Tumor Budding Assessment in Colorectal Carcinoma: Normalization Revisited.

Tumor budding (TB) is a powerful prognostic factor in colorectal cancer (CRC). An internationally standardized method for its assessment (International Tumor Budding Consensus Conference [ITBCC] method) has been adopted by most CRC pathology protocols. This method requires that TB counts are reported by field area (0.785 mm 2 ) rather than objective lens and a normalization factor is applied for this purpose. However, the validity of this approach is yet to be tested. We sought to validate the ITBCC method with a particular emphasis on normalization as a tool for standardization. In a cohort of 365 stage I-III CRC, both normalized and non-normalized TB were significantly associated with disease-specific survival and recurrence-free survival ( P <0.0001). Examining both 0.95 and 0.785 mm 2 field areas in a subset of patients (n=200), we found that normalization markedly overcorrects TB counts: Counts obtained in a 0.95 mm 2 hotspot field were reduced by an average of 17.5% following normalization compared with only 3.8% when counts were performed in an actual 0.785 mm 2 field. This resulted in 45 (11.3%) cases being downgraded using ITBCC grading criteria following normalization, compared with only 5 cases (1.3%, P =0.0007) downgraded when a true 0.785 mm 2 field was examined. In summary, the prognostic value of TB was retained regardless of whether TB counts in a 0.95 mm 2 field were normalized. Normalization resulted in overcorrecting TB counts with consequent downgrading of most borderline cases. This has implications for risk stratification and adjuvant treatment decisions, and suggests the need to re-evaluate the role of normalization in TB assessment.

A Novel Combined Tumor Budding-Poorly Differentiated Clusters Grading System Predicts Recurrence and Survival in Stage I-III Colorectal Cancer.

Tumor budding (TB) and poorly differentiated clusters (PDCs) are powerful prognostic factors in colorectal cancer (CRC). Despite their morphologic and biological overlap, TB and PDC are assessed separately and are distinguished by an arbitrary cutoff for cell cluster size. This cutoff can be challenging to apply in practice and its biological significance remains unclear. We developed a novel scoring system that incorporates TB and PDC into a single parameter ("Combined Score"; CS), eliminating the need for such cutoffs and allowing the prognostic value of PDC to be captured alongside TB. In a cohort of 481 stage I-III CRC resections, CS was significantly associated with American Joint Committee on Cancer (AJCC) stage, T-stage, N-stage, histologic grade, tumor deposits, lymphovascular invasion, and perineural invasion ( P <0.0001). In addition, CS was significantly associated with decreased 5-year recurrence-free survival, overall survival, and disease-specific survival ( P <0.0001). TB and PDC showed similar associations with oncologic outcomes, with hazard ratios consistently lower than for CS. The association between CS and oncologic outcomes remained significant in subgroup analyses stratified by AJCC stage, anatomic location (rectum/colon) and neoadjuvant therapy status. On multivariable analysis, CS retained its significant association with oncologic outcomes ( P =0.0002, 0.005, and 0.009) for recurrence-free survival, disease-specific survival, and overall survival, respectively. In conclusion, CS provides powerful risk stratification in CRC which is at least equivalent to that of TB and PDC assessed individually. If validated elsewhere, CS has practical advantages and a biological rationale that may make it an attractive alternative to assessing these features separately.

Outcomes of Surgical and Chemotherapeutic Treatments of Goblet Cell Carcinoid Tumors of the Appendix.

BACKGROUND: Goblet cell carcinoids (GCCs) of the appendix are rare mucinous neoplasms, for which optimal therapy is poorly described. We examined prognostic clinical and treatment factors in a population-based cohort. METHODS: Patients diagnosed with GCC from 1984 to 2014 were identified from the British Columbia Cancer Agency and the Vancouver Lower Mainland Pathology Archive. RESULTS: Of 88 cases with confirmed appendiceal GCCs, clinical data were available in 86 cases (annual population incidence: 0.66/1,000,000). Median age was 54 years (range 25-91) and 42 patients (49%) were male. Metastasis at presentation was the strongest predictor of overall survival (OS), with median OS not reached for stage I-III patients, and measuring 16.2 months [95% confidence interval (CI) 9.1-29] for stage IV patients. In 67 stage I-III patients, 51 (76%) underwent completion hemicolectomy and 9 (17%) received adjuvant 5-fluorouracil-based chemotherapy. No appendicitis at initial presentation and Tang B histology were the only prognostic factors, with inferior 5-year recurrence-free survival (53 vs. 83% with appendicitis, p = 0.02; 45% Tang B vs. 89% Tang A, p < 0.01). Of 19 stage IV patients, 10 (62.5%) received 5-fluorouracil-based chemotherapy and 11 (61%) underwent multiorgan resection (MOR) ± hyperthermic intraperitoneal chemotherapy (HIPEC). Low mitotic rate and MOR ± HIPEC were associated with improved 2-year OS, but only MOR ± HIPEC remained significant on multivariate analysis (hazard ratio 5.4, 95% CI 1.4-20.9; p = 0.015). CONCLUSIONS: In this population-based cohort, we demonstrate excellent survival outcomes in stage I-III appendiceal GCCs and clinical appendicitis. Hemicolectomy remains the standard treatment. In metastatic disease, outcomes remain poor, although MOR ± HIPEC may improve survival.

The role and outcomes of palliative surgery for retroperitoneal sarcoma.

Categories of noncurative surgery for retroperitoneal sarcoma include: i) grossly incomplete resection (R2) of primary or locally recurrent tumor; ii) resection in the setting of distant metastatic disease; and iii) true palliative-intent symptom-directed surgery. The value of R2 resection is debatable, since most series do not report initial operative intent. Debulking surgery provides symptom relief in the majority of patients, but relief is generally not durable. Quality of life is poorly studied.

Simplified 2-tier histologic grading system accurately predicts outcomes in goblet cell carcinoid of the appendix.

Goblet cell carcinoid (GCC) is a rare appendiceal malignancy with both neuroendocrine and glandular features. Clinical outcomes of patients with GCC vary widely and a histology-based 3-tiered prognostic scheme has been previously suggested; however, this scheme is subjective and challenging to apply in day-to-day practice. We sought to construct a simplified and prognostic grading system based on objective histologic features with specific criteria. A continuous population-based cohort of GCC with clinical outcome data and archival tissue available for review was extracted from regional databases. For the 78 patients with confirmed appendiceal GCC, specific histologic features, including cytologic atypia, peritumoral stromal desmoplasia, and solid growth pattern, were recorded, and a scoring system was devised, which separates patients with GCC into low-grade (n = 55; 71%) or high-grade (n = 23; 29%) histology. Correspondingly, clinical follow-up data show good prognosis in those with low-grade histology with median and 10-year overall survival of 51.0 months and 80.5%, respectively, whereas those with high-grade histology have a poor prognosis with median and 10-year overall survival of 16.5 months (P = .006) and 0% (P < .001), respectively. Multivariate Cox proportional hazard modeling demonstrates that this 2-tier histologic system remains predictive of overall survival when controlled for TNM clinicopathological stage. These data show that a simple and objective histologic scoring system separates GCC into low- and high-grade histology with divergent clinical outcomes.

Severity of inflammation as a risk factor for ileo-anal anastomotic leak after a pouch procedure in ulcerative colitis.

PURPOSE: The pelvic pouch procedure (PPP) carries significant post-operative complication risks including a 4-14 % risk of ileo-anal anastomotic (IAA) leak [1-4]. The aim of this study is to evaluate the severity of disease at the distal resection margin as an independent risk factor for an IAA leak following the PPP for patients with ulcerative colitis (UC). METHODS: A retrospective matched case-control study was undertaken. The distal margin of each subject's specimen was reviewed by a blinded pathologist and the degree of inflammation was scored using a modified histological activity index (mHAI)--a 0 to 5 graded scale with HAI of 5 representing ulcerations >25 % the depth of bowel wall. RESULTS: Forty-nine patients with perioperative IAA leaks (mean 11 days ±0.92) were identified and matched for gender, age and year of surgery. The case cohort had 33 males (67 %) of mean age at time of surgery of 36.3 years (±1.42). The severity of distal inflammation did not increase the risk of IAA leak. The presence of a diverting ileostomy was associated with a decreased incidence of an IAA leak (p = 0.01). CONCLUSION: Studies with greater power will be required to evaluate the association (if any) between histological severity of UC at the distal margin of a PPP procedure and IAA leak rate. This risk factor could influence preoperative management and post-operative outcome in patients requiring the PPP.

Oncolytic vaccinia virus synergizes with irinotecan in colorectal cancer.

Metastatic colorectal cancer (CRC) is complex clinical challenge for which there are limited treatment options. Chemotherapy with or without surgery provides moderate improvements in overall survival and quality of life; nevertheless the 5-year survival remains below 30%. Oncolytic vaccinia virus (VV) shows strong anti-tumour activity in models of CRC, however transient delays in disease progression are insufficient to lead to long-term survival. Here we examined the efficacy of VV with oxaliplatin or SN-38 (active metabolite of irinotecan) in CRC cell lines in vitro and VV with irinotecan in an orthotopic model of metastatic CRC. Synergistic improvements in in vitro cell killing were observed in multiple cell lines. Combination therapy was well tolerated in tumour-bearing mice and the median survival was significantly increased relative to monotherapy despite a drug-dependent decrease in the mean tumour titer. Increased apoptosis following in vitro and in vivo combination therapy was observed. In vitro cell cycle analysis showed increases in S-phase cells following infection occurred in both infected and uninfected cell populations. This corresponded to a 4-fold greater increase in apoptosis in the uninfected compared to infected cells following combination therapy. Combination treatment strategies are among the best options for patients with advanced cancers. VV is currently under clinical investigation in patients with CRC and the data presented here suggest that its combination with irinotecan may provide benefit to a subset of CRC patients. Further, investigation of this combination is necessary to determine the tumour characteristics responsible for mediating synergy.

Perioperative measures to optimize margin clearance in breast conserving surgery.

Margin status is one of the most important determinants of local recurrence following breast conserving surgery. The fact that up to 60% of patients undergoing breast conserving surgery require re-excision highlights the importance of optimizing margin clearance. In this review we summarize the following perioperative measures that aim to enhance margin clearance: (1) patient risk stratification, specifically risk factors and nomograms, (2) preoperative imaging, (3) intraoperative techniques including wire-guided localization, radioguided surgery, intraoperative ultrasound-guided resection, intraoperative specimen radiography, standardized cavity shaving, and ink-directed focal re-excision; (4) and intraoperative pathology assessment techniques, namely frozen section analysis and imprint cytology. Novel surgical techniques as well as emerging technologies are also reviewed. Effective treatment requires accurate preoperative planning, developing and implementing a consistent definition of margin clearance, and using tools that provide detailed real-time intraoperative information on margin status.

Can we select fetuses with intra-abdominal calcification for delivery in neonatal surgical centres?

BACKGROUND: Prenatal ultrasound (US) diagnosis of fetal intra-abdominal calcification (iAC) is frequently caused by an in utero perforation causing meconium peritonitis. Our ability to predict which fetuses will require postnatal surgery is limited. The aim of our study is to correlate iAC and associated US findings with postnatal outcome. METHODS: A single centre retrospective review of all cases of fetal iAC diagnosed between 2004 and 2010 was performed. Maternal demographics, fetal US findings, and outcomes (need for surgery and mortality) were collected. Descriptive and comparative statistical analyses were performed. RESULTS: Twenty-three cases of iAC were identified. There were no cases of fetal demise or postnatal deaths. Three liveborns (13%) required abdominal surgery at a median of 2 days (0-3) for intestinal atresia. US findings of iAC and dilated bowel with (p=0.008) or without (p=0.005) polyhydramnios predicted a need for postnatal surgery as did the combination of iAC, polyhydramnios, and ascites (p=0.008). Conversely, iAC alone or associated with oligohydramnios, polyhydramnios, ascites, or growth restriction did not predict need for postnatal surgery. CONCLUSION: The majority of fetuses with iAC on prenatal US do not require surgery. Associated US findings (bowel dilation) can be used to select fetuses for delivery in neonatal surgical centres.

Mounting a strategic offense: fighting tumor vasculature with oncolytic viruses.

Blood supply within a tumor drives progression and ultimately allows for metastasis. Many anticancer therapies target tumor vasculature, but their individual effectiveness is limited because they induce indirect cell death. Agents that disrupt nascent and/or established tumor vasculature while simultaneously killing cancer cells would certainly have a greater impact. Oncolytic virotherapy utilizes attenuated viruses that replicate specifically within a tumor. They induce cytotoxicity through a combination of direct cell lysis, antitumor immune stimulation, and recently identified antitumor vascular effects. This review summarizes the novel preclinical and clinical evidence regarding the antitumor vascular effects of oncolytic viruses, which include infection and lysis of tumor endothelial cells, natural or genetically engineered antiangiogenic properties, and combination therapy with clinically approved antivascular agents.

The intrathoracic kidney: should we fix it?

BACKGROUND: Intrathoracic kidney is a rare congenital anomaly, with only 13 cases reported in the pediatric age group over the past 25 years. The relevant literature is limited to individual case reports or small case series with no follow-up data. Both operative and nonoperative management has been advocated. We report our experience in the management of children with an intrathoracic kidney as well as the efficacy of nonoperative management in select patients. METHODS: Five cases of intrathoracic kidney were collected prospectively since 1992 and carefully followed up long term. RESULTS: Two children presented with acute respiratory distress and underwent right diaphragmatic hernia repair and nephropexy. Incidental diagnosis of a left intrathoracic kidney was made in 3 children. Long-term follow-up has demonstrated normal function and development of these kidneys in all 5 children with no late bowel herniation in the nonoperative group. CONCLUSION: Intrathoracic kidney associated with bowel in the chest should undergo standard repair and nephropexy. An isolated intrathoracic kidney without evidence of bowel herniation can safely be observed. This is the largest pediatric series of intrathoracic kidney as well as the first to document the efficacy of nonoperative management with long-term follow-up.