Intermittent parathyroid hormone enhances the healing of medication-related osteonecrosis of the jaw lesions in rice rats.

Medication-related osteonecrosis of the jaw (MRONJ) is a potentially severe adverse event in patients treated with antiresorptives. Management of MRONJ is challenging, and no non-antibiotic, established medical treatment exists. Intermittent parathyroid hormone (iPTH) has been used off-label to treat MRONJ with favorable results. However, its medical efficacy has rarely been substantiated in clinical or preclinical experiments. Using a validated rice rat, infection-based model of MRONJ, we evaluated the effects of iPTH on established MRONJ. We hypothesize that iPTH contributes to MRONJ resolution by enhancing alveolar bone turnover and healing oral soft tissues. Eighty-four rice rats began a standard rodent chow diet at age 4 weeks to induce localized periodontitis. Rats were simultaneously randomized to receive saline (vehicle, VEH) or zoledronic acid (ZOL, 80 µg/kg IV) every 4 weeks. Oral exams were conducted bi-weekly to assign a gross quadrant grade (GQG, 0-4) to evaluate any lesion at the lingual aspect of the interdental space between maxillary molar (M2) and M3. 14 of 20 VEH-treated rice rats (70%) developed maxillary localized periodontitis with GQG 2-3 after 30 ± 10 weeks of saline. Additionally, 40 of 64 ZOL-treated rice rats with periodontitis developed MRONJ-like lesions after 30 ± 10 weeks of ZOL treatment. Rice rats with localized periodontitis or MRONJ-like lesions were treated with saline or iPTH (40 µg/kg) subcutaneously (SC) 3 times/week For 6 weeks until euthanasia. We found that iPTH -treated ZOL rats had a lower prevalence of MRONJ (p < 0.001), with lower severity extent of oral lesions (p = 0.003) and percentage of empty osteocyte lacunae (p < 0.001). ZOL rats treated with iPTH displayed a higher osteoblast surface (p < 0.001), more osteoblasts (p < 0.001), higher osteoclast surface (p < 0.001) and more osteoclasts (p = 0.002) at alveolar bone surfaces than ZOL/VEH rats. Greater gingival epithelial thickness and epithelial cell proliferation rate was found in the oral mucosa and gingiva of ZOL/PTH rats than in ZOL/VEH rats (p < 0.001). Our data suggest that iPTH is an efficacious non-operative medicinal therapy that accelerates oral healing and enhances the resolution of MRONJ lesions in ZOL-treated rice rats.

Intraoperative frozen section analysis of margin status as a quality indicator in gastric cancer surgery.

INTRODUCTION: Positive pathologic margins following gastric cancer (GC) resection carries a poor prognosis. We evaluated intraoperative frozen section (IFS) analysis of resection margins (RMs) as a quality indicator in GC surgery. METHODS: Patients referred to a provincial cancer agency with surgically resected non-metastatic GC between 2004 and 2012 were included. Associations between IFS analysis, other baseline characteristics, RMs, and overall survival (OS) were assessed using logistic regression, Kaplan-Meier analyses, and Cox proportional hazards modeling. RESULTS: Among 377 patients, median age was 67 years, 68% were male, and 16% had +RMs. Thirty-four percent of patients underwent IFS analysis, which protected against +RMs (odds ratio [OR]: 0.34, 95% confidence interval [CI]: 0.16-0.73, p = 0.006) and improved OS (hazards ratio [HR]: 0.72, 95% CI: 0.54-0.98, p = 0.037). OS following re-resection of IFS positive patients was similar to IFS negative patients (69 vs. 54 months, p = 0.317). Stage III disease (OR: 12.8, 95% CI: 3.00-55.0, p = 0.001) and gastroesophageal junction tumors (OR: 2.25, 95% CI: 1.05-4.78, p = 0.036) predicted +RMs. Stage III disease led to worse OS (HR: 2.89, 95% CI: 1.92-4.34, p < 0.001) while intestinal histology improved OS (HR: 0.67, 95% CI: 0.50-0.90, p = 0.007). CONCLUSIONS: IFS analysis reduce +RMs and improve OS and should be incorporated in curative intent GC surgery for patients with locally advanced GC.

Treatment of cutaneous basal cell carcinoma with combined laser extirpation and methyl aminolevulinic acid: five-year success rates.

INTRODUCTION: Basal cell carcinoma is the most common cancer. Excisional surgery is associated with a high clearance rate, at the expense of significant functional and aesthetic morbidity, especially within the T-zone or for extensive lesions. We report five-year follow-up outcomes for carbon dioxide laser extirpation of cutaneous basal cell carcinoma, assisted by immediate methyl aminolevulinate photodynamic therapy and cost-benefit considerations. MATERIALS AND METHODS: Retrospective cohort database analysis of adult patients with biopsy-proven primary cutaneous basal cell carcinoma, completing five years of follow-up. Direct per-lesion cost was compared with conventional wide local excision. Patients with morphoeic basal cell carcinoma were excluded. RESULTS: Treated lesions were up to 1% total body surface area and up to 3.8mm (1.38 ± 0.695cm, mean ± standard deviation) in biopsy-proven depth. At the five-year follow-up mark, 93.6% of treated areas remained free of recurrence. Nodular basal cell carcinoma was the most common subtype (41.5%). A mean tumour depth greater than 2 ± 0.872mm was significantly associated with recurrence (Mann-Whitney, p = 0.0487). For a service delivered through the NHS at 2015 prices, we report a 43% saving, equating to a saving of £235 per basal cell carcinoma or a national annualised saving of £70 million by 2025 for the NHS. CONCLUSION: Our results suggest that CO2-assisted photodynamic therapy is non-inferior to excision but may offer better functional and cosmetic preservation at a fraction of the direct like for like cost of operative surgery. Investigation of this method by randomised controlled methodology is warranted.

Preventing or controlling periodontitis reduces the occurrence of osteonecrosis of the jaw (ONJ) in rice rats (Oryzomys palustris).

INTRODUCTION: Osteonecrosis of the jaw (ONJ) is an adverse event that requires association of both systemic risk factors, such as powerful anti-resorptives (pARs; e.g. zoledronic acid [ZOL]), and local oral risk factors (e.g. tooth extraction, periodontitis). Whereas optimal oral health prior to initiate pARs is recognized as critically important for minimizing ONJ risk, the efficacy of preventive/maintenance measures in patients who are taking pARs is understudied. Rice rats fed a standard diet (STD), rich in insoluble fiber, develop localized periodontitis. STD-rats with localized periodontitis treated with ZOL for 18-24 wk develop ONJ. Hence, we hypothesized that controlling/preventing localized periodontitis in the ZOL-treated rats, reduces ONJ occurrence. METHODS: We used two approaches to attempt reducing periodontitis prevalence: 1) periodontal cleaning (PC); and 2) replacing the STD-diet with a nutritionally-equivalent diet high in soluble fiber (SF). 75 four-week-old male rats were weight-randomized into five groups (n = 15) in a 24-week experiment. Three groups ate the STD-diet and two the high SF-diet. STD-diet groups received intravenous (IV) vehicle (VEH) q4wks (STD + VEH), 80 µg/kg ZOL q4wks IV (STD + ZOL), or ZOL plus PC q2wks (STD + ZOL + PC). The SF-diet groups received VEH (SF + VEH) or ZOL (SF + ZOL). Jaws were processed for histopathology and evaluated for ONJ prevalence and tissue-level periodontitis. RESULTS: 1) 40% of STD + VEH rats developed maxillary localized periodontitis with no ONJ; 2) 50% of STD + ZOL rats developed ONJ; 3) 7% of STD + ZOL + PC rats developed ONJ (p < 0.01 vs. STD + ZOL); and 4) one SF + ZOL rat developed localized periodontitis, and no SF + VEH or SF + ZOL rats developed ONJ (p < 0.001 vs. STD + ZOL). CONCLUSIONS: 1) Periodontal cleaning in ZOL-treated rats decreases localized periodontitis severity and reduces ONJ prevalence; and 2) feeding a SF-diet to ZOL-treated rats reduces both incidence of localized periodontitis and ONJ. Our data indicates strong oral microbial community shifts according to oral health condition and trends in the shifts associated with diet.

Anti-vascular endothelial growth factor antibody monotherapy causes destructive advanced periodontitis in rice rats (Oryzomys palustris).

OBJECTIVE: Angiogenesis inhibitors (AgI) are commonly used in combination chemotherapy protocols to treat cancer, and have been linked to osteonecrosis of the jaw (ONJ). However, it is unknown if AgI therapy alone is sufficient to induce ONJ. We have previously established an ONJ model in rice rats with localized periodontitis that receive zoledronic acid (ZOL). The purpose of this study was to use this model to determine the role of anti-vascular endothelial growth factor A (anti-VEGF) antibody treatment of rice rats with localized maxillary periodontitis. We hypothesized that rice rats with localized maxillary periodontitis given anti-VEGF monotherapy will develop oral lesions that resemble ONJ, defined by exposed, necrotic alveolar bone. METHODS: At age 4 weeks, 45 male rice rats were randomized into three groups (n = 15): 1) VEH (saline), 2) ZOL (80 µg/kg body weight, intravenously once monthly), and 3) anti-VEGF (5 mg B20-4.1.1/kg body weight, subcutaneously twice weekly). After 24 weeks, rats were euthanized, jaws were excised and a high-resolution photograph of each quadrant was taken to assign a severity grade based on gross appearance. Jaws were then fixed, scanned by MicroCT, decalcified and sectioned for histopathologic and immunohistochemical analyses. RESULTS: 40-80% of the rats in the three groups developed gross oral lesions. 50% of ZOL rats developed ONJ. In contrast, 80% of the anti-VEGF rats developed destructive advanced periodontitis that was characterized by extreme alveolar bone loss and fibrosis. Anti-VEGF rats never developed exposed, necrotic bone. Furthermore, only anti-VEGF rats developed mild to severe mandibular periodontitis. Compared to VEH rats, more T-cells were found in periodontal lesions of anti-VEGF rats and more cells of the monocyte lineage were found in ONJ lesions of ZOL rats. CONCLUSIONS: Anti-VEGF monotherapy administered to a validated rodent model of ONJ caused a destructive advanced form of periodontitis that differed significantly from ONJ.

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.

Prognostic Factors for Locoregional Recurrence in Neuroendocrine Tumors of the Rectum.

BACKGROUND: Optimal management of rectal neuroendocrine tumors is not yet well defined. Various pathologic factors, particularly tumor size, have been proposed as prognostic markers. OBJECTIVE: We characterized sequential patients diagnosed with rectal neuroendocrine tumors in a population-based setting to determine whether tumor size and other pathologic markers could be useful in guiding locoregional management. DESIGN: This study is a retrospective analysis of data from the British Columbia provincial cancer registry. SETTINGS: The study was conducted at a tertiary care center. PATIENTS: Sequential patients diagnosed with rectal neuroendocrine tumors between 1999 and 2011 were identified. Neuroendocrine tumors were classified as G1 and G2 tumors with a Ki-67 ≤20% and/or mitotic count ≤20 per high-power field. MAIN OUTCOME MEASURES: Baseline clinicopathologic data including TNM staging, depth of invasion, tumor size, treatment modalities, and outcomes including survival data were measured. RESULTS: Of 91 rectal neuroendocrine tumors, the median patient age was 58 years, and 35 were men. Median tumor size was 6 mm. Median length of follow-up was 58.1 months, with 3 patients presenting with stage IV disease. Treatment included local ablation (n = 5), local excision (n = 79), surgical resection (n = 4), and pelvic radiation (n = 1; T3N1 tumor). Final margin status was positive in 17 cases. Local relapse occurred in 8 cases and 1 relapse to bone 13 months after T3N1 tumor resection. Univariate analysis demonstrated an association between local relapse and Ki-67, mitotic count, grade, and lymphovascular invasion (p < 0.01). Larger tumor size was associated with decreased disease-free survival. LIMITATIONS: Sample size was 91 patients in the whole provincial population over a 13-year time period because of the low incidence of rectal neuroendocrine tumors. CONCLUSIONS: In this population-based cohort, rectal neuroendocrine tumors generally presented with small, early tumors and were treated with local excision or surgical resection without pelvic radiation. Pathologic markers play a role in risk stratification and prognostication. See Video Abstract at http://links.lww.com/DCR/A514.

Distinguishing Benign from Malignant Pancreatic and Periampullary Lesions Using Combined Use of ¹H-NMR Spectroscopy and Gas Chromatography-Mass Spectrometry.

Previous work demonstrated that serum metabolomics can distinguish pancreatic cancer from benign disease. However, in the clinic, non-pancreatic periampullary cancers are difficult to distinguish from pancreatic cancer. Therefore, to test the clinical utility of this technology, we determined whether any pancreatic and periampullary adenocarcinoma could be distinguished from benign masses and biliary strictures. Sera from 157 patients with malignant and benign pancreatic and periampullary lesions were analyzed using proton nuclear magnetic resonance (¹H-NMR) spectroscopy and gas chromatography-mass spectrometry (GC-MS). Multivariate projection modeling using SIMCA-P+ software in training datasets (n = 80) was used to generate the best models to differentiate disease states. Models were validated in test datasets (n = 77). The final ¹H-NMR spectroscopy and GC-MS metabolomic profiles consisted of 14 and 18 compounds, with AUROC values of 0.74 (SE 0.06) and 0.62 (SE 0.08), respectively. The combination of ¹H-NMR spectroscopy and GC-MS metabolites did not substantially improve this performance (AUROC 0.66, SE 0.08). In patients with adenocarcinoma, glutamate levels were consistently higher, while glutamine and alanine levels were consistently lower. Pancreatic and periampullary adenocarcinomas can be distinguished from benign lesions. To further enhance the discriminatory power of metabolomics in this setting, it will be important to identify the metabolomic changes that characterize each of the subclasses of this heterogeneous group of cancers.

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.

Testosterone and trenbolone enanthate increase mature myostatin protein expression despite increasing skeletal muscle hypertrophy and satellite cell number in rodent muscle.

The androgen-induced alterations in adult rodent skeletal muscle fibre cross-sectional area (fCSA), satellite cell content and myostatin (Mstn) were examined in 10-month-old Fisher 344 rats (n = 41) assigned to Sham surgery, orchiectomy (ORX), ORX + testosterone (TEST; 7.0 mg week-1 ) or ORX + trenbolone (TREN; 1.0 mg week-1 ). After 29 days, animals were euthanised and the levator ani/bulbocavernosus (LABC) muscle complex was harvested for analyses. LABC muscle fCSA was 102% and 94% higher in ORX + TEST and ORX + TREN compared to ORX (p < .001). ORX + TEST and ORX + TREN increased satellite cell numbers by 181% and 178% compared to ORX, respectively (p < .01), with no differences between conditions for myonuclear number per muscle fibre (p = .948). Mstn protein was increased 159% and 169% in the ORX + TEST and ORX + TREN compared to ORX (p < .01). pan-SMAD2/3 protein was ~30-50% greater in ORX compared to SHAM (p = .006), ORX + TEST (p = .037) and ORX + TREN (p = .043), although there were no between-treatment effects regarding phosphorylated SMAD2/3. Mstn, ActrIIb and Mighty mRNAs were lower in ORX, ORX + TEST and ORX + TREN compared to SHAM (p < .05). Testosterone and trenbolone administration increased muscle fCSA and satellite cell number without increasing myonuclei number, and increased Mstn protein levels. Several genes and signalling proteins related to myostatin signalling were differentially regulated by ORX or androgen therapy.

Surgical management of rectal carcinoids: trends and outcomes from the Surveillance, Epidemiology, and End Results database (1988 to 2012).

BACKGROUND: Local excision of small (<10 mm) rectal carcinoids is a standard treatment. Actual patterns of care and outcomes are understudied because of the rarity of this tumor. METHODS: Surveillance, Epidemiology, and End Results database (1988 to 2012) was interrogated for rectal carcinoid patients. Chi-square testing and Kaplan-Meier survival analysis were used to compare survival outcomes. RESULTS: Of all, 11,329 patients were identified-9,605 with only localized disease. The majority (77%) underwent local excision only. Full rectal resection was performed more frequently for tumors greater than 10 mm (11.7% to 12.2%) than for tumors less than 10 mm (4.5% to 4.9%, P < .001), and for higher T stage (T1: 4.0%, T2: 11.4%, T3/4:30.4%, P < .001). Nonoperative management was more common after year 2000 (11.2% to 13.7%) than prior (7.4% to 8.5%, P < .001). Cancer-specific survival improved across time periods but did not differ between nonoperative, local excision, or surgical resection. CONCLUSIONS: Nonexcisional management of small, localized rectal carcinoids is becoming more common and may offer equivalent survival to excision or resection.

Effects of testosterone treatment on markers of skeletal muscle ribosome biogenesis.

The effects of testosterone (TEST) treatment on markers of skeletal muscle ribosome biogenesis in vitro and in vivo were examined. C2 C12 myotubes were treated with 100 nm TEST for short-term (24-h) and longer-term (96-h) treatments. Moreover, male 10-month-old Fischer 344 rats were housed for 4 weeks, and the following groups were included in this study: (i) Sham-operated (Sham) rats, (ii) orchiectomised rats (ORX) and (iii) ORX+TEST-treated rats (7.0 mg week-1 ). For in vitro data, TEST treatment increased c-Myc mRNA expression by 38% (P = 0.004) after 96 h, but did not affect total RNA, 47S pre-rRNA, Raptor mRNA, Nop56 mRNA, Bop1 mRNA, Ncl mRNA at 24 h or 96 h following the treatment. For in vivo data, ORX decreased levator ani/bulbocavernosus (LABC) myofibril protein versus Sham (P = 0.006), whereas ORX+TEST (P = 0.015) rescued this atrophic effect. ORX also decreased muscle ribosome content (total RNA) compared to Sham (P = 0.046), whereas ORX+TEST tended to rescue this effect (P = 0.057). However, other markers of ribosome biogenesis including c-Myc mRNA, Nop56 mRNA, Bop1 mRNA, Ncl mRNA decreased with ORX independently of TEST treatments (P < 0.05). Finally, lower phospho-(Ser235/236)-to-total rps6 protein and lower rpl5 protein levels existed in ORX+TEST rats versus other treatments, suggesting that chronic TEST treatment may lower translational capacity.

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.

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.

Personalized oncogenomics: clinical experience with malignant peritoneal mesothelioma using whole genome sequencing.

Peritoneal mesothelioma is a rare and sometimes lethal malignancy that presents a clinical challenge for both diagnosis and management. Recent studies have led to a better understanding of the molecular biology of peritoneal mesothelioma. Translation of the emerging data into better treatments and outcome is needed. From two patients with peritoneal mesothelioma, we derived whole genome sequences, RNA expression profiles, and targeted deep sequencing data. Molecular data were made available for translation into a clinical treatment plan. Treatment responses and outcomes were later examined in the context of molecular findings. Molecular studies presented here provide the first reported whole genome sequences of peritoneal mesothelioma. Mutations in known mesothelioma-related genes NF2, CDKN2A, LATS2, amongst others, were identified. Activation of MET-related signaling pathways was demonstrated in both cases. A hypermutated phenotype was observed in one case (434 vs. 18 single nucleotide variants) and was associated with a favourable outcome despite sarcomatoid histology and multifocal disease. This study represents the first report of whole genome analyses of peritoneal mesothelioma, a key step in the understanding and treatment of this disease.

Management of open lower limb injuries in South West England and Wales.

INTRODUCTION: The joint British Association of Plastic, Reconstructive and Aesthetic Surgeons/British Orthopaedic Association standards define best practice management in open diaphyseal fractures of the lower limb. The aim of our study was to review the regional approach and experience in South West England and Wales. A further objective was to evaluate service provision with regard to the standards' key recommendations. METHODS: A prospective audit was undertaken of open diaphyseal fracture patients. Compliance with published standards within all orthoplastic services in South West England and Wales was assessed, and facilities were evaluated. RESULTS: A total of 86 patients were managed between October 2012 and March 2013. This was a 56% increase from 2008. Over half (56%) presented directly to the orthoplastic services with all patients undergoing debridement within 24 hours. Two-thirds (66%) of procedures were in daylight hours excluding those requiring immediate surgical intervention. Adherence to correct antibiotic therapy was 88% at admission, 50% at primary surgery and 62% at definitive surgery. Almost two-thirds (60%) of primary procedures were performed with combined senior orthoplastic teams, with 81% achieving definitive soft tissue coverage and fixation within seven days. Compliance improved in units with larger patient caseloads and where there was an early combined approach during daylight hours. CONCLUSIONS: Increased open lower limb fracture workload was demonstrated across South West England and Wales, probably owing to centralisation of trauma services. An improvement in early transfer of this patient group to orthoplastic facilities has allowed all patients to be assessed and debrided within the recommended timeframe. Standards were most likely to be met in those centres seeing higher numbers of injuries and when there was a daylight hours procedure by combined orthoplastic teams.

Bone loss in a new rodent model combining spinal cord injury and cast immobilization.

OBJECTIVES: Characterize bone loss in our newly developed severe contusion spinal cord injury (SCI) plus hindlimb immobilization (IMM) model and determine the influence of muscle contractility on skeletal integrity after SCI. METHODS: Female Sprague-Dawley rats were randomized to: (a) intact controls, (b) severe contusion SCI euthanized at Day 7 (SCI-7) or (c) Day 21 (SCI-21), (d) 14 days IMM-alone, (e) SCI+IMM, or (f) SCI+IMM plus 14 days body weight supported treadmill exercise (SCI+IMM+TM). RESULTS: SCI-7 and SCI-21 exhibited a >20% reduction in cancellous volumetric bone mineral density (vBMD) in the hindlimbs (p⋜0.01), characterized by reductions in cancellous bone volume (cBV/TV%), trabecular number (Tb.N), and trabecular thickness. IMM-alone induced no observable bone loss. SCI+IMM exacerbated cancellous vBMD deficits with values being >45% below Controls (p⋜0.01) resulting from reduced cBV/TV% and Tb.N. SCI+IMM also produced the greatest cortical bone loss with distal femoral cortical area and cortical thickness being 14-28% below Controls (p⋜0.01) and bone strength being 37% below Controls (p⋜0.01). SCI+IMM+TM partially alleviated bone deficits, but values remained below Controls. CONCLUSIONS: Residual and/or facilitated muscle contractility ameliorate bone decrements after severe SCI. Our novel SCI+IMM model represents a clinically-relevant means of assessing strategies to prevent SCI-induced skeletal deficits.

Preoperative computed tomography does not predict resectability in peritoneal carcinomatosis.

BACKGROUND: Obtaining a complete cytoreduction in patients with peritoneal carcinomatosis (PC) is one of the most significant prognostic variables for long-term survival. This study explored features on preoperative computed tomography (CT) to predict unresectability. METHODS: A retrospective case-control study was conducted of 15 patients with unresectable PC and 15 patients with completely resected PC matched by intraoperative peritoneal cancer index (PCI) and pathology type. Two surgical oncologists blindly analyzed all abdominopelvic CT scans. RESULTS: PCI estimated on imaging was not higher in unresectable patients (P = .851) and significantly underestimated intraoperative PCI measurement (P = .003). No single concerning feature was associated with unresectability. However, patients with 2 or more concerning features were more likely to be unresectable (87.5% vs 36.4%, P = .035). CONCLUSIONS: Two or more concerning CT imaging features appear to be associated with a higher risk of unresectability in patients with PC. However, no specific imaging feature should exclude a patient from an attempted cytoreduction.

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.