Macroscopic and microscopic characteristics of low grade appendiceal mucinous neoplasms (LAMN) on appendectomy specimens and correlations with pseudomyxoma peritonei development risk.

Low grade appendiceal mucinous neoplasm (LAMN) is the primary source of pseudomyxoma peritonei (PMP). PMP may develop after seemingly complete resection of primary tumor by appendectomy, which is unpredictable due to lack of reliable prognostic indicators. We retrospectively reviewed 154 surgically resected LAMNs to explore if any of the macroscopic and microscopic characteristics may be associated with increasing risk of PMP development. Our major findings include: (1) As compared to those without PMP, the cases that developed PMP were more frequent to have (a) smaller luminal diameter (<1 cm) and thicker wall, separate mucin aggregations, and microscopic perforation/rupture, all suggestive of luminal mucin leakage; (b) microscopic acellular mucin presenting on serosal surface and not being confined to mucosa; and (c) neoplastic epithelium dissecting outward beyond mucosa, however, with similar frequency of neoplastic cells being present in muscularis propria. (2) Involvement of neoplastic cells or/and acellular mucin at surgical margin did not necessarily lead to tumor recurrence or subsequent PMP, and clear margin did not absolutely prevent PMP development. (3) Coexisting diverticulum, resulted from neoplastic or non-neoplastic mucosa being herniated through muscle-lacking vascular hiatus of appendiceal wall, was seen in a quarter of LAMN cases, regardless of PMP. The diverticular portion of tumor involvement was often the weakest point where rupture occurred. In conclusion, proper evaluation of surgical specimens with search for mucin and neoplastic cells on serosa and for microscopic perforation, which are of prognostic significance, should be emphasized.

Inspiring hope-A physician's responsibility, translating the science into clinical practice.

Giving hope to patients is our responsibility. It is the essence of a meaningful practice in medicine. Science now allows us to understand this complex and multidimensional human dynamic, and translate it into clinical practice. Quantitative research has shown hope is strong even in terminal illness. Through qualitative methodology hope fostering strategies and hope hindering behaviors have been identified. This exciting new knowledge facilitates the challenging task of disclosure of bad news while enabling hope.

Outcomes of surgical treatment alone in patients with superficial soft tissue sarcoma regardless of size or grade.

BACKGROUND AND OBJECTIVES: Currently, standard treatment of soft tissue sarcoma (STS) is wide local excision and adjuvant radiation, but radiation may be unnecessary in superficial STS. The primary objective is to assess local recurrence rates in patients treated with surgical management alone for superficial STS. METHODS: A retrospective cancer registry review of patients treated with surgery alone for superficial STS at the Tom Baker Cancer Center (TBCC) was performed. Patient and tumor characteristics as well as recurrence data were collected. RESULTS: Sixty-one patients met study criteria. Local and overall recurrence rates were 7/61 (11.5%) and 12/61 (19.7%), respectively. The proportion with a T2 tumor was 38.8% versus 33.3% (P = 0.69), with Grade 2 or 3 tumors was 59.2% versus 83.3% (P = 0.14), and with resection margins <1 cm was 28.6% versus 75.0% (P = 0.008) for patients without and with recurrence, respectively. Median time to recurrence was 1.7 (0.4-5.2) years. CONCLUSIONS: Surgical resection alone appears to be a viable option for superficial STS that can save patients from potential side effects of radiation. The association between recurrence and inadequate margins (<1 cm) requires additional treatment be offered to this subset of patients.

Quality of life, functional outcomes, and wound complications in patients with soft tissue sarcomas treated with preoperative chemoradiation: a prospective study.

BACKGROUND: Preoperative irradiation reduces local recurrence of soft tissue sarcomas (STSs), but major wound complication rates approach 25-35 %. Using a novel neoadjuvant chemoradiation protocol, we prospectively documented functional outcomes and quality of life (QOL) and hypothesized a lower major wound complication rate. METHODS: Patients with STS deep to muscular fascia were treated with 3 days of doxorubicin (30 mg/day) and 10 days of irradiation (300 cGy/day) followed by limb-sparing surgery. Wound complications were assessed, and functional assessment and QOL were followed prospectively using the Toronto Extremity Salvage Score (TESS), Musculoskeletal Tumor Society (MSTS), and Short Form (SF)-36 questionnaires preoperatively and 6 and 12 months postoperatively. RESULTS: Altogether, 52 consecutive patients were accrued during 2006-2011. Overall, 80.8 % of STSs were >5 cm, and 67.3 % involved the lower extremity. Seven (13.5 %) major wound complications occurred, all requiring reoperation. Preoperative scores for TESS, MSTS, and SF-36 physical (PCS) and mental (MCS) health components were 83.3, 86.7, 40.6, and 49.4, respectively. There were no differences seen 6 months postoperatively. By 12 months, however, patients showed improved functional scores (TESS 93.0, p = 0.02; MSTS 93.3, p < 0.01) and QOL scores (PCS 45.1, p = 0.02; MCS = 52.9, p = 0.05). No differences in scores were seen between patients with or without wound complications. CONCLUSIONS: Patients treated with our neoadjuvant chemoradiation protocol had stable QOL and functional scores 6 months postoperatively and showed improvement by 12 months. Importantly, the major wound complication rate was low.

Cytoreductive surgery with hyperthermic intraperitoneal chemotherapy: an emerging treatment option for advanced goblet cell tumors of the appendix.

BACKGROUND: The debate remains whether appendiceal goblet cell cancers behave as classical carcinoid or adenocarcinoma. Treatment options are unclear and reports of outcomes are scarce. Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (CRS+HIPEC) is considered optimal treatment for peritoneal involvement of other epithelial appendiceal tumors. METHODS: Prospective cohorts of patients treated for advanced appendiceal tumors from three peritoneal malignancy centres were collected (1994-2011). All patients underwent complete CRS+HIPEC, when possible, or tumor debulking. Demographic and outcome data for patients with goblet cell cancers were compared to patients with low- or high-grade epithelial appendiceal tumors treated during the same time period. RESULTS: Details on 45 goblet cell cancer patients were compared to 708 patients with epithelial appendix lesions. In the goblet cell group, 57.8 % were female, median age was 53 years, median peritoneal cancer index (PCI) was 24, and CRS+HIPEC was achieved in 71.1 %. These details were similar in patients with low- or high-grade epithelial tumors. Lymph nodes were involved in 52 % of goblet cell patients, similar to rates in high-grade cancers, but significantly higher than in low-grade lesions (6.4 %; p < 0.001). At 3 years, overall survival (OS) was 63.4 % for goblet cell patients, intermediate between that for high-grade (40.4-52.2 %) and low-grade (80.6 %) tumors. On multivariate analysis, tumor histology, PCI, and achievement of CRS+HIPEC were independently associated with OS. CONCLUSIONS: This data supports the concept that appendiceal goblet cell cancers behave more as high-grade adenocarcinomas than as low-grade lesions. These patients have reasonable long-term survival when treated using CRS+HIPEC, and this strategy should be considered.

Cytoreduction and heated intraperitoneal chemotherapy for colorectal cancer: are we excluding patients who may benefit?

BACKGROUND: Cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) are increasingly used to treat peritoneal carcinomatosis from colorectal cancer. It is still relatively unknown which poor prognostic factors to avoid in order to optimize patient selection for CRS + HIPEC. METHODS: Between February 2003 and October 2011, 68 consecutive colorectal cancer patients who underwent CRS + HIPEC with a complete cytoreduction were identified from a prospective database. Survival analysis was performed using the Kaplan-Meier method, with log rank testing of differences between groups. Multivariate analysis was conducted using Cox proportional hazard regression. RESULTS: Median follow-up was 30.3 (range, 2-88) months amongst survivors. Patients with a peritoneal cancer index (PCI) of 10 or less showed improved survival over those with a PCI of 11 or higher (P = 0.03). No difference in survival was seen for the other potentially poor prognostic variables including lymph node status, synchronous peritoneal disease, peri-operative systemic chemotherapy, and rectal cancer primary. CONCLUSIONS: A low PCI was associated with improved survival. Complete CRS + HIPEC appears to result in similar survival outcomes regardless of delivery of peri-operative systemic chemotherapy. Rectal origin, lymph node status, and synchronous peritoneal disease should not be used as an absolute exclusion criteria for CRS + HIPEC based on current data.

Appendiceal goblet cell carcinoid and mucinous neoplasms are closely associated tumors: lessons from their coexistence in primary tumors and concurrence in peritoneal dissemination.

BACKGROUND: Goblet cell carcinoid (GCC) and appendiceal mucinous neoplasms (AMNs) are considered as different appendiceal tumors. Coexistence of both tumors was occasionally noted. We further observed the concurrence in both primary tumors and their peritoneal dissemination, that is, peritoneal carcinomatosis (PC) including pseudomyxoma peritonei (PMP). METHODS: Review of our 10-year file identified two subgroups of cases with such concurrence. Group 1 is 14 cases of PC/PMP treated by surgical cytoreduction. Morphologic components of GCC, low-grade mucinous neoplasm (LMN), mucinous adenocarcinoma (MCA), and non-mucinous adenocarcinoma (NMCA) were identified separately in different organs/tissues. Group 2 is eight cases of localized primary tumors of appendix and ileocecal junction. RESULTS: In Group 1, primary tumors (11 GCC, 1 GCC + LMN, 1 MCA, 1 NMCA) were identified in appendix (13) and in rectum (1). Further review identified mixed morphologic components in 7/12 GCC cases, including GCC + LMN (2), GCC + MCA (2), GCC + NMCA (1), and GCC + MCA + NMCA (2). Over peritoneal dissemination, GCC and/or other components were coexistent at different sites and in variable combinations. In Group 2, primary tumors were initially diagnosed as GCC (7) and MCA (1). Further review identified mixed components in all cases, including GCC + LMN (3), GCC + LMN + MCA (3), GCC + MCA + NMCA (2). CONCLUSIONS: GCC may present as a component mixed with AMNs and even with conventional adenocarcinoma in both primary tumors and metastatic lesions. AMN in any given single case may show a wide morphologic spectrum. GCC and AMN may share a common tumor stem cell with potential of multiple lineage differentiations.

HIPEC + EPIC versus HIPEC-alone: differences in major complications following cytoreduction surgery for peritoneal malignancy.

INTRODUCTION: Peritoneal metastases (PM) can be treated with cytoreduction surgery (CRS) with intraoperative heated intraperitoneal chemotherapy (HIPEC) plus or minus early postoperative intraperitoneal chemotherapy (EPIC). HIPEC + EPIC may be associated with more complications than HIPEC alone. METHODS: A prospective database of consecutive patients undergoing CRS + HIPEC ± EPIC at the University of Calgary between February 2000 and May 2011 was reviewed. Patient, tumor, and perioperative variables included peritoneal cancer index (PCI), completeness of cytoreduction (CCR) score, HIPEC ± EPIC type, and grade III/IV complications. RESULTS: 198 patients had a CCR score of 0/1 and received: (1) HIPEC mitomycin C + EPIC 5-fluorouracil for 5 days (n = 85; February 2000-January 2008); or (2) HIPEC oxaliplatin with IV 5-fluorouracil + no EPIC (n = 113; February 2008-May 2011). Clinicodemographics were similar except PCI was higher in the HIPEC-alone group (mean PCI 22 vs. 17; P = 0.02). The rate of grade III/IV complications was higher in the HIPEC + EPIC group (44.7% vs. 31.0%; P = 0.05). On multivariate logistic regression only HIPEC + EPIC and PCI > 26 were associated with an increased rate of complications. CONCLUSION: In patients with PM, the use of EPIC, in combination with CRS and HIPEC, is associated with an increased rate of complications. Surgeons should consider using HIPEC only (without EPIC).

Systematic review on the efficacy of multimodal treatment of sarcomatosis with cytoreduction and intraperitoneal chemotherapy.

BACKGROUND: Peritoneal sarcomatosis carries a dismal prognosis with median survival of 12 months and no 5-year survivors. The treatment for sarcomatosis has mostly been chemotherapy and surgery for palliation. Recently, cytoreduction (CRS) and intraperitoneal chemotherapy (IPC) has been tried as an alternative for improving regional control and survival, but the efficacy of this combined treatment is difficult to determine. The objective of this review is to evaluate all available evidence to determine the efficacy of this treatment modality. MATERIALS AND METHODS: Searches for studies published in peer-reviewed journals before October 2010 were carried out on 3 databases. The reference lists of all identified articles were reviewed for further relevant studies. Relevant studies were then evaluated by 3 investigators, and the quality of each study was assessed. Studies that met an established criterion were reviewed for clinical effectiveness with a tabulation of all results. RESULTS: Eight prospective and one randomized trial were available representing 240 patients treated with CRS and IPC. The median disease-free survival ranged from 2.3 to 22 months, median survival ranged from 5.5 to 39.6 months, and the 5-year survival ranged from 7% to 65%. The surgical morbidity varied from 9% to 44% and the mortality from 0% to 11%. CONCLUSIONS: Based on the available data, this treatment approach is currently not recommended in the treatment of sarcomatosis except in experienced centers, in well-selected patients and as part of an experimental protocol.

Operative salvage for retroperitoneal nodal recurrence in colorectal cancer: a systematic review.

BACKGROUND: Retroperitoneal nodal recurrence after curative resection of colorectal cancer is an uncommon and challenging problem. The evidence for salvage surgery is limited and remains controversial, particularly when major vascular structures are involved. Some reports have demonstrated a survival benefit after metachronous resection of retroperitoneal metastasis with and without concomitant aortic resection. We conducted a systematic review of the literature to find evidence in favor of or against salvage surgery. METHODS: Electronic searches of the MEDLINE, Cochrane, and EMBASE database were performed. Additional papers were identified by a manual search of the references from the key articles. Only peer-reviewed articles published in the English language were evaluated. RESULTS: A total of nine suitable studies were identified: three case reports and six larger series, of which one was a case-control study. Including our case reports, the total number of patients who underwent surgical resection that are available for review was 110. Median overall survival was between 34 and 44 months and median disease-free survival between 17 and 21 months. Concomitant resection of major vessels with graft replacement was feasible with survival ranging from 19 months to 18 years. There was no reported mortality associated with surgical salvage of retroperitoneal recurrence and the overall morbidity was 17-33%. CONCLUSIONS: The current literature suggests that more aggressive surgical treatment of retroperitoneal nodal recurrence in CRC has acceptable morbidity and may be associated with an improved survival in well-selected patients.

Neoadjuvant radiotherapy and reconstruction using autologous vein graft for the treatment of inferior vena cava leiomyosarcoma.

BACKGROUND AND OBJECTIVES: Inferior vena cava (IVC) leiomyosarcomas are rare and are a relatively small subset of retroperitoneal sarcomas. The current approach is resection and ligation or reconstruction of the IVC. This study was undertaken to analyze the outcomes associated with the use of neoadjuvant radiotherapy and IVC reconstruction in the treatment of IVC leiomyosarcoma. METHODS: A retrospective clinicopathological review of patients treated during a 10-year period. RESULTS: Four patients were treated with neoadjuvant radiotherapy, median 47.5 Gy, all underwent margin negative resection with 75% of the tumors being high grade and all patients requiring resection of adjacent organs. Reconstruction of the IVC was performed with an autologous superficial femoral vein graft. There were no mortalities and the morbidity rate was 50%. At a median follow up of 37 months; two patients had a patent IVC, no patients had a local recurrence, and one patient developed a distant metastases treated successfully with metastectomy. CONCLUSIONS: Neoadjuvant radiotherapy and resection of the IVC leiomyosarcoma resulted in 100% local control, and all patients are alive at median follow up of 37 months. IVC reconstruction with the superficial femoral vein is safe and associated with acceptable short and long term morbidity.

Dramatic innovations in modern surgical subspecialties.

Innovation is defined as the introduction of something new, whether an idea, method or device. In this article, we describe the most important and innovative concepts and techniques that have advanced patient care within modern surgical subspecialties. We performed a systematic literature review and consulted academic subspecialty experts to evaluate recent changes in practice. The identified innovations included reduced blood loss and improved training in hepatobiliary surgery, total mesorectal excision and neoadjuvant therapies in colorectal surgery, prosthetic mesh in outpatient surgery, sentinel lymph node theory in surgical oncology, endovascular and wire-based skills in vascular and cardiovascular surgery, and the acceptance of abnormal anatomy through damage-control procedures in trauma and critical care. The common denominator among all subspecialties is an improvement in patient care manifested as a decrease in morbidity and mortality. Surgeons must continue to pursue innovative thinking, technological advances, improved training and systematic research.

Desmoids: a revelation in biology and treatment.

INTRODUCTION: Using a preoperative neoadjuvant chemoradiation protocol, followed by complete excision, we have achieved local control rates exceeding that found in most large series. METHODS: From October 1990 through May 2008, resectable desmoids were initially treated with a preoperative protocol using Adriamycin 30 mg x 3 days continuous intravenous infusion followed by 3,000 cGy of radiation (300 cGy fractions over 10 days). Resection was performed 4-6 weeks later. After 2001, all patients were initially offered Tamoxifen 120 mg/day and Celebrex 400 mg/day for 1 year. Patients who progressed on Tamox/Celeb were treated with protocol and those with stabilization or regression were observed. Patient demographics, tumor size, history of previous recurrences, and follow-up status were recorded prospectively. RESULTS: There were 40 females and 12 males with a mean follow-up of 45 months. Forty patients presented with primary tumors and eight presented with recurrent disease. Thirty-nine patients had surgical resection and 13 were observed. Thirty patients underwent the neoadjuvant protocol. Tamoxifen and Celebrex were used in 16 patients, 6 had stabilization in growth, 1 had a 50% reduction in the size of the tumor, there was 1 complete regression, and 8 progressed. Of the patients who had resectable disease Tamoxifen and Celebrex obviated surgery in 30%. Overall 13% (5) of patients developed a recurrence. There were three recurrences among the protocol group for a local control rate of 90%. CONCLUSION: Although our neoadjuvant protocol demonstrates the best results to date in eradication of disease, an initial conservative approach is reasonable to determine who would most benefit from surgery.

Colorectal cancer screening among first-degree relatives of colorectal cancer patients: benefits and barriers.

BACKGROUND: Individuals with a first-degree family history of colorectal cancer (CRC) are at increased risk of CRC. Study objectives were: (1) to estimate the proportion of first-degree relatives (FDR) of CRC patients being screened for CRC and (2) to identify predictors of screened behavior. METHODS: A questionnaire was mailed to 640 stage I-III CRC patients from a population-based registry to identify FDR. A survey was sent to 747 FDR, aged 40 or older, to assess CRC screening, knowledge, demographics, access, benefits, and barriers of CRC screening. Factor analysis was used to detect underlying constructs. Predictors of screening were explored by multivariate analysis (MVA). RESULTS: There was a 54% and 51% response for patients and FDR, respectively. Among FDR, 86% were born in Canada, 94% spoke English, 93.5% had a high school education, 73% were married, and 55% were employed. The age distribution was: 40-44 years (19.7%), 45-49 (19.1%), 50-54 (16%), 55-59 (15.2%), 60-64 (9.8%), and >65 (18%). Seventy percent had undergone CRC screening with 60% adherent to current guidelines. Of those screened, 33.7% had fecal occult blood testing, 19.4% had barium enema, 10.7% had sigmoidoscopy, and 58.7% had colonoscopy. Five constructs influencing CRC screening include: salience and coherence, perceived susceptibility, response efficacy, social influence, and cancer worries. MVA determined age >50 years as the most important predictor of screening. CONCLUSION: In this survey, 70% of FDR of CRC patients had undergone screening; age was the most important predictor. Understanding underlying constructs influencing screening behavior may improve uptake of CRC screening in this population.

A prospective evaluation of venous thromboembolism in patients undergoing cytoreductive surgery and hyperthermic intraperitoneal chemotherapy.

BACKGROUND: We sought to investigate the incidence of perioperative venous thromboembolism (VTE)--pulmonary embolism, superior mesenteris vein thrombosis and deep vein thrombosis--in patients with peritoneal carcinomatosis after cytoreductive surgery combined with hyperthermic intraperitoneal chemotherapy. METHODS: We performed cytoreductive surgery and hyperthermic intraperitoneal chemotherapy on 60 consecutive patients with a mean age of 52 (range 24-76) years. We reviewed a prospective database recording complications and patient, tumour and surgical characteristics to determine the incidence of VTE. We reviewed hospital charts of patients with VTE to obtain clinical information including vital signs, risk factors, presence of comorbid conditions, VTE prophylaxis and subjective clinical symptoms. RESULTS: A total of 6 of 60 patients (10%) who had cytoreductive surgery and hyperthermic intraperitoneal chemotherapy experienced VTE. All patients with VTE had extensive peritoneal disease and long durations of surgery: the median duration was 431 (range 330-683) minutes. Tachycardia (mean 104 beats/min) was the only consistent abnormal vital sign recorded, with only 33% of patients experiencing clinical symptoms. CONCLUSION: This prospective study demonstrates a high rate of VTE in this patient population. Unfortunately, clinical signs and symptoms are a poor predictor of VTE. Therefore, routine screening of this specific population at high risk for VTE is warranted.

Differing expression profiles of Notch/enterocyte and Wnt/secretory lineage signallings are associated with morphological diversity of appendiceal tumours.

BACKGROUND: Tumours of appendix, including classic carcinoid tumour (CCT), goblet cell carcinoid (GCC), low-grade appendiceal mucinous neoplasm, high-grade appendiceal mucinous neoplasm/mucinous carcinoma (MCA) and non-mucinous adenocarcinoma (NMA), show different and sometimes mixed morphological features. It was hypothesised that these tumours originate from common tumour stem cell(s) with potential of various cell lineage differentiation. In normal intestinal epithelium, absorptive lineage (enterocytes) differentiation is driven by Notch-Hes1 pathway, while secretory lineage is driven by Wnt-Math1 pathway and further separated by different downstream signallings into three sublineages (Gfi1-Klf4/Elf3 for goblet cells, Gfi1-Sox9 for Paneth cells and Ngn3-Pdx1/Beta2/Pax4 for enteroendocrine cells). METHODS: The expressions of various signalling proteins in different appendiceal tumours were detected by immunohistochemistry on tumour tissue microarray. RESULTS: CCT showed reduced Hes1/Elf3 and Sox9/Klf4 coupled with elevated Math1, in keeping with endocrine phenotype. As compared with CCT, GCC showed higher Klf4 and similar Ngn3/Pax4, indicative of a shift of differentiation towards goblet cells as well as endocrine cells. GCC displayed a Notch signalling similar to adenocarcinoma. Mucinous tumours showed lower Elf3 than normal appendiceal epithelium and higher Math1/Gfi1/Klf4, suggestive of a differentiation towards less enterocytes but more goblet cells. NMA showed Notch signalling similar to other glandular tumours, but lower Klf4. However, some seemingly paradoxical changes were also observed, probably suggesting gene mutations and/or our incomplete understanding of the intestinal cell differentiation. CONCLUSIONS: Wnt/secretory lineage protein and Notch/absorptive lineage protein expression profiles are generally associated with the tumour cell differentiation and morphological diversity of common appendiceal tumours.

Hyperthermic intraperitoneal chemotherapy + early postoperative intraperitoneal chemotherapy versus hyperthermic intraperitoneal chemotherapy alone: assessment of survival outcomes for colorectal and high-grade appendiceal peritoneal carcinomatosis.

BACKGROUND: Cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) have improved survival for colorectal and high-grade appendiceal carcinomatosis. We compared the overall and recurrence-free survival (OS and RFS) of patients treated with HIPEC with mitomycin c and early postoperative intraperitoneal chemotherapy (EPIC) with fluorouracil versus HIPEC alone using oxaliplatin and simultaneous IV infusion of fluorouracil. METHODS: Ninety-three patients with colorectal or high-grade appendiceal carcinomatosis were treated with CRS and HIPEC + EPIC or HIPEC alone. OS and RFS were analyzed using Kaplan-Meier curves and log-rank testing. RESULTS: Survival did not differ between HIPEC regimens. The 3-year OS and RFS rates were 50% and 21% for HIPEC + EPIC and 46% and 6% for HIPEC alone (P = .72 and P = .89, respectively). HIPEC + EPIC patients experienced more grade III/IV complications (43.2% vs 19.6%, P = .01). CONCLUSIONS: There was no difference in OS and RFS between colorectal and high-grade appendiceal adenocarcinoma patients treated with CRS and HIPEC + EPIC versus HIPEC alone. However, HIPEC + EPIC patients suffered greater morbidity, making HIPEC alone the preferable regimen.