Laparoscopic cytoreductive surgery and hyperthermic intraperitoneal chemotherapy for perforated low-grade appendiceal mucinous neoplasms.

INTRODUCTION: Cytoreductive surgery with hyperthermic intraperitoneal chemotherapy (CRS/HIPEC) is an established treatment for pseudomyxoma peritonei (PMP) from perforated low-grade appendiceal mucinous neoplasms (LAMN II). In a selected group of LAMN II patients without established PMP, CRS/HIPEC can be performed laparoscopically (L-CRS/HIPEC); however the short-term benefits and safety of this approach have yet to be determined. This study aims to determine the short-term outcomes from a series of L-CRS/HIPEC LAMN II patients compared to those who have undergone a similar open operation (O-CRS/HIPEC) for low-volume PMP. METHODS: LAMN II patients undergoing L-CRS/HIPEC at a UK national peritoneal tumour centre were compared to O-CRS/HIPEC patients (peritoneal cancer index ≤ 7). Outcomes of interest included Clavien-Dindo complication grade, operative time, blood transfusions, high dependency unit (HDU) admission, length of hospital stay, and histopathological findings. RESULTS: 55 L-CRS/HIPEC were compared to 29 O-CRS/HIPEC patients (2003-2017). Groups were matched for age, sex, and procedures. Median operative time was 8.8 (IQR 8.1-9.5) h for L-CRS/HIPEC versus 7.3 (IQR 6.7-8) h for O-CRS/HIPEC (Mann-Whitney test p < 0.001). Post-operative HDU admission was 56% versus 97% (OR 0.04 95% CI 0.01-0.34) and median length of stay = 6 (IQR 5-8) versus 10 (IQR 8-11) days (p < 0.001) for L- versus O-CRS/HIPEC. Despite a normal pre-operative CT scan, 13/55 (23.6%) L-CRS/HIPEC patients had acellular mucin and 2/55 (3.5%) had mucin with epithelium present in their specimens. Residual appendix tumour was identified in 2/55 patients (3.6%). Clavien-Dindo Grade 1-4 complications were similar in both groups with no mortality. CONCLUSION: L-CRS/HIPEC for LAMN II takes longer; however patients have significantly reduced length of HDU and overall stay, without increased post-operative complications. A significant proportion of LAMN II patients undergoing L-CRS/HIPEC have extra-appendiceal acellular mucin with some cases demonstrating residual cellular epithelium from the LAMN II. The risk of these patients developing PMP without surgery is under current review.

Referral pathways and outcome of patients with colorectal peritoneal metastasis (CRPM).

INTRODUCTION: Traditionally patients with colorectal peritoneal metastases (CRPM) were offered palliative chemotherapy and best supportive care. With the introduction of cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC), patients in the UK have been referred to nationally approved centres. This study describes the pattern of referral and outcomes of patients managed through one UK centre. METHODS: and Methods: A prospective register recorded referrals, demographics, prior treatment pathways, and specialist multidisciplinary team (MDT) decisions (2002-2015). Peritoneal cancer index (PCI) was recorded intra-operatively; complete cytoreduction was deemed when a CC0/1 was achieved. Complications were classified using NCI CTCAE. v.4. Median overall survivals (OS) were described for those treated by CRS/HIPEC and in derived estimates for patients with isolated peritoneal metastases treated by chemotherapy alone in the ARCAD trials consortium. RESULTS: Two-hundred-eighty-six patients with CRPM were referred. Despite increasing numbers of referrals annually, the proportion of patients selected for CRS/HIPEC decreased from 64.5%, to 40%, and to 37.1% for 2002-09, 2010-12, and 2013-15, respectively (p < 0.017). CRS/HIPEC was undertaken in 117 patients with a median PCI of 7 and CC0/1 achieved in 86.3%. NCI CTCAE grade 3/4 complication rates were 9.4%; 30-day mortality was 0.85%. Median OS following CRS/HIPEC was 46.0 months: that for patients not receiving CRS/HIPEC was 13.2 months. CONCLUSION: The evolution of the national peritoneal treatment centre over 14 years has been associated with increased referral numbers, refinement of selection for major surgery, matched with achievements of low complication rates and survival advantages in selected patients compared with traditional non-surgical treatments.

Predicting Survival After Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy for Appendix Adenocarcinoma.

BACKGROUND: Appendix adenocarcinomas are rare tumors with propensity for peritoneal metastasis. Cytoreductive surgery with hyperthermic intraperitoneal chemotherapy is an established treatment with curative intent, but, to date, studies reporting survival have been heterogeneous with regard to their patient groups (including other tumor types), interventions (not all patients receiving intraperitoneal chemotherapy), and follow-up (varying surveillance protocols). OBJECTIVE: The aim of this study is to quantify the impact of this intervention on survival in a homogeneous group of patients with appendix adenocarcinoma receiving standardized treatment and follow-up, and to determine the impact of prognostic indicators on survival. DESIGN: This is a retrospective analysis of a prospective database at a national peritoneal tumor center where all patients had their appendix pathology reviewed and management planned by a specialized peritoneal tumor multidisciplinary team. MAIN OUTCOME MEASURES: Data were extracted on prognostic indicators including peritoneal cancer index, completeness of cytoreduction score, preoperative tumor markers, and histological features. Overall and disease event-free survival from the date of intervention were evaluated using Kaplan Meier curves and univariate Cox proportional hazards regression analysis. RESULTS: A total of 65 patients underwent cytoreductive surgery with hyperthermic intraperitoneal chemotherapy for appendix adenocarcinoma between 2005 and 2015. Median follow-up was 44.3 months. The overall survival was 55.5% and disease event-free survival was 36.1% (5-year rate). Peritoneal Cancer Index <7, complete cytoreduction score of 0, and preoperative CEA of <6 were all associated with significantly higher overall and disease event-free survival. CA19-9 <38 and CA125 <31 were not associated with a significantly higher overall or disease event-free survival. LIMITATIONS: The sample size was limited because of the rarity of this tumor type. CONCLUSIONS: This study quantifies the impact of cytoreductive surgery with hyperthermic intraperitoneal chemotherapy on overall and disease event-free survival for appendix adenocarcinoma, identifying key prognostic indicators that may guide treatment. It supports the referral of these rare tumors to specialist centers with appropriate expertise for initial management and follow-up. See Video Abstract at http://links.lww.com/DCR/A595.

Long-term Quality of Life After Cytoreductive Surgery and Heated Intraperitoneal Chemotherapy for Pseudomyxoma Peritonei: A Prospective Longitudinal Study.

BACKGROUND: Cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) are an established treatment for pseudomyxoma peritonei (PMP), but it is a major surgical procedure and may be associated with long-term morbidity. To date, health-related quality-of-life (HRQL) data among survivors are lacking. METHODS: A two-period qualitative study investigated patients undergoing CRS-HIPEC for PMP at a national peritoneal tumor center between 2003 and 2011. First, the European Organization for Research and Treatment (EORTC)-QLQ C30 HRQL questionnaire was used longitudinally preoperatively and at postoperative months 3, 6, 9, 12, 18, and 24, then yearly thereafter. Second, it was updated in 2016 as a cross-sectional study. Both studies were compared with age- and sex-matched reference populations (one-way t tests). RESULTS: A total of 553 longitudinal HRQL questionnaires were completed for 137 patients, truncated at 60 months. In the 2016 update, 85 responses were received from 103 survivors (mean follow-up period, 8.11 years). Patients' physical, role, and social function scores were impaired until 12 months postoperatively, after which the scores did not differ significantly from those of with reference populations. Similarly, fatigue, appetite loss, insomnia, and financial difficulties worsened significantly compared with reference populations in the first 12-months and then normalized. In contrast, impaired cognitive function (82.3 vs 88.5; P = 0.017), constipation (13.7 vs 7.3; P = 0.032), and diarrheal symptoms (15.1 vs 4.9; P = 0.0006) persisted through both periods. Global health scores did not differ significantly from those of the reference population. CONCLUSIONS: Beyond 12 months postoperatively, CRS-HIPEC for PMP is associated with a good quality of life except for some cognitive functional impairment and bowel disturbances.

Bio-fortification and shelf-life extension of idli batter using curry leaves (Murraya koenigii).

Among several traditional foods of India, idli is one of the most popular and commonly consumed steamed products. A new method of adding Murraya koenigii (curry leaves) to idli batter as a vehicle for fortification and extension of shelf-life has been developed. Dried curry leaves powder was incorporated with other ingredients like rice and dehusked black gram in different proportions to optimize the most palatable formulation. Rate of fermentation and microbial changes in the batter; nutritional qualities, texture and sensory properties of the prepared product were assessed. Incorporation of curry leaves powder (5 %) in idli batter increased the shelf-life and also increased the flavour, texture and appearance of the idli. The calcium content of the prepared idli was 10 times more than that of the control idli, while dietary fiber content increased by 18.6 %. Anti-microbial activity of the curry leaves in idli batter extended the shelf-life from 2 to 5 days when stored at 30 °C.

Computerized tomography providing definitive diagnosis of colonic lipoma: a case series.

Lipomas are common benign mesenchymal tumors. They can develop in virtually all organs throughout the body. Colonic lipomas are uncommon, benign, submucosal adipose tumors that are usually asymptomatic. Large lipomas can cause symptoms such as constipation, abdominal pain, rectal bleeding, and intussusception. We report a case series of 2 colonic submucosal lipomas with varying clinical presentations, elaborating the importance of computerized tomography imaging in the diagnosis and preoperative planning.

Single-center comparative study of laparoscopic versus open colorectal surgery: a 2-year experience.

AIM: To examine the change in practice from open to laparoscopic practice in our local trust, a national training colorectal unit. METHODS: Retrospective comprehensive review of clinical case notes of all colorectal resections between October 2007 and October 2009. Patients were identified through clinical coding and data were analyzed using SPSS. RESULTS: Comparison of 113 open versus 103 laparoscopic colorectal surgeries for various indications and short-term outcomes was made. There was an expected overall increase in the laparoscopic colorectal resections. The mean age was 73 years for open and 68 years for laparoscopic surgeries. There was no significant difference between the 2 groups with respect to age, sex, and the American Society of Anaesthesiologists. Of the 103 patients who were initially treated with laparoscopy-assisted colectomy, 12 (11.7%) were shifted to open procedures. Perioperative recovery was faster in the laparoscopic-surgery group than in the open-colectomy group, as reflected by a shorter hospital stay (median, 8 vs. 13 d). The overall complication rate was significantly less in the laparoscopy-assisted colectomy group than in the open-colectomy group (33% vs. 46%, P=0.05). CONCLUSIONS: Our local hospital practices support the many benefits of laparoscopic colorectal surgery. Substantial improvements in rates of hospital stay and wound infection were noted, hence shifting our practice safely in a district general hospital.

Assessment of screening colonoscopy competency in colon and rectal surgery fellows: a single institution experience.

BACKGROUND: The American Board of Surgery and the American Board of Colorectal Surgery requirements for certification include 80 and 140 colonoscopic procedures, respectively. However, little data support the attainment of colonoscopic competency. The aim of this retrospective study is to report the colonoscopy learning experience for colorectal surgery fellows at a single high-volume training program. MATERIAL AND METHODS: A prospective database recorded the experience of six colorectal fellows over two consecutive academic years. Univariate, moving average curves, and change point analysis were used to assess learning curve trends over time. Screening colonoscopy competency was defined by a significant reduction in total procedure time and 80% cecal intubation rate within 35 min. RESULTS: From 2004 to 2006, a total of 2904 screening colonoscopies were performed, including 1498 (52%) by fellows (mean 249 procedures per fellow). The mean procedure time for fellows was 30.2 ± 15 min. Procedure time decreased significantly up to 120 procedures but not thereafter. Overall, fellows' total procedure time decreased by 7.6 min over the course of the year (P < 0.0001); 66% of fellows were able to complete 80% of the procedure in 40 min in the last 2 mo of training. The combined learning curve of all the fellows and the change point analysis showed a significant change occurs at 94 procedures. Using the moving average curve, we have shown 114 procedures are needed to achieve 80% completion rate in 35 min in majority of the fellows. CONCLUSIONS: Colorectal surgery fellows were observed to achieve screening colonoscopy competency approximately between 94 and 114 procedures. In the era of working time restrictions, prospective documentation of individual trainee performance may allow tailored training based on observed competency.

An update on contrast echocardiography.

Ultrasound contrast agents, used with contrast-specific imaging techniques, have an established role for diagnostic cardiovascular imaging in the echocardiography laboratory. The advent of tissue harmonic imaging, albeit a significant advancement in ultrasound technology, still fail to produce diagnostically useful images in a significant proportion of patients. This therefore, often leads to inaccurate assessment of left ventricular function, neccesitating the use of other more laborious and expensive imaging techniques purely for diagnostic purposes. Historically, contrast agents have not been an integral component of the echocardiography imaging laboratory. However the need for a more robust method for the assessment of left ventricular function facilitated the developement of a unique class of contrast agents composed of microbubbles, which together with ultrasound, produce opacification of the left ventricular cavity, thus enabling accurate quantification of its function. The use of these contrast agents have now gone beyond the assessment of wall motion and function to the assessment of myocardial perfusion. Myocardial contrast echocardiography has enabled the assessment of cardiac anatomy, function and perfusion, all in one sitting, by the bedside. Contrast ultrasound imaging has now been applied to even newer techniques such as real-time three-dimensional echocardiography and is also showing promise in the assessment of carotid ultrasound for intima-media thickness. Contrast agents therefore have a significant role in cardiovascular diagnostics and its use can only improve patient care.

P-selectin antagonism reduces thrombus formation in humans.

BACKGROUND: Interaction of P-selectin with its glycoprotein ligand (P-selectin glycoprotein ligand type 1) mediates inflammatory processes that may also include vascular thrombosis. Platelet P-selectin expression is increased in patients with coronary heart disease, and its antagonism represents a potential future therapeutic target for the prevention and treatment of atherothrombosis. AIM: To investigate the effects of the novel small molecule P-selectin antagonist PSI-697 on thrombus formation in humans. METHODS AND RESULTS: In a double-blind randomized crossover study, thrombus formation was measured in 12 healthy volunteers, using the Badimon ex vivo perfusion chamber under conditions of low and high shear stress. Saline placebo, low-dose (2 m) and high-dose (20 m) PSI-697 and the glycoprotein IIb-IIIa receptor antagonist tirofiban (50 ng mL(-1)) were administered into the extracorporeal circuit prior to the perfusion chamber. As compared with saline placebo, blockade of platelet glycoprotein IIb-IIIa receptor with tirofiban produced 28% and 56% reductions in thrombus formation in the low-shear and high-shear chambers, respectively. PSI-697 caused a dose-dependent, but more modest, reduction in thrombus formation. Low-dose PSI-796 (2 m) reduced total thrombus area by 14% (P = 0.04) and 30% (P = 0.0002) in the low-shear and high-shear chambers, respectively. At the high dose (20 m), PSI-697 reduced total thrombus area by 18% (P = 0.0094) and 41% (P = 0.0008) in the low-shear and high-shear chambers, respectively. CONCLUSIONS: P-selectin antagonism with PSI-697 reduces ex vivo thrombus formation in humans. These findings provide further evidence that P-selectin antagonism may be a potential target for the prevention and treatment of cardiovascular disease.

Effect of infliximab on short-term complications in patients undergoing operation for chronic ulcerative colitis.

BACKGROUND: Total proctocolectomy and ileal pouch anal anastomosis (IPAA) is the preferred operation for patients with chronic ulcerative colitis (CUC) refractory to medical therapy. Infliximab (IFX), an antitumor necrosis factor-alpha antibody, has demonstrated efficacy in medical management of CUC. The aim of this study is to determine if IFX before IPAA impacts short-term outcomes. STUDY DESIGN: A prospective institutional database was retrospectively reviewed for short-term complications after IPAA for CUC. Postoperative outcomes were compared between patients who received pre-IPAA IFX and those who did not. RESULTS: Between 2002 and 2005, 47 patients received IFX before IPAA, and 254 patients received none. There were no gender (p = 0.16) or body mass index (p = 0.07) differences between groups. IFX patients were younger than non-IFX patients (mean age 28.1 to 39.3 years) (p < 0.001). In IFX patients, 70% were receiving preoperative IFX, azathioprine, and corticosteroids. Mortality was nil. Overall surgical morbidity was similar: 61.7% and 48.8%, IFX and non-IFX, respectively (p = 0.10). Anastomotic leaks (p = 0.02), pouch-specific (p = 0.01) and infectious (p < 0.01) complications were more common in IFX patients. Multivariable analysis revealed IFX as the only factor independently associated with infectious complications (odds ratio [OR] = 3.5; CI, 1.6-7.5). In a separate analysis, incorporating age, high-dose corticosteroids, azathioprine, and severity of colitis, IFX remained significantly associated with infectious complications (OR = 2.7; CI, 1.1-6.7). CONCLUSIONS: CUC patients treated with IFX before IPAA have substantially increased the odds of postoperative pouch-related and infectious complications. Additional prospective studies are required to determine if IFX alone or other factors contribute to the observed increases in infectious complications.

Constitutive properties, not molecular adaptations, mediate extraocular muscle sparing in dystrophic mdx mice.

Extraocular muscle (EOM) is spared in Duchenne muscular dystrophy. Here, we tested putative EOM sparing mechanisms predicted from existing dystrophinopathy models. Data show that mdx mouse EOM contains dystrophin-glycoprotein complex (DGC)-competent and DGC-deficient myofibers distributed in a fiber type-specific pattern. Up-regulation of a dystrophin homologue, utrophin, mediates selective DGC retention. Counter to the DGC mechanical hypothesis, an intact DGC is not a precondition for EOM sarcolemmal integrity, and active adaptation at the level of calcium homeostasis is not mechanistic in protection. A partial, fiber type-specific retention of antiischemic nitric oxide to vascular smooth muscle signaling is not a factor in EOM sparing, because mice deficient in dystrophin and alpha-syntrophin, which localizes neuronal nitric oxide synthase to the sarcolemma, have normal EOMs. Moreover, an alternative transmembrane protein, alpha7beta1 integrin, does not appear to substitute for the DGC in EOM. Finally, genomewide expression profiling showed that EOM does not actively adapt to dystrophinopathy but identified candidate genes for the constitutive protection of mdx EOM. Taken together, data emphasize the conditional nature of dystrophinopathy and the potential importance of nonmechanical DGC roles and support the hypothesis that broad, constitutive structural cell signaling, and/or biochemical differences between EOM and other skeletal muscles are determinants of differential disease responsiveness.

Molecular organization of the extraocular muscle neuromuscular junction: partial conservation of and divergence from the skeletal muscle prototype.

PURPOSE: The phenotypically novel extraocular muscles (EOMs) exhibit fundamental differences in innervation and neuromuscular junction (NMJ) morphology from other skeletal muscles. In the current study, the morphology and molecular organization of NMJs of EOM singly innervated (SIF) and multiply innervated (MIF) fiber types were evaluated and the distribution of molecules involved in formation and maintenance of NMJs were specifically characterized. METHODS: Adult mouse EOM NMJ organization was examined by immunofluorescence and confocal microscopy. Differential cellular localization of components of two established synaptic signaling pathways, (1) neuregulin and erbB receptors 2, 3, and 4 and (2) agrin, MuSK, and rapsyn and select NMJ-associated structural proteins were studied for EOM SIF and MIF populations. Endplate topography and structure were also studied, using both confocal microscopy and transmission electron microscopy, with NMJ morphologic organization correlated with specific EOM fiber types. RESULTS: Confocal fluorescence microscopy demonstrated that, for NMJs of both EOM SIFs and MIFs, components of neuregulin and agrin pathways and the major components of the junctional dystrophin-glycoprotein complex (DGC) colocalized with acetylcholine receptor (AChR) aggregates. However, EOM exhibited novel fiber-type-specific extrasynaptic localization of two key DGC signaling-related molecules: alpha-dystrobrevin 1 (global MIFs) and syntrophin beta1 (global MIFs and orbital MIFs and SIFs). CONCLUSIONS: The data establish that the molecular organization of EOM SIF and MIF NMJs includes the same signaling and structural molecules previously characterized for other skeletal muscles. By contrast, divergence in other aspects of the synaptic and nonsynaptic sarcolemmal organization of EOM fiber types may underlie the unique responses of these muscles in a variety of neuromuscular disorders.

Differential susceptibility of the ocular motor system to disease.

This review summarizes an alternative approach to the understanding of neuromuscular disease. By contrasting disease susceptibility of extraocular muscle and ocular motor neurons, it is hoped that unique insights into disease mechanisms may be identified. Disorder of eye movements leads to dramatic symptoms for patients and the ocular motor system is relatively limited in its ability to compensate rapidly for such disruptions. However, more profound reasons exist as to why myasthenia gravis compromises neuromuscular transmission at ocular muscle synapses as well as why Graves' ophthalmopathy exists. In contrast, muscular dystrophies spare the eye muscles while devastating all other skeletal muscles; the same is true for motor neuron diseases. It is hoped that this review will encourage others to view the world of neuromuscular diseases as delineated into those that spare the ocular motor system and those that do not.

A chronic inflammatory response dominates the skeletal muscle molecular signature in dystrophin-deficient mdx mice.

Mutations in dystrophin cause Duchenne muscular dystrophy (DMD), but absent dystrophin does not invariably cause necrosis in all muscles, life stages and species. Using DNA microarray, we established a molecular signature of dystrophinopathy in the mdx mouse, with evidence that secondary mechanisms are key contributors to pathogenesis. We used variability controls, adequate replicates and stringent analytic tools, including significance analysis of microarrays to estimate and manage false positive rates. In leg muscle, we identified 242 differentially expressed genes, >75% of which have not been previously reported as altered in human or animal dystrophies. Data provide evidence for coordinated activity of numerous components of a chronic inflammatory response, including cytokine and chemokine signaling, leukocyte adhesion and diapedesis, invasive cell type-specific markers, and complement system activation. Selective chemokine upregulation was confirmed by RT-PCR and immunoblot, and may be a key determinant of the nature of the inflammatory response in dystrophic muscle. Up-regulation of secreted phosphoprotein 1 (minopontin, osteopontin) mRNA and protein in dystrophic muscle identified a novel linkage between inflammatory cells and repair processes. Extracellular matrix genes were up-regulated in mdx to levels similar to those in DMD. Since, unlike DMD, mdx exhibits little fibrosis, data suggest that collagen regulation at post-transcriptional stages mediates extensive fibrosis in DMD. Taken together, these data identify a relatively neglected aspect of DMD, suggest new treatment avenues, and highlight the value of genome-wide profiling in study of complex disease processes.