles. Leg lymphatic vessels were cannulated, connected to 6.6Fr low-profile implantable subcutaneous delivery ports, and used to infuse 12 doses of DC over each 72 h-long cycle (every 6 h), followed by heparin flushes of the cannula-port system (one 72 h-long cycle per month). The patients who opted for alternative route of vaccine administration (2 patients) or whose ports became non-functional between cycles, continued treatment via intranodal (one injection/cycle) or intradermal (four injections/cycle) routes. Results A total of nine lymphatic cannulations and implantations of subcutaneous delivery ports were attempted in seven patients, with a success rate of eight out of nine (89 %). The average patency of the IL delivery system was 7.5 (±3.2) weeks. All six patients with IL ports successfully completed at least one complete 72 h-long DC infusion cycle (12 injections). Five patients (56 %) completed two full IL cycles (24 IL injections). No patients received more than two IL cycles without replacement of the IL port, due to catheter occlusion and/or local side effects: cellulitis and hematoma. Intranodal and intradermal backup options were used in, respectively, one and two patients. Overall cohort survival was >28 (±25) months. One patient with aggressive recurrent carcinomatosis, who received DC vaccines by intranodal route is alive at > 90 months, without evidence of disease. Conclusions We conclude that an intermediate-duration IL delivery of multiple doses of immunotherapeutic factors using implantable delivery ports is feasible, highly-tolerable and can be reproducibly performed in cancer patients to administer immune cells, or potentially, other immune factors. However, long-term IL port placement (>7.5 weeks), is not a currently-feasible option. Trial registration NCT00558051, registered Nov. 13, 2007.
    Article · Apr 2016
  • [Show abstract] [Hide abstract] ABSTRACT: Since its discovery in 1995, tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) has sparked growing interest among oncologists due to its remarkable ability to induce apoptosis in malignant human cells, but not in most normal cells. However, one major drawback is its fast clearance rate in vivo. Thus, the development of an alternative means of delivery may increase the effectiveness of TRAIL-based therapy. In this study, we developed a secretory TRAIL-armed natural killer (NK) cell-based therapy and assessed its cytotoxic effects on colorectal cancer cells and its tumoricidal efficacy on colorectal peritoneal carcinomatosis xenograft. We generated genetically-modified NK cells by transduction with a lentiviral vector consisting of a secretion signal domain, a trimerization domain, and an extracellular domain of the TRAIL gene. These NK cells secreted a glycosylated form of TRAIL fusion protein that induced apoptotic death. Intraperitoneally-, but not intravenously-, injected NK cells effectively accumulated at tumor sites, infiltrated tumor tissue, induced apoptosis, and delayed tumor growth. These results shed light on the therapeutic potential of genetically engineered NK cells to treat peritoneal carcinomatosis.
    Article · Apr 2016 · Molecular Cancer Therapeutics
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    Lily Francis · Z.Sheng Guo · Zuqiang Liu · [...] · David L.Bartlett
    [Show abstract] [Hide abstract] ABSTRACT: An oncolytic poxvirus such as vvDD-CXCL11 can generate potent systemic antitumor immunity as well as targeted oncolysis, yet the antitumor effect is limited probably due to limited homing to and suppressed activity of tumor-specific adaptive immune cells in the tumor microenvironment (TME). We reasoned that a chemokine modulating (CKM) drug cocktail, consisting of IFN-α, poly I:C, and a COX-2 inhibitor, may skew the chemokine (CK) and cytokine profile into a favorable one in the TME, and this pharmaceutical modulation would enhance both the trafficking into and function of antitumor immune cells in the TME, thus increasing therapeutic efficacy of the oncolytic virus. In this study we show for the first time in vivo that the CKM modulates the CK microenvironment but it does not modulate antitumor immunity by itself in a MC38 colon cancer model. Sequential treatment with the virus and then CKM results in the upregulation of Th1-attracting CKs and reduction of Treg-attracting CKs (CCL22 and CXCL12), concurrent with enhanced trafficking of tumor-specific CD8+ T cells and NK cells into the TME, thus resulting in the most significant antitumor activity and long term survival of tumor-bearing mice. This novel combined regimen, with the oncolytic virus (vvDD-CXCL11) inducing direct oncolysis and eliciting potent antitumor immunity, and the CKM inducing a favorable chemokine profile in the TME that promotes the trafficking and function of antitumor Tc1/Th1 and NK cells, may have great utility for oncolytic immunotherapy for cancer.
    Full-text available · Article · Mar 2016 · Oncotarget