Canadian guidelines on the management of colorectal peritoneal metastases.

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.

Multidisciplinary management of locally advanced and metastatic cutaneous squamous cell carcinoma.

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 patient eligibility for surgery and rt, and an overview of the available systemic treatment options for advanced cscc and of the benefits of a multidisciplinary approach to patient management.

Locoregional management of in-transit metastasis in melanoma: an Ontario Health (Cancer Care Ontario) clinical practice guideline.

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-transit lesions. "Maximal itm" is defined as large-volume disease with multiple (>15-20) 2-3 cm nodules or subcutaneous or deeper lesions over a wide area.■ In patients presenting with minimal itm, complete surgical excision with negative pathologic margins is recommended. In addition to complete surgical resection, adjuvant treatment may be considered.■ In patients presenting with moderate unresectable itm, consider using this approach for localized treatment: intralesional interleukin 2 or talimogene laherparepvec as 1st choice, topical diphenylcyclopropenone as 2nd choice, or radiation therapy as 3rd choice. Evidence is insufficient to recommend intralesional bacille Calmette- Guérin or CO2 laser ablation outside of a research setting.■ In patients presenting with maximal itm confined to an extremity, isolated limb perfusion, isolated limb infusion, or systemic therapy may be considered. In extremely select cases, amputation could be considered as a final option in patients without systemic disease after discussion at a multidisciplinary case conference.■ In cases in which local, regional, or surgical treatments for itm might be ineffective or unable to be performed, or if a patient has systemic metastases at the same time, systemic therapy may be considered.

Guidelines on the use of cytoreductive surgery and hyperthermic intraperitoneal chemotherapy in patients with peritoneal surface malignancy arising from colorectal or appendiceal neoplasms.

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.

Gemcitabine-mediated tumour regression and p53-dependent gene expression: implications for colon and pancreatic cancer therapy.

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 14-3-3σ 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, 14-3-3σ 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.

Eastern Canadian colorectal cancer consensus conference: application of new modalities of staging and treatment of gastrointestinal cancers.

The annual Eastern Canadian Colorectal Cancer Consensus Conference was held in Ottawa, Ontario, October 22-23, 2010. Health care professionals involved in the care of patients with colorectal cancer participated in presentation and discussion sessions for the purpose of developing the recommendations presented here. This consensus statement addresses current issues in the management of colorectal cancer, such as the use of epidermal growth factor inhibitors in metastatic colon cancer, the benefit of calcium and magnesium with oxaliplatin chemotherapy, the role of microsatellites in treatment decisions for stage II colon cancer, the staging and treatment of rectal cancer, and the management of colorectal and metastatic pancreatic cancers.

Sentinel lymph node mapping and biopsy: a potentially valuable tool in the management of childhood extremity rhabdomyosarcoma.

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 pre-treatment 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.

Quality of cancer surgery: challenges and controversies.

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.

Prolongation of rat kidney allograft survival by nematodes.

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.

Development of a mouse aortic transplant model of chronic rejection.

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 > 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.