Harold J. Wanebo

Landmark Medical Center, Вунсокет, Rhode Island, United States

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Publications (258)1084.49 Total impact

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    ABSTRACT: Exogenous cell-permeable C6 ceramide has been demonstrated to act synergistically with chemotherapeutic drugs, including paclitaxel, cisplatin, doxorubicin and the histone deacetylase inhibitor, trichostatin A, to induce cell death in a variety of cancer cells. We previously demonstrated that C6 ceramide and paclitaxel function synergistically to induce ovarian cancer cell death via modulation of the PI3/AKT cell survival pathway. In the present study, the entry pattern of C6 ceramide into ovarian cancer cells was investigated using fluorescent short chain C6-NBD sphingomyelin (C6-NBD). Confocal microscopy revealed that C6-NBD enters the cells in a polarized pattern, characterized by marked signals at one cellular end, representing a likely mitosis initiation site. Pretreatment of the cells with filipin, an inhibitor of the lipid raft/caveolae endocytosis pathway, decreases C6-NBD entry into the cells. A pretreatment with the water channel inhibitor, CuSO4, was also found to reduce the entry of C6-NBD. Notably, the pretreatment with paclitaxel was shown to disrupt the polarized entry of C6-NBD into the cells, resulting in an even distribution of C6-NBD in the cytoplasm. In addition, the pretreatment of the cells with paclitaxel destabilized the cytoskeletal proteins, releasing an increased number of short tubulin fragments. The results of the present study indicate that C6 ceramide preferentially enters the cells via a predetermined initiation site of mitosis. In addition to diffusion, short chain C6 ceramide may also enter cells via water channels and caveolae-mediated endocytosis. Paclitaxel disrupts the cell cytoskeleton and induces an even distribution of C6 ceramide in the cytoplasm resulting in synergistic ovarian cancer cell death.
    Full-text · Article · Jun 2013 · Oncology letters
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    ABSTRACT: Objectives: To assess the effect on progression-free and overall survival from the addition of cetuximab to paclitaxel-based chemoradiation for patients with squamous cell head and neck cancer from Brown University Oncology Group studies. Methods: BrUOG HN-204 patients with stage III or IV locally advanced squamous cell cancer of the head and neck without distant organ metastases received 4 weeks of induction cetuximab followed by weekly cetuximab, paclitaxel, carboplatin, and concurrent radiation. Recurrence and survival data were compared with previous Brown University studies utilizing the same paclitaxel-based chemoradiation with and without induction chemotherapy. Results: The progression-free survival and overall survival at 3 years for all 37 patients initiating chemoradiation was 54% and 57%, respectively. All surviving patients were followed for at least 3 years and the median follow-up is 4.4 years. Of 14 patients who recurred within 3 years, 7 patients recurred locally only, 5 had a systemic recurrence, and 2 recurred both locally and systemically. Conclusions: The addition of cetuximab to paclitaxel, carboplatin, and radiation achieves overall survival that is virtually identical to prior Brown University Oncology Group studies of paclitaxel-based chemoradiation without cetuximab. Improvements in locoregional control are needed despite the use of 3 agents to enhance the effects of radiation.
    No preview · Article · Dec 2012 · American journal of clinical oncology
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    ABSTRACT: An overview of colorectal cancer discussed (Philip Paty) the good outcome after primary management with local control in 90-95 % of colon and 85 % in rectal cancer patients with major progression to metastases and to death related to hematogenous dissemination. The major disease pathways include the APC, aneuploid pathway involving mutations of P53, KRAS, SMAD 4, or the CMP/MSI pathway, mismatched repair defect as characterized by Lynch syndrome, the major hereditary form which may also have KRAS and P53 mutations. The common sporadic colorectal cancers are MS1 high, with many patients having BRAF and KRAS mutations. The sentinel node biopsy in colorectal cancer surgery may provide more definitive staging and perhaps modification of the extent of resection with better outcome as suggested by Dr. Saha. The identification of sentinel lymph nodes outside of the planned bowel resection may increase the resection biologically indicated by the sentinel lymph node location leading to better outcome. In a small study by Dr. Saha, the operation was enhanced in 21 % by extending the length of bowel resection, which increased node recovery to 18.5 nodes versus 12 nodes with the more conventional resection, increasing nodal recovery, and positivity to 60 % with reduction to five year recurrence rate to 9 % versus 27 % with the conventional resection. A new (Swiss) technique for pathologic node examination, the OSNA (the One Step Nucleic Acid diagnostic system), was presented which demonstrated increased detection of micro-metastases in a focused pathology study of 22 patients (Zuber) to 11 out of 15 patients versus the 7 micro-metastases identified by the standard single slide per node, and compared to 14 out of 15 with an intensive multi-slide technique. This suggests value in pursuing OSNA study by other centers with relevant clinical trials to establish its true value. An analysis of liver resection for metastatic colorectal cancer (CRC) emphasized the value of 10-year follow-up (DeAngelica). The 10-year survival of 102 patients among 612 patients was 17 % (Memorial Sloan Kettering data). At the five-year point 99 of 102 survivors were NED and 86 have been free of disease since the resection. The usual five-year figure after hepatic resection reveals that one-third of five-year survivors die from recurrence of distant disease suggesting the value of longer term follow-up in these patients. An additional question reviewed related to the role of neoadjuvant systemic chemotherapy (with response rates in the 50 % range) to produce down staging of the hepatic metastases and allow one to retrieve these patients with possible residual disease. In a series of 116 patients who had hepatic resection of CRC metastases in presence of regional node metastases, post neoadjuvant chemotherapy (normally not candidates for resection) these patients were demonstrated to have a 95 % recurrence at median time of 9 months. This raises a cautionary note to the literature report of five-year survivals in the 20-30 % range for hepatic metastases in presence of extra hepatic disease. Such may reflect patient selection rather than a true measure of the biology of disease, and warrant clinical trial evaluation. Lastly, regional therapy and overall systemic therapy were addressed by Dr. Kemeny. The CALGB study of hepatic artery infusion (HAI) with FUDR, dexamethasone versus 5FU leucovorin showed an overall survival of 24.4 months with HAI versus 20 months with systemic therapy (P = 0.0034). An adjuvant trial of HAI at MSK in 156 patients showed an overall survival benefit at 2 year and recent long term 10yr follow-up showing a significant overall survival of 41 % with HAI versus 27 % with systemic therapy (5FU leucovorin). In the neoadjuvant Nordlinger trial for hepatic metastases, there was a significant outcome differences-the preoperative therapy group had 9.2 % increase of progression free survival versus the surgery alone group which suggests the value of combining neoadjuvant surgery in good risk liver resection candidates. Conclude the final lesson from this well presented mini symposium confirms the need for continued evaluation of the numerous discussion points by clinical trial.
    No preview · Article · Oct 2012 · Clinical and Experimental Metastasis
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    ABSTRACT: A major challenge to nanomaterial-based medicine is the ability to release drugs on-command. Here, we describe an innovative drug delivery system based on carbon nanotubes (CNTs), in which compounds can be released inside cells from within the nanotube "on-command" by inductive heating with an external alternating current or pulsed magnetic field. Without inductive heating the drug remains safely inside the CNTs, showing no toxicity in cell viability tests. Similar to the "Trojan-Horse" in function, we demonstrate the delivery of a combination of chemotherapeutic agents with low aqueous solubility, paclitaxel (Taxol), and C6-ceramide, to multidrug resistant pancreatic cancer cells. Nanotube encapsulation permitted the drugs to be used at a 100-fold lower concentration compared to exogenous treatment yet achieve a comparable ∼70% cancer kill rate.
    Full-text · Article · Oct 2012 · Nano Letters
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    Constantine P Karakousis · Harold Wanebo

    Preview · Article · Sep 2012 · International Journal of Surgical Oncology
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    ABSTRACT: Background: Ten- to 15-year survival results were analyzed from a prospective multi-institutional randomized surgical trial that involved 740 stages I and II melanoma patients with intermediate thickness melanomas (1.0 to 4.0 mm) and compared elective (immediate) lymph node dissection (ELND) with clinical observation of the lymph nodes as well as prognostic factors that independently predict outcomes. Methods: Eligible patients were stratified according to tumor thickness, anatomical site, and ulceration, and then prerandomized to either ELND or nodal observation. By using Cox stepwise multivariate regression analysis, the independent predictors of outcome were tumor thickness ( P , .001), the presence of tumor ulceration (P , .001), trunk site (P 5 .003), and patient age more than 60 years (P 5 .01). Results: Overall 10-year survival was not significantly different for patients who received ELND or nodal observation (77% vs. 73%; P 5 .12). Among the prospectively stratified subgroups of patients, 10-year survival rates favored those patients with ELND, with a 30% reduction in mortality rate for the 543 patients with nonulcerated melanomas (84% vs. 77%; P 5 .03), a 30% reduction in mortality rate for the 446 patients with tumor thickness of 1.0 to 2.0 mm (86% vs. 80%; P 5 .03), and a 27% reduction in mortality rate for 385 patients with limb melanomas (84% vs. 78%; P 5 .05). Of these subgroups, the presence or absence of ulceration should be the key factor for making treatment recommendations with regard to ELND for patients with intermediate thickness melanomas. Conclusions: These long-term survival rates from patients treated at 77 institutions demonstrate that ulceration and tumor thickness are dominant predictive factors that should be used in the staging of stages I and II melanomas, and confer a survival advantage for these subgroups of prospectively defined melanoma patients.
    No preview · Article · Apr 2012 · Annals of Surgical Oncology
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    ABSTRACT: The long-term outcomes of selective organ preservation in operable, locally advanced head and neck cancers in two sequential chemoradiotherapy (CRT) protocols (HN-53, HN-67) are reported. A total of 65 patients were treated with CRT consisting of carboplatin (AUC=1/week) and paclitaxel (60 or 40 mg/m2/week) with radiation (1.8 Gy/day). After 5 weeks of CRT, if primary site biopsies were pathologically negative, then completion CRT to 67-72 Gy was done with neck dissection in node-positive cases. Alternatively, a positive rebiopsy required primary site resection and neck dissection followed by radiotherapy boost as deemed necessary. Pathologic complete responses occurred in 71% patients who then completed CRT; the remaining 29% patients underwent primary site surgery. The 5-year and median overall survival were 47% and 57 months with no statistically significant differences between the two groups. Overall long-term failure rates were: 6% local, 6% regional, and 32% distant. This strategy of selective organ preservation was effective in 71% patients with CRT, whereas salvage surgery was required in the remainder. Long-term survival was equivalent in both treatment groups.
    No preview · Article · May 2011 · Annals of Surgical Oncology
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    ABSTRACT: To perform a phase II trial evaluating dose dense induction chemotherapy for locally advanced head and neck cancer. Thirty-five patients received 6 weekly doses of carboplatin (area under the curve=2) and paclitaxel (135 mg/m) followed by concurrent weekly paclitaxel (40 mg/m) and carboplatin (area under the curve=1) and daily radiation (66-72 Gy). There was 1 induction death from neutropenic sepsis and 1 sudden death during chemoradiotherapy. The overall response rate with induction was 79%. With >40 months of follow-up, the 36-month overall survival was 67% and squamous cell carcinoma of the head and neck survival 84%. Patients undergoing biopsy of the primary tumor site after the therapies had 17/18 (94%) pathologic complete response rate. The locoregional relapse rate was 40% (24 mo 28%) and distant relapse rate was 8% with only 1 distant site. Therapy was active but patients must be carefully selected and monitored. Compared with the historical controls, dose dense and intense induction chemotherapy decreased distant failure rate without compromising the locoregional control.
    No preview · Article · Feb 2011 · American journal of clinical oncology
  • Harold Wanebo

    No preview · Article · Dec 2010 · Journal of Surgical Oncology
  • Harold J Wanebo · David Berz
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    ABSTRACT: Liver metastasis represents a common systemic complication of colorectal cancers (CRCs). Partial liver resection has been demonstrated to result in long-term survival in certain well-selected patients with otherwise well-controlled systemic disease. Neoadjuvant therapy has been demonstrated to result in improved resectability and potentially longer survival in patients with liver metastases from CRC. The addition of biologic agents to chemotherapy has been shown to improve response rates and overall survival in patients with metastatic CRC. Here, we are discussing the role of biologic agents in the treatment of patients with liver metastases from CRC. We also discuss the role of biomarkers for response and resistance to such novel therapies.
    No preview · Article · Dec 2010 · Journal of Surgical Oncology
  • H Wanebo
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    ABSTRACT: No abstract is available for this article.
    No preview · Article · Dec 2010 · Journal of Surgical Oncology
  • Kimberly A Varker · Harold J Wanebo
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    ABSTRACT: Although the incidence of locally recurrent colorectal cancer has been reduced by improved surgical techniques and the frequent use of multimodality therapy, pelvic recurrence remains a significant problem. Radiation or chemotherapy may provide palliation but it is often short-lived. For fit candidates without evidence of extrapelvic disease, surgical resection (anterior resection, abdominoperineal resection, pelvic exenteration, or abdominosacral resection) may be the most appropriate treatment. For patients with unresectable disease, isolated pelvic perfusion may provide effective palliation.
    No preview · Article · Jun 2010 · Journal of Surgical Oncology
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    ABSTRACT: To determine the feasibility and toxicity of the addition of cetuximab to paclitaxel, carboplatin, and concurrent radiation for patients with head and neck cancer. Patients with stage III or IV locally advanced squamous cell cancer of the head and neck, without distant organ metastases, were eligible. Patients received 4 weeks of induction cetuximab followed by weekly cetuximab, paclitaxel, carboplatin, and concurrent radiation. Thirty-two patients were assessable for chemoradiation toxicities. Grade 3 and grade 4 mucositis occurred in 53% and 16% of patients, respectively. Grade 3 and grade 4 radiation dermatitis occurred in 44% and 9% of patients, respectively. Grade 3/4 radiation dermatitis was associated with the use of intensity modulated radiation therapy (64% vs.14%, respectively, P < 0.0001). Grade 3 and grade 4 cetuximab associated acneiform rash developed in 6% and 3% of patients. Overall 21 patients (66%) had any grade 3 toxicity and 10 patients (31%) had any grade 4 toxicity. The percentages of the intended total dose delivered of carboplatin, cetuximab, paclitaxel, and radiation were 86%, 89%, 89%, and 96%, respectively. Cetuximab, when combined with paclitaxel, carboplatin and intensity modulated radiation therapy, increases dermatologic toxicity but does not increase mucosal toxicity as compared with previous Brown University Oncology Group studies of paclitaxel, carboplatin, and conventional radiation for patients with head and neck cancer.
    No preview · Article · Sep 2009 · American journal of clinical oncology

  • No preview · Article · May 2009 · Gastroenterology
  • Giovanni Begossi · James F Belliveau · Harold J Wanebo
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    ABSTRACT: Isolated pelvic perfusion (IPP) is a form of intra-arterial local-regional treatment of tumor-bearing organs. IPP using a simplified balloon occlusion technique has shown promise in palliation of resectability of advanced rectal cancer in patients not amenable to treatment with conventional chemoradiation. This article reviews technique criteria and the response to IPP from seven literature studies of isolated pelvic perfusion with colorectal cancer. Current efforts should be directed to improving anti-tumor responses by optimizing chemotherapeutic protocols and modifying perfusion parameters, so that hopefully, this will lead to a more standardized and improved procedure for the isolated pelvic perfusion technique.
    No preview · Article · Nov 2008 · Surgical Oncology Clinics of North America
  • James F Belliveau · Harold J Wanebo
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    ABSTRACT: The pharmacokinetic results of this study indicate that there is significant enhancement of pelvic drug levels with isolated pelvic perfusion, with the potential of increasing the therapeutic index and clinical efficacy. This system would seem to be ideal for evaluating fast-acting and highly toxic experimental drugs on human pelvic cancers having treatment protocols of limited clinical success. Pharmacokinetic modeling using empiric approximations for the kinetic rate constants is a convenient and novel way of fitting data using relatively simple mathematics and commercially available spreadsheets.
    No preview · Article · Nov 2008 · Surgical Oncology Clinics of North America
  • Harold J Wanebo
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    ABSTRACT: No abstract is available for this article.
    No preview · Article · Sep 2008 · Journal of Surgical Oncology
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    ABSTRACT: Previously irradiated recurrent rectal cancer is a formidable patient threat with limited treatment options. Isolated pelvic perfusion (IPP) by the balloon-occlusion technique provides high-dose regional chemotherapy that may facilitate resection if appropriate or palliate pain and fungating tumor mass in the symptomatic patient. We currently report our results in 49 recurrent rectal cancer patients (26 had neoadjuvant IPP with intent to resect and 23 had IPP for palliation). IPP was done for 1 hour with paclitaxel 30 mg/m(2), 5 fluorouracil 1500 mg/m(2), cisplatin/oxaliplatin 60-130 mg/m(2), and mitomycin C 10 to 15 mg/m(2) (the latter three achieving pelvic-to-systemic drug ratios of 6-9:1). Neoadjuvant perfusion in 26 patients achieved a response in 14 patients (made resectable). Seven had R0 resections (clear margins), six by abdominal sacral resection (ABSR), and one by an extended APR. Of seven other patients, one had a complete pathologic response negating planned resection, one had >50% tumor regression in pelvis (but developed distant metastases), and three refused ABSR. Planned ABSR in two patients was aborted because of complicating cardiovascular issues. A variety of medical and cancer issues precluded resection in the remaining 12 of these 26 neoadjuvant patients. Within the neoadjuvant group, median survival was 24 months in the responding (made resectable) group (14 patients) and it was 8 months in the non-resectable group (12 patients), p = 0.0001. In the responding (made resectable) group, seven patients had R0 resections (median survival 26 months) and seven patients were not resected (median survival 18 months), p = 0.0198. In the IPP group for palliation, 17 of 23 patients (74%) had significant relief of pain, and other tumor-related symptoms (mean survival 11 months). Isolated pelvic perfusion using a simplified balloon-occlusion technique has promise in palliation of or augmenting resectability of advanced rectal malignancy in patients not amenable to treatment with conventional modalities.
    No preview · Article · Apr 2008 · Annals of Surgical Oncology
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    ABSTRACT: Background.A phase II study was conducted using concurrent paclitaxel, carboplatin, and external beam radiotherapy (RT) in patients with advanced head and neck cancer.Methods.Forty-three patients (stage III, n = 12; stage IV, n = 31) were treated with 8 cycles of weekly paclitaxel (60 mg/m2), carboplatin (area under the curve [AUC] = 1), and RT (1.8 Gy daily; total dose, 66–72 Gy). Patients with initially palpable lymph nodes underwent neck dissection.Results.The overall clinical response rate was 91% (65% complete, 26% partial). Severe mucositis occurred in 37 (90%) patients, necessitating hospitalization in 13 (31%) patients. With a median follow-up of 49 months, the locoregional and distant failure rates were 26% and 21%, respectively.Conclusions.Concurrent paclitaxel, carboplatin, and RT for advanced head and neck cancer results in high complete response rates. Long-term follow-up has revealed the curative potential of this regimen, though the doses used resulted in unacceptable toxicity. © 2007 Wiley Periodicals, Inc. Head Neck 2008
    Preview · Article · Mar 2008 · Head & Neck
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    ABSTRACT: To determine the feasibility and toxicity of the addition of cetuximab with paclitaxel, carboplatin, and radiation for patients with esophagogastric cancer on a Phase II study. Patients with locoregional esophageal and proximal gastric cancer without distant organ metastases were eligible. All patients received cetuximab, paclitaxel, and carboplatin weekly for 6 weeks with 50.4 Gy radiation. Sixty patients were enrolled, 57 with esophageal cancer and 3 with gastric cancer. Forty-eight had adenocarcinoma and 12 had squamous cell cancer. Fourteen of 60 patients (23%) had Grade 3 dermatologic toxicity consisting of a painful, pruritic acneiform rash on the face outside of the radiation field. The rates of Grades 3 and 4 esophagitis were 12% and 3%, respectively. Three patients had Grade 3/4 cetuximab hypersensitivity reactions and were not assessable for response. Forty of 57 patients (70%) had a complete clinical response after chemoradiation. Cetuximab can be safely administered with chemoradiation for esophageal cancer. Dermatologic toxicity and hypersensitivity reactions were associated with the addition of cetuximab. There was no increase in esophagitis or other radiation-enhanced toxicity.
    No preview · Article · Mar 2008 · International Journal of Radiation OncologyBiologyPhysics

Publication Stats

10k Citations
1,084.49 Total Impact Points


  • 2010-2013
    • Landmark Medical Center
      Вунсокет, Rhode Island, United States
  • 1998-2012
    • Boston University
      • • Department of Medicine
      • • Department of Surgery
      Boston, Massachusetts, United States
  • 1989-2012
    • Brown University
      • • Department of Surgery
      • • Division of Surgical Oncology
      • • Department of Medicine
      Providence, Rhode Island, United States
  • 1992-2008
    • Roger Williams University
      Bristol, Rhode Island, United States
  • 2006
    • University of Maryland, Baltimore
      Baltimore, Maryland, United States
  • 1974-2006
    • Memorial Sloan-Kettering Cancer Center
      • • Department of Medicine
      • • Department of Surgery
      • • Gynecology Service
      New York City, New York, United States
  • 2005
    • Renji Hospital
      Shanghai, Shanghai Shi, China
  • 1982-2004
    • University of Virginia
      • Department of Surgery
      Charlottesville, Virginia, United States
  • 2001
    • University of Rhode Island
      Kingston, Rhode Island, United States
  • 1992-2000
    • Alpert Medical School - Brown University
      • Department of Surgery
      Providence, Rhode Island, United States
  • 1999
    • University of Groningen
      Groningen, Groningen, Netherlands
    • Beverly Hospital, Boston MA
      Beverly, Massachusetts, United States
  • 1996
    • Northern Inyo Hospital
      BIH, California, United States
  • 1990-1996
    • Rhode Island Hospital
      Providence, Rhode Island, United States
  • 1986
    • Mount Sinai Medical Center
      New York, New York, United States
    • University of Alabama at Birmingham
      • Department of Biostatistics
      Birmingham, Alabama, United States