Biomarkers and targeted therapeutics in colorectal cancer.

The development of colorectal cancer is characterized by a multitude of molecular events that can occur through the pathways of loss of heterozygosity, microsatellite instability, and CpG-island methylation. The accumulation of these molecular events ultimately results in polyps formed from previously normal mucosa to develop the fundamental characteristics of cancerization: uncontrolled proliferation, growth, and invasion. Advances in the understanding of molecular events leading to colorectal cancer have led to the development of biomarkers, patient-specific and tumor-specific molecular signatures that have potential as tools for accurate risk assessment, personalized treatment planning, development of targeted agents, and evaluation of treatment response.

Soft tissue tumors of the anorectum: rare, complex and misunderstood.

Anorectal soft tissue tumors are uncommon and often present both diagnostic and therapeutic challenges. Although many of these tumors are identified with imaging performed for unrelated reasons, most present with nonspecific symptoms that can lead to a delay in diagnosis. Historically, radical surgery (abdominoperineal resection) has been the mainstay of treatment for both benign and malignant anorectal soft tissue tumors. However, a lack of proven benefit in benign disease along with changes in technology has called this practice into question. In addition, the role of radiation and/or chemotherapy remains controversial. In this manuscript, we review the history and current status of anorectal soft tissue tumor management, with a particular focus on challenges in optimizing survival.

Postoperative adjuvant chemotherapy use in patients with stage II/III rectal cancer treated with neoadjuvant therapy: a national comprehensive cancer network analysis.

PURPOSE: Practice guidelines recommend that patients who receive neoadjuvant chemotherapy and radiation for locally advanced rectal cancer complete postoperative adjuvant systemic chemotherapy, irrespective of tumor downstaging. PATIENTS AND METHODS: The National Comprehensive Cancer Network (NCCN) Colorectal Cancer Database tracks longitudinal care for patients treated at eight specialty cancer centers across the United States and was used to evaluate how frequently patients with rectal cancer who were treated with neoadjuvant chemotherapy also received postoperative systemic chemotherapy. Patient and tumor characteristics were examined in a multivariable logistic regression model. RESULTS: Between September 2005 and December 2010, 2,073 patients with stage II/III rectal cancer were enrolled in the database. Of these, 1,193 patients receiving neoadjuvant chemoradiotherapy were in the analysis, including 203 patients not receiving any adjuvant chemotherapy. For those seen by a medical oncologist, the most frequent reason chemotherapy was not recommended was comorbid illness (25 of 50, 50%); the most frequent reason chemotherapy was not received even though it was recommended or discussed was patient refusal (54 of 74, 73%). After controlling for NCCN Cancer Center and clinical TNM stage in a multivariable logistic model, factors significantly associated with not receiving adjuvant chemotherapy were age, Eastern Cooperative Oncology Group performance status ≥ 1, on Medicaid or indigent compared with private insurance, complete pathologic response, presence of re-operation/wound infection, and no closure of ileostomy/colostomy. CONCLUSION: Even at specialty cancer centers, a sizeable minority of patients with rectal cancer treated with curative-intent neoadjuvant chemoradiotherapy do not complete postoperative chemotherapy. Strategies to facilitate the ability to complete this third and final component of curative intent treatment are necessary.

Metastasectomy for stage IV colorectal cancer.

Metastatic colorectal cancer traditionally has been considered incurable. Over the past 3 decades, however, resection of low-volume hepatic disease has been recognized as beneficial in some cases. More recently, resection of isolated pulmonary metastases has been shown to offer long-term survival in carefully selected patients. Resection of metastases to more unusual sites (ovary, brain, peritoneal cavity) is more controversial; nevertheless, retrospective data suggest that a few patients may be cured with resection of these tumors. In this article, we review the history and current status of metastasectomy in stage IV colorectal cancer.

Inhibition of hyaluronan synthase-3 decreases subcutaneous colon cancer growth in mice.

PURPOSE: Hyaluronan and hyaluronan synthases have been implicated in cancer progression. Hyaluronan synthase-3 is up-regulated in metastatic colon cancer cells (SW620), and its expression mediates cellular growth in vitro. We hypothesized that inhibition of hyaluronan synthase-3 would decrease tumor formation and/or alter the pattern of metastasis in mouse models of colon cancer growth. METHODS: Hyaluronan synthase-3 was inhibited in SW620 cells by transfection with small interfering RNA (silenced cells); a scrambled sequence served as a negative control. To study primary tumor growth, transfected cells were injected into the flanks of BALB/c nude mice. To study metastasis, an orthotopic model was used. Metastases were confirmed histologically. Student t test and Fisher exact probability test were used for statistical analysis. RESULTS: Inhibition of hyaluronan synthase-3 significantly decreased subcutaneous tumor growth; tumor weight was 0.94 +/- 0.17 g in the hyaluronan synthase-3-silenced group vs 1.70 +/- 0.26 g in the control scrambled group (P < .01). In contrast, metastases were similar in both groups: liver metastases were present in 22% of the silenced group vs 11% of the scrambled group; lung metastases were present in 6% of the silenced group vs 0% of the scrambled group (P = not significant). CONCLUSION: Inhibition of hyaluronan synthase-3 expression in SW620 colon cancer cells decreases subcutaneous tumor growth in mice, but has less of an effect on lung and liver metastases. This observation suggests that hyaluronan synthase-3 may enhance primary colon cancer growth.

Retrorectal tumors.

Retrorectal or presacral tumors are rare and can be challenging to diagnose and treat. Because the retrorectal space contains multiple embryologic remnants derived from various tissues, the tumors that develop in this space are heterogeneous. Most lesions are benign, but malignant neoplasms are not uncommon. Lesions are classified as congenital, neurogenic, osseous, inflammatory, or miscellaneous. Although treatment depends on diagnosis and anatomic location, most retrorectal lesions will require surgical resection.

Anastomotic sinuses after ileoanal pouch construction: incidence, management, and outcome.

PURPOSE: This study was designed to analyze the incidence, management, and outcome of pouch sinuses after ileal pouch-anal anastomosis at one institution. METHODS: We identified 282 ileal pouch-anal anastomosis patients between 1992 and 2002 who had a pouchogram before planned ileostomy closure. The management and outcome of patients with pouchograms revealing pouch sinuses were reviewed. RESULTS: Twenty-two patients (7.8 percent) had a pouch sinus at pouchogram. Nineteen patients were observed and underwent repeat pouchogram. Of these, ten had sinus resolution (mean, 3.6 months) and underwent successful ileostomy closure. Eight patients underwent examination under anesthesia +/- sinus debridement. Six of these patients had subsequent pouchograms with five showing sinus resolution. The patient without resolution was not reversed. Of the eight patients who underwent examination under anesthesia +/- debridement, seven underwent ileostomy closure (mean, 4.9 months), with healing in six and pelvic sepsis in one. Four patients underwent successful ileostomy takedown despite persistent sinus. Overall, 21 of the 22 pouch sinus patients underwent ileostomy closure and only 1 had postoperative pelvic sepsis. CONCLUSIONS: Pouch sinuses after ileal pouch-anal anastomosis with ileostomy are uncommon. Most heal within six months. The majority of patients with sinuses eventually undergo successful ileostomy closure. Pelvic septic complications are rare but can occur despite sinus healing on pouchogram.

The effect of a hyaluronan-carboxymethylcellulose membrane vs. polyglactin 910 mesh on intra-abdominal tumor formation in mice.

PURPOSE: Hyaluronan mediates growth of SW620 colon cancer cells. Because hyaluronan is the active ingredient in Seprafilm, we hypothesized that Seprafilm would affect intraperitoneal tumor growth in a mouse model of peritoneal seeding. METHODS: Immunodeficient mice underwent laparotomy and intraperitoneal inoculation of 10(5) SW620 cells. Seprafilm (n = 22), Vicryl mesh (foreign body control; n = 24), or no material (sham; n = 19) was placed under the incision. Mice were killed after four weeks and tumors were dissected, counted, and weighed. RESULTS: Ninety-five percent of mice in the sham group and 96 percent in the Vicryl group developed intraperitoneal tumors. In contrast, only 64 percent of mice in the Seprafilm group developed tumors (P = 0.024), and these tumors were smaller than those in the sham group; (Seprafilm = 42 +/- 9 mg vs. sham = 82 +/- 17 mg; P = 0.05). In contrast, tumors in the Vicryl group were dramatically larger (349 +/- 49 mg; P < 0.001 vs. sham or Seprafilm). CONCLUSIONS: Despite previous data that suggested that hyaluronan increases colon cancer cell growth, we found that Seprafilm decreased tumor formation and tended to decrease size in this model. In contrast, Vicryl mesh increased tumor formation and size. Our results suggest that Seprafilm does not promote intraperitoneal tumor growth, especially compared with Vicryl mesh.

Surgical management of rectal cancer.

Rectal cancer affects more than 40,000 people in the United States annually. Despite recent advances in radiation and chemotherapy, surgical resection remains an integral part of curative therapy for this disease. Although rectal cancer is thought to be biologically similar to colon cancer, the anatomic complexity of the pelvis makes therapy for this disease considerably more complicated. Local recurrence is also a greater concern in rectal cancer than in colon cancer. The choice of surgical therapy depends on the location of the tumor, depth of rectal wall invasion, and clinical stage. Surgical options include local excision (transanal excision and transanal endoscopic microsurgery) and radical resection (low anterior resection, extended low anterior resection with coloanal anastomosis, abdominoperineal resection [APR], and pelvic exenteration). Technical advances such as transanal endoscopic microsurgery and laparoscopy also are changing the surgical approach to rectal tumors. Finally, chemotherapy and radiation are now frequently recommended in conjunction with surgical therapy. This article reviews the current surgical approach to treating patients with rectal cancer.

The role of surgical intervention in non-Hodgkin's lymphoma of the colon and rectum.

BACKGROUND: Gastrointestinal involvement of non-Hodgkin's lymphoma (NHL), although rare, may require surgical intervention. The purpose of the current study was to determine the incidence, presentation, and management of patients with NHL of the colon or rectum. METHODS: Demographic data, signs, symptoms, disease stage, and treatment of patients with a primary gastrointestinal lymphoma treated between 1973 and 2005 were identified. RESULTS: Forty-three of 244 gastrointestinal lymphoma patients (18%) had colon or rectal involvement. Most common symptoms on presentation were pain (49%), hematochezia (49%), change in bowel habits (23%), and weight loss (19%). Most common site of involvement was the ileocecum. Twenty-six patients (60%) required surgery. The majority (56%) had urgent or emergent operations. CONCLUSIONS: Colorectal involvement by NHL occurred in 18% of patients with gastrointestinal lymphoma. Surgery was required for pain, obstruction, and/or bleeding. Physicians caring for patients must be aware of the potential need for surgery in treating this patient population.