Harry S. Cooper

Clinical practice guidelines in oncology

Ductal carcinoma in situ (DCIS) of the breast represents a heterogeneous group of neoplastic lesions in the breast ducts. The goal for management of DCIS is to prevent the development of invasive breast cancer. This manuscript focuses on the NCCN Guidelines Panel recommendations for the workup, primary treatment, risk reduction strategies, and surveillance specific to DCIS.

Prognostic factors in colorectal cancer. College of American Pathologists Consensus Statement 1999.

BACKGROUND Under the auspices of the College of American Pathologists, the current state of knowledge regarding pathologic prognostic factors (factors linked to outcome) and predictive factors (factors predicting response to therapy) in colorectal carcinoma was evaluated. A multidisciplinary group of clinical (including the disciplines of medical oncology, surgical oncology, and radiation oncology), pathologic, and statistical experts in colorectal cancer reviewed all relevant medical literature and stratified the reported prognostic factors into categories that reflected the strength of the published evidence demonstrating their prognostic value. Accordingly, the following categories of prognostic factors were defined. Category I includes factors definitively proven to be of prognostic import based on evidence from multiple statistically robust published trials and generally used in patient management. Category IIA includes factors extensively studied biologically and/or clinically and repeatedly shown to have prognostic value for outcome and/or predictive value for therapy that is of sufficient import to be included in the pathology report but that remains to be validated in statistically robust studies. Category IIB includes factors shown to be promising in multiple studies but lacking sufficient data for inclusion in category I or IIA. Category III includes factors not yet sufficiently studied to determine their prognostic value. Category IV includes factors well studied and shown to have no prognostic significance. MATERIALS AND METHODS The medical literature was critically reviewed, and the analysis revealed specific points of variability in approach that prevented direct comparisons among published studies and compromised the quality of the collective data. Categories of variability recognized included the following: (1) methods of analysis, (2) interpretation of findings, (3) reporting of data, and (4) statistical evaluation. Additional points of variability within these categories were defined from the collective experience of the group. Reasons for the assignment of an individual prognostic factor to category I, II, III, or IV (categories defined by the level of scientific validation) were outlined with reference to the specific types of variability associated with the supportive data. For each factor and category of variability related to that factor, detailed recommendations for improvement were made. The recommendations were based on the following aims: (1) to increase the uniformity and completeness of pathologic evaluation of tumor specimens, (2) to enhance the quality of the data needed for definitive evaluation of the prognostic value of individual prognostic factors, and (3) ultimately, to improve patient care. RESULTS AND CONCLUSIONS Factors that were determined to merit inclusion in category I were as follows: the local extent of tumor assessed pathologically (the pT category of the TNM staging system of the American Joint Committee on Cancer and the Union Internationale Contre le Cancer [AJCC/UICC]); regional lymph node metastasis (the pN category of the TNM staging system); blood or lymphatic vessel invasion; residual tumor following surgery with curative intent (the R classification of the AJCC/UICC staging system), especially as it relates to positive surgical margins; and preoperative elevation of carcinoembryonic antigen elevation (a factor established by laboratory medicine methods rather than anatomic pathology). Factors in category IIA included the following: tumor grade, radial margin status (for resection specimens with nonperitonealized surfaces), and residual tumor in the resection specimen following neoadjuvant therapy (the ypTNM category of the TNM staging system of the AJCC/UICC). (ABSTRACT TRUNCATED)

Endoscopically removed malignant colorectal polyps: Clinicopathologic correlations

BACKGROUND/AIMS Treatment options for patients with endoscopically removed malignant colorectal polyps are polypectomy alone vs. polypectomy followed by surgery. The aim of this study was to define histopathologic parameters that can be used for clinically relevant treatment decisions. METHODS Five pathologists evaluated 140 polyps for the presence or absence of unfavorable histology. Unfavorable histology was tumor at or near (< or = 1.0 mm) the margin and/or grade III and/or lymphatic and/or venous invasion. Adverse outcome was recurrent and/or local cancer and/or lymph node metastasis. RESULTS Adverse outcome was 19.7% (14 of 71), 8.6% (2 of 23), and 0% (0 of 46) when unfavorable histology was present, indefinite (lack of agreement), and absent, respectively (P < 0.0005, present vs. absent). Four patients with cancer > 1.0 mm from the margin had an adverse outcome (2 with lymphatic invasion and 2 indefinite for lymphatic invasion). Four patients with negative resections later developed distant metastases. Eight patients (6.3%) died of disease, and 2 of 69 without unfavorable histology (both indefinite for lymphatic invasion) had an adverse outcome. Interobserver strength of agreement was substantial to almost perfect for margin, grade, and venous invasion and fair to substantial for lymphatic invasion. CONCLUSIONS This system is usable clinically. Patients with unfavorable histology are probably best managed by resection postpolypectomy, whereas in the absence of unfavorable histology, they probably can be treated by polypectomy only.

Effect of preoperative chemoradiotherapy on surgical margin status of resected adenocarcinoma of the head of the pancreas

We examined the effect of preoperative chemoradiotherapy on the ability to obtain pathologically negative resection margins in patients undergoing pancreaticoduodenectomy for adenocarcinoma of the head of the pancreas. Between 1987 and 2000, 100 patients underwent Whipple resection with curative intent for primary adenocarcinoma of the head of the pancreas. Pathologic assessment of six margins (proximal and distal superior mesenteric artery, proximal and distal superior mesenteric vein, pancreas, retroperkoneum, common bile duct, and hepatic artery) was undertaken by either frozen section (pancreas and common duct) or permanent section. A margin was considered positive if tumor was present less than 1 mm from the inked specimen. Margins noted to be positive on frozen section were resected when-ever possible. Of the 100 patients treated, 47 (47%) underwent postoperative radiation and chemotherapy (group I) and 53 (53%) received preoperative chemoradiotherapy (group II) with either 5-fluorouracil (32 patients) or gemcitabine (21 patients). Patient demographics and operative parameters were similar in the two groups, with the exception of preoperative tumor size (CT scan), which was greater in group II (P <0.001), and number of previous operations, which was greater in group II (P <0.0001). Statistical analysis of the number of negative surgical margins clear of tumor was performed using Fisher’s exact test. All patients (100%) had six margins assessed for microscopic involvement with tumor. In the preoperative therapy group, 5 (7.5%) of 53 patients had more than one positive margin, whereas 21 (44.7%) of 47 patients without preoperative therapy had more than one margin with disease extension (P < 0.001). Additionally, only 11 (25.6%) of the 47 patients without preoperative therapy had six negative margins vs. 27 (50.9%) of 53 in the group receiving preoperative therapy (P = 0.013). Survival analysis reveals a significant increase in survival in margin-negative patients (P = 0.02). Similarly, a strong trend toward improved disease-free and overall survival is seen in patients with a single positive margin vs. multiple margins. Overall, we find a negative impact on survival with an increasing number of positive margins (P = 0.025, hazard ratio 1.3). When stratified for individual margin status, survival was decreased in patients with positive superior mesenteric artery (P = 0.06) and vein (P = 0.04) margins. However, this has not yet resulted in a significant increase in disease-free or overall survival for patients receiving preoperative therapy (P = 0.07).

CYTOMEGALOVIRUS INCLUSIONS IN PATIENTS WITH ULCERATIVE COLITIS AND TOXIC DILATION REQUIRING COLONIC RESECTION

Microscopic examination of 50 colon resection specimens from 46 patients with ulcerative colitis revealed 6 patients whose colons contained intranuclear inclusions characteristic for cytomegalovirus (CMV). All patients were male, 47 years of age or older, and all had marked severe and fulminating courses. Five of the 6 patients had toxic dilation of the colon. Three of our patients had received no steroid therapy before their toxic dilation, however, all received steroids during attempts at medical management. Two other patients were found to have toxic dilation of the colon among our 46 patients, however, no evidence of CMV could be found in these 2 cases. There were 6 patients without toxic dilation whose colon specimens showed destructive inflammation and granulation tissue extending into the muscularis propria or transmurally. None of the colons from these 6 patients contained CMV inclusions. In our patients, the finding of CMV may be coincidental, but it is suggested that in our group of patients with ulcerative colitis, the CMV may play a role in altering the clinical course of these patients.

Dextran sulfate sodium-induced colitis-associated neoplasia: a promising model for the development of chemopreventive interventions

AbstractIndividuals diagnosed with ulcerative colitis face a significantly increased risk of developing colorectal dysplasia and cancer during their lifetime. To date, little attention has been given to the development of a chemopreventive intervention for this high-risk population. The mouse model of dextran sulfate sodium (DSS) -induced colitis represents an excellent preclinical system in which to both characterize the molecular events required for tumor formation in the presence of inflammation and assess the ability of select agents to inhibit this process. Cyclic administration of DSS in drinking water results in the establishment of chronic colitis and the development of colorectal dysplasias and cancers with pathological features that resemble those of human colitis-associated neoplasia. The incidence and multiplicity of lesions observed varies depending on the mouse strain used (ie, Swiss Webster, C57BL/6J, CBA, ICR) and the dose (0.7%–5.0%) and schedule (1–15 cycles with or without a subsequent recovery period) of DSS. The incidence of neoplasia can be increased and its progression to invasive cancer accelerated significantly by administering DSS in combination with a known colon carcinogen (azoxymethane (AOM), 2-amino-3-methylimidazo[4,5-f]quinoline (IQ), 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP)) or iron. More recent induction of colitis-associated neoplasia in genetically defined mouse strains has provided new insight into the role of specific genes (ie, adenomatous polyposis coli (Apc), p53, inducible nitric oxide synthase (iNOS), Msh2) in the development of colitis-associated neoplasias. Emerging data from chemopreventive intervention studies document the efficacy of several agents in inhibiting DSS-induced neoplasia and provide great promise that colitis-associated colorectal neoplasia is a preventable disease.

Constitutive activation of epithelial TLR4 augments inflammatory responses to mucosal injury and drives colitis-associated tumorigenesis

Background: Chronic intestinal inflammation culminates in cancer and a link to Toll‐like receptor‐4 (TLR4) has been suggested by our observation that TLR4 deficiency prevents colitis‐associated neoplasia. In the current study we address the effect of the aberrant activation of epithelial TLR4 on induction of colitis and colitis‐associated tumor development. We take a translational approach to address the consequences of increased TLR signaling in the intestinal mucosa. Methods: Mice transgenic for a constitutively active TLR4 under the intestine‐specific villin promoter (villin‐TLR4 mice) were treated with dextran sodium sulfate (DSS) for acute colitis and azoxymethane (AOM)‐DSS TLR4 expression was analyzed by immunohistochemistry in colonic tissue from patients with ulcerative colitis (UC) and UC‐associated cancer. The effect of an antagonist TLR4 antibody (Ab) was tested in prevention of colitis‐associated neoplasia in the AOM‐DSS model. Results: Villin‐TLR4 mice were highly susceptible to both acute colitis and colitis‐associated neoplasia. Villin‐TLR4 mice had increased epithelial expression of COX‐2 and mucosal PGE2 production at baseline. Increased severity of colitis in villin‐TLR4 mice was characterized by enhanced expression of inflammatory mediators and increased neutrophilic infiltration. In human UC samples, TLR4 expression was upregulated in almost all colitis‐associated cancer and progressively increased with grade of dysplasia. As a proof of principle, a TLR4/MD‐2 antagonist antibody inhibited colitis‐associated neoplasia in the mouse model. Conclusions: Our results show that regulation of TLRs can affect the outcome of both acute colitis and its consequences, cancer. Targeting TLR4 and other TLRs may ultimately play a role in prevention or treatment of colitis‐associated cancer. (Inflamm Bowel Dis 2010;)

Randomized Phase II Study of Gemcitabine Plus Radiotherapy Versus Gemcitabine, 5-Fluorouracil, and Cisplatin Followed by Radiotherapy and 5-Fluorouracil for Patients With Locally Advanced, Potentially Resectable Pancreatic Adenocarcinoma

A randomized phase II trial (E1200) was designed to assess toxicities and surgical resection rates in two neoadjuvant gemcitabine‐based chemoradiation regimens in patients with borderline resectable pancreatic cancer. The trial was terminated early due to poor accrual.

Colon cancer, version 1.2017: Clinical practice guidelines in oncology

This selection from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Bladder Cancer focuses on systemic therapy for muscle-invasive urothelial bladder cancer, as substantial revisions were made in the 2017 updates, such as new recommendations for nivolumab, pembrolizumab, atezolizumab, durvalumab, and avelumab. The complete version of the NCCN Guidelines for Bladder Cancer addresses additional aspects of the management of bladder cancer, including non-muscle-invasive urothelial bladder cancer and nonurothelial histologies, as well as staging, evaluation, and follow-up.

Neoadjuvant chemoradiotherapy for adenocarcinoma of the pancreas: Analysis of histopathology and outcome

To examine the histopathologic effect of neoadjuvant therapy and its impact on survival in patients with carcinoma of the pancreas, we retrospectively reviewed the records of 116 patients who underwent resections for pancreatic cancer from 1987 to 2000. Median follow-up of surviving patients was 19 mo (range 4–150 mo). Preoperative chemotherapy was administered in 61 patients (53%) and consisted of 5-fluorouracil/mitomycin C in 35 patients and gemcitabine in 26 patients, given concurrently with external beam radiation (5040 cGy). All resections were performed with curative intent (98 Whipples, 11 total, 6 distal, and 1 central pancreatectomy). Histopathologic examination included an estimation of the amount of fibrosis present in the tumor specimen (expressed as the percentage of fibrosis identified relative to the amount of neoplastic cells present). The mean fibrosis level for the series was 56% (range 5% to 100%). The administration of neoadjuvant therapy resulted in greater fibrosis (73%) than no preoperative treatment (38%) (p=0.0001). Higher mean fibrosis levels were observed in patients with negative lymph nodes (p=0.0006) and negative margins (p=0.05). Factors associated with improved survival (log rank test) included: negative margins (p=0.001), negative lymph nodes (p=0.03), and use of neoadjuvant therapy (p=0.03). Median survival in the neoadjuvant group was 23 mo vs 16 mo without preoperative therapy (p=0.03). In conclusion, the use of neoadjuvant therapy resulted in a greater degree of fibrosis in the specimen. Patients with negative margins and negative lymph nodes had a greater amount of fibrosis present, and these were significant predictors of improved outcome. Although retrospective, this series suggests an improvement in survival in patients treated with neoadjuvant therapy.