C. Giacomantonio - Academia.edu (original) (raw)

Papers by C. Giacomantonio

Current oncology (Toronto, Ont.), 2015

To meet the needs of patients, Canadian surgical and medical oncology leaders in the treatment of... more To meet the needs of patients, Canadian surgical and medical oncology leaders in the treatment of peritoneal surface malignancies (psms), together with patient representatives, formed the Canadian HIPEC Collaborative Group (chicg). The group is dedicated to standardizing and improving the treatment of psm in Canada so that access to treatment and, ultimately, the prognosis of Canadian patients with psm are improved. Patients with resectable psm arising from colorectal or appendiceal neoplasms should be reviewed by a multidisciplinary team including surgeons and medical oncologists with experience in treating patients with psm. Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy should be offered to appropriately selected patients and performed at experienced centres. The aim of this publication is to present guidelines that we recommend be applied across the country for the treatment of psm.

Transplantation, 1996

Nippostrongylus infection strongly stimulates TH2 activity in vivo. Given the evidence of cross r... more Nippostrongylus infection strongly stimulates TH2 activity in vivo. Given the evidence of cross regulation between TH2 and TH1 cells, and the link between TH1 activity and graft rejection, we examined the effects of Nippostrongylus infection on the fate of kidney allografts in rats. Both prior Nippostrongylus infection and prior treatment with a soluble worm product significantly delayed kidney allograft rejection. Control graft rejection occurred at 9.7 +/- 1.2 days whereas grafts in Nippostrongylus- or worm extract-treated recipients lasted 32.7 +/- 11.3 days and 21.5 +/- 4.6 days, respectively. At day 5 posttransplant mononuclear cell infiltration was much reduced in the Nippostrongylus-treated recipients. Flow cytometry of isolated graft-infiltrating leukocytes showed a marked decrease in infiltrating T cells (82.8% reduction) with both CD4+ cells (81.0% reduction) and CD8+ cells (84.6% reduction) being reduced. CD8+ T cells, in particular, made up a much smaller proportion of the graft-infiltrating cells (22% rather than 49%) in the Nippostrongylus-treated animals as compared with untreated controls. Immunohistochemical assay of the graft tissue confirmed the flow cytometric results. Interleukin 4 expression was clearly demonstrated by RT-PCR of the isolated graft-infiltrating leukocytes from the Nippostrongylus-treated recipients but not from the control recipients. These data are consistent with our current hypothesis that Nippostrongylus delays graft rejection by inducing a cross-regulatory suppression of TH1 activity.

Current oncology, 2020

Modern management of colorectal cancer (CRC) with peritoneal metastasis (PM) is based on a combin... more Modern management of colorectal cancer (CRC) with peritoneal metastasis (PM) is based on a combination of cytoreductive surgery (CRS), systemic chemotherapy, and hyperthermic intraperitoneal chemotherapy (HIPEC). Although the role of hipec has recently been questioned with respect to results from the PRODIGE 7 trial, the role and benefit of a complete CRS were confirmed, as observed with a 41-month gain in median survival in that study, and 15% of patients remaining disease-free at 5 years. Still, CRC with PM is associated with a poor prognosis, and good patient selection is essential. Many questions about the optimal management approach for such patients remain, but all patients with PM from CRC should be referred to, or discussed with, a PM surgical oncologist, because cure is possible. The objective of the present guideline is to offer a practical approach to the management of PM from CRC and to reflect on the new practice standards set by recent publications on the topic.

Non-melanoma skin cancers are the most prevalent form of cancer, with cutaneous squamous cell car... more Non-melanoma skin cancers are the most prevalent form of cancer, with cutaneous squamous cell carcinoma (cscc) being the 2nd most common type. Patients presenting with high-risk lesions associated with locally advanced or metastatic cscc face high rates of recurrence and mortality. Accurate staging and risk stratification for patients can be challenging because no system is universally accepted, and no Canadian guidelines currently exist. Patients with advanced cscc are often deemed ineligible for either or both of curative surgery and radiation therapy (rt) and, until recently, were limited to off-label systemic cisplatin-fluorouracil or cetuximab therapy, which offers modest clinical benefits and potentially severe toxicity. A new systemic therapy, cemiplimab, has been approved for the treatment of locally advanced and metastatic cscc. In the present review, we provide recommendations for patient classification and staging based on current guidelines, direction for determining pat...

Current Oncology

Objective: The purpose of this guideline is to provide guidance on appropriate management of sate... more Objective: The purpose of this guideline is to provide guidance on appropriate management of satellite and in-transit metastasis (itm) from melanoma. Methods: The guideline was developed by the Program in Evidence-Based Care (pebc) of Ontario Health (Cancer Care Ontario) and the Melanoma Disease Site Group. Recommendations were drafted by a Working Group based on a systematic review of publications in the medline and embase databases. The document underwent patient- and caregiver-specific consultation and was circulated to the Melanoma Disease Site Group and the pebc Report Approval Panel for internal review; the revised document underwent external review. Recommendations: “Minimal itm” is defined as lesions in a location with limited spread (generally 1–4 lesions); the lesions are generally superficial, often clustered together, and surgically resectable. “Moderate itm” is defined as more than 5 lesions covering a wider area, or the rapid development (within weeks) of new in-transi...

Surgical oncology clinics of North America, 2000

It is generally accepted that the quality of cancer surgery delivered to a patient impacts the pa... more It is generally accepted that the quality of cancer surgery delivered to a patient impacts the patient's overall prognosis significantly. Often, the fact that all surgery and surgeons are not equal is not considered. Furthermore, it should not be assumed that surgeons who perform a particular operation frequently perform it better. Using breast cancer, melanoma, and colorectal cancer as examples, this article illustrates that proper surgical education and training are paramount in assuring that both the selection and delivery of a particular procedure is appropriate in the management of cancer.

Cell Death and Disease, 2013

Gemcitabine is a chemotherapeutic that is widely used for the treatment of a variety of haematolo... more Gemcitabine is a chemotherapeutic that is widely used for the treatment of a variety of haematological malignancies and has become the standard chemotherapy for the treatment of advanced pancreatic cancer. Combinational gemcitabine regimes (e.g.with doxorubicin) are being tested in clinical trials to treat a variety of cancers, including colon cancer. The limited success of these trials has prompted us to pursue a better understanding of gemcitabine's mechanism of cell killing, which could dramatically improve the therapeutic potential of this agent. For comparison, we included gamma irradiation that triggers robust cell cycle arrest and Cr(VI), which is a highly toxic chemical that induces a robust p53-dependent apoptotic response. Gemcitabine induced a potent p53-dependent apoptosis that correlated with the accumulation of pro-apoptotic proteins such as PUMA and Bax. This is accompanied by a drastic reduction in p2l and 14-3-3r protein levels, thereby significantly sensitizing the cells to apoptosis. In vitro and in vivo studies demonstrated that gemcitabine required PUMA transcription to instigate an apoptotic programme. This was in contrast to Cr(VI)-induced apoptosis that required Bax and was independent of transcription. An examination of clinical colon and pancreatic cancer tissues shows higher p53, p21, 14-3-3r and Bax expression compared with matched normal tissues, yet there is a near absence of PUMA protein. This may explain why gemcitabine shows only limited efficacy in the treatment of these cancers. Our results raise the possibility that targeting the Bax-dependent cell death pathway, rather than the PUMA pathway, could result in significantly improved patient outcome and prognosis for these cancers.

Pediatric Surgery International, 2003

Multimodal therapy, involving surgery, chemotherapy and radiation, now dominates the management o... more Multimodal therapy, involving surgery, chemotherapy and radiation, now dominates the management of rhabdomyosarcoma (RMS) in childhood. Yet, despite improvements in these practices, extremity tumors continue to fare relatively poorly. Several investigators have identified prognostic factors that can be used to direct therapy and predict outcome. These factors include histology and metastatic disease, the latter requiring accurate staging to identify. The presence of lymph node metastases has been shown to be of prognostic significance and is incorporated into pretreatment staging schemes. Up to 50% of all surgically evaluated nodes and 17% of clinically negative nodes in extremity RMS may harbor tumor, underscoring the increased risk of understaging the disease if accurate lymph node dissection is not undertaken. Despite its importance, there appears to be no standard format by which regional nodal status is evaluated in extremity RMS. Sentinel lymph node mapping and biopsy are a minimally invasive technique, currently used in the staging of adult breast cancer and melanoma. In adults, the technique is associated with optimum nodal yield and low morbidity. We describe a case in which sentinel node mapping and dissection were used to easily and accurately stage a distal upper extremity alveolar RMS in a child with clinically and radiologically negative regional lymph nodes. The procedure yielded no positive nodes, was associated with no morbidity and spared the child more extensive radiotherapy. We propose the further evaluation of this simple and innovative technique in the overall management of this childhood malignancy.

…, 1995

Chronic rejection is the most common cause of late graft failure after solid organ transplantatio... more Chronic rejection is the most common cause of late graft failure after solid organ transplantation. A model of chronic rejection, the rat aortic allograft, has histologic features that parallel those in the vessels of human transplanted organs. However, the molecular tools required to dissect the immunology of chronic rejection are unavailable in the rat. We developed aortic transplantation in the mouse as a new model of chronic rejection. This will allow the use of the diversity of recombinant cytokines and monoclonal antibodies available for the mouse and its well-defined genetics to investigate chronic rejection in greater detail. We describe the perioperative care and surgical technique for the model in which a 1 cm segment of donor thoracic aorta was used to replace a section of recipient abdominal aorta below the renal arteries and above the aortic bifurcation. Mortality rates were initially high (70%) due to thrombosis and shock. Changes in technique and operator facility resulted in a high rate of success (75%). After 192 operations, the current success rate is &amp;amp;amp;gt; 80%. Mice free from complications at 12 hrs postop had indefinite survival, and after 2 months the typical vascular lesion of chronic rejection was present. This new model of chronic rejection will be a valuable tool to study the molecular immunology and genetics of chronic rejection.

Current Oncology, 2013

from across Eastern Canada for the purpose of recommending management strategies for patients wit... more from across Eastern Canada for the purpose of recommending management strategies for patients with colorectal cancer (crc) and other selected gastrointestinal cancers. 1.1 Terms of Reference The participants in the 2011 Eastern Canadian Colorectal Cancer Consensus Conference consisted of oncology professionals from across Ontario, Quebec, and the Atlantic provinces. Several invited participants from Western Canada also attended. The target audience for this report is primarily health care professionals involved in the care of patients with crc and other selected gastrointestinal cancers. The report provides information about standards of care to administrators responsible for program funding decisions and to key players in the implementation of best practices. While not specifically targeted to patients, the report also provides information that may be useful in guiding patients who must make decisions about their own care. 1.2 Basis of Recommendations The recommendations provided here are based on presentation and discussion of the best available evidence. Where applicable, references are cited.

European Journal of Cancer Supplements, 2010

International Journal of Oncology, 2004

Immunotherapy based on the administration of the mycobacterium bacillus Calmette-Guerin has been ... more Immunotherapy based on the administration of the mycobacterium bacillus Calmette-Guerin has been successfully used in the treatment of in situ transitional cell bladder cancer, and may be applicable to the treatment of cutaneous malignant melanoma. Antigen 85A (Ag85A) and heat shock protein 65 kDa (hsp65) are major secreted proteins of Mycobacterium species and potent stimulators of cell-mediated immunity. This study evaluated the ability of Ag85A and hsp65 gene transfection to limit tumor growth by B16-F10 mouse melanoma cells. Immunoblotting confirmed protein expression and secretion by B16-F10 cells that were transiently transfected with plasmid DNA containing the Ag85A or hsp65 gene. Groups of syngeneic C57BL/6 mice were injected subcutaneously with 1x10(5) untransfected B16-F10 cells or B16-F10 cells transiently transfected with either empty vector or vector containing the Ag85A or hsp65 gene. Ag85A-expressing B16-F10 cells exhibited a dramatic 76% reduction (p&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt;0.05, Mann-Whitney U test) in tumor weight in comparison to empty vector controls at 14 days post-inoculation. In contrast, hsp65-transfected B16-F10 cells did not show any change in tumorigenicity. Decreased tumorigenicity by Ag85A-transfected B16-F10 cells was not due to a reduced ability of Ag85A-transfected B16-F10 cells to proliferate since both mock- and Ag85A-transfected B16-F10 cells showed increased in vitro proliferation in comparison to untransfected cells. Hematoxylin and eosin staining revealed that Ag85A-transfected B16-F10 tumors contained an inflammatory leukocyte infiltrate that was not present in hsp65-transfected tumors. Reduced tumor progression by Ag85A-transfected B16-F10 melanoma cells suggests that immunotherapy based on the transient induction of Ag85A expression may be an effective approach for the treatment of cutaneous malignant melanoma.

Neoplasia, 2014

INTRODUCTION: Incisional biopsies, including the diagnostic core needle biopsy (CNB), routinely p... more INTRODUCTION: Incisional biopsies, including the diagnostic core needle biopsy (CNB), routinely performed before surgical excision of breast cancer tumors are hypothesized to increase the risk of metastatic disease. In this study, we experimentally determined whether CNB of breast cancer tumors results in increased distant metastases and examine important resultant changes in the primary tumor and tumor microenvironment associated with this outcome. METHOD: To evaluate the effect of CNB on metastasis development, we implanted murine mammary 4T1 tumor cells in BALB/c mice and performed CNB on palpable tumors in half the mice. Subsequently, emulating the human scenario, all mice underwent complete tumor excision and were allowed to recover, with attendant metastasis development. Tumor growth, lung metastasis, circulating tumor cell (CTC) levels, variation in gene expression, composition of the tumor microenvironment, and changes in immunologic markers were compared in biopsied and non-biopsied mice. RESULTS: Mice with biopsied tumors developed significantly more lung metastases compared to non-biopsied mice. Tumors from biopsied mice contained a higher frequency of myeloid-derived suppressor cells (MDSCs) accompanied by reduced CD4+ T cells, CD8+ T cells, and macrophages, suggesting biopsy-mediated development of an increasingly immunosuppressive tumor microenvironment. We also observed a CNB-dependent up-regulation in the expression of SOX4, Ezh2, and other key epithelial-mesenchymal transition (EMT) genes, as well as increased CTC levels among the biopsy group. CONCLUSION: CNB creates an immunosuppressive tumor microenvironment, increases EMT, and facilitates release of CTCs, all of which likely contribute to the observed increase in development of distant metastases. Neoplasia (2014) 16, 950-960 www.neoplasia.com Volume 16 Number 11 November 2014 pp. 950-960 950

Molecular Therapy, 2009

Recent evidence suggests that cancer stem cells (CSCs) play an important role in cancer, as these... more Recent evidence suggests that cancer stem cells (CSCs) play an important role in cancer, as these cells possess enhanced tumor-forming capabilities and are resistant to current anticancer therapies. Hence, novel cancer therapies will need to be tested for both tumor regression and CSC targeting. Herein we show that oncolytic reovirus that induces regression of human breast cancer primary tumor samples xenografted in immunocompromised mice also effectively targets and kills CSCs in these tumors. CSCs were identified based on CD24(-)CD44(+) cell surface expression and overexpression of aldehyde dehydrogenase. Upon reovirus treatment, the CSC population was reduced at the same rate as non-CSCs within the tumor. Immunofluorescence of breast tumor tissue samples from the reovirus- and mock-treated mice confirmed that both CSCs and non-CSCs were infectible by reovirus, and terminal deoxynucleotidyl transferase biotin-dUTP nick end labeling (TUNEL) assay showed that both populations died by apoptosis. Ras, which has been shown to mediate reovirus oncolysis, was found to be present at similar levels in all cell types, and this is consistent with their comparable sensitivity to reovirus. These experiments indicate that oncolytic reovirus has the potential to induce tumor regression in breast cancer patients. More important, the CSC population was equally reduced and was as susceptible to reovirus treatment as the non-CSC population.

Journal of Surgical Oncology, 2012

Background: Malignant triton tumors (MTT) are a rare form of peripheral nerve sheath tumors that ... more Background: Malignant triton tumors (MTT) are a rare form of peripheral nerve sheath tumors that follows a particularly aggressive course. Given its rarity, only case reports and small series of patients have been published. Methods: A Pubmed search was conducted using the terms ''triton tumor,'' ''rhabdomyosarcoma,'' and ''malignant peripheral nerve sheath tumor.'' The reference lists of retrieved articles were searched. Cases were included when the diagnosis was clear, the patient underwent surgery, and follow-up data were available. Univariate and multivariate analyses were conducted for predictors of positive resection margin, local recurrence/progression, development of metastases, and mortality. Results: A total of 124 cases were included. The overall 5-year survival was 14% and the median time to death was 13 months. The overall local recurrence/progression rate was 50% and the median time to recurrence/progression was 6 months. On multivariate Cox proportional hazards analysis, positive margin status (HR 2.2, P ¼ 0.01), local recurrence/progression (HR 3.1, P ¼ 0.003), and development of metastases (HR 2.6, P ¼ 0.003) were associated with mortality. Adjuvant radiotherapy was associated with improved survival (HR 0.4, P ¼ 0.005). Conclusion: Complete surgical resection and adjuvant radiotherapy should be the cornerstones of treatment for MTT.