Recent Developments and Challenges in Optimization-Based Process Synthesis.

This article first reviews recent developments in process synthesis and discusses some of the major challenges in the theory and practice in this area. Next, the article reviews key concepts in optimization-based conceptual design, namely superstructure representations, multilevel models, optimization methods, and modeling environments. A brief review of the synthesis of major subsystems and flowsheets is presented. Finally, the article closes with a critical assessment and future research challenges for the process synthesis area.

Survival analysis of the CEAwatch multicentre clustered randomized trial.

BACKGROUND: The CEAwatch randomized trial showed that follow-up with intensive carcinoembryonic antigen (CEA) monitoring (CEAwatch protocol) was better than care as usual (CAU) for early postoperative detection of colorectal cancer recurrence. The aim of this study was to calculate overall survival (OS) and disease-specific survival (DSS). METHODS: For all patients with recurrence, OS and DSS were compared between patients detected by the CEAwatch protocol versus CAU, and by the method of detection of recurrence, using Cox regression models. RESULTS: Some 238 patients with recurrence were analysed (7·5 per cent); a total of 108 recurrences were detected by CEA blood test, 64 (55·2 per cent) within the CEAwatch protocol and 44 (41·9 per cent) in the CAU group (P = 0·007). Only 16 recurrences (13·8 per cent) were detected by patient self-report in the CEAwatch group, compared with 33 (31·4 per cent) in the CAU group. There was no significant improvement in either OS or DSS with the CEAwatch protocol compared with CAU: hazard ratio 0·73 (95 per cent 0·46 to 1·17) and 0·78 (0·48 to 1·28) respectively. There were no differences in survival when recurrence was detected by CT versus CEA measurement, but both of these methods yielded better survival outcomes than detection by patient self-report. CONCLUSION: There was no direct survival benefit in favour of the intensive programme, but the CEAwatch protocol led to a higher proportion of recurrences being detected by CEA-based blood test and reduced the number detected by patient self-report. This is important because detection of recurrence by blood test was associated with significantly better survival than patient self-report, indirectly supporting use of the CEAwatch protocol.

Double-blind randomized controlled trial of collagen mesh for the prevention of abdominal incisional hernia in patients having a vertical rectus abdominis myocutaneus flap during surgery for advanced pelvic malignancy.

AIM: The study investigated the effect of collagen mesh-assisted closure at the donor site in preventing the formation of incisional hernia following construction of a vertical rectus abdominis myocutaneus (VRAM) flap as part of pelvic surgery for recurrent colorectal cancer. METHOD: The study was a double-blinded randomized controlled superiority trial that was designed and performed according to the Consolidated Standards of Reporting Trials (CONSORT) Statement. Eligible patients undergoing surgery that included a VRAM flap for advanced colorectal pelvic malignancy were prospectively randomized to conventional abdominal wound closure or collagen mesh-assisted closure. The primary end-point was incisional herniation at 1 year confirmed by CT. Secondary end-points were CT-verified incisional herniation at 3 and 36 months, clinically recognizable incisional herniation, donor-site and reconstructive-site complications, surgical mortality, postoperative morbidity, postoperative recovery and survival. RESULTS: In total, 58 (29 conventional closure; 29 mesh-assisted closure) patients were included. At 1 year, incisional herniation on the CT scan was found in 12 (50%) of 24 patients in the conventional closure group, and in 8 (33%) of 24 in the mesh-assisted closure group (P = 0.38). No significant difference between the groups was found in surgical mortality, early or late complications or survival. Donor-site morbidity was comparable between the two groups. CONCLUSION: No preventative effect of collagen mesh-assisted closure was observed following VRAM flap reconstruction.

High mortality rates after nonelective colon cancer resection: results of a national audit.

AIM: Colon cancer resection in a nonelective setting is associated with high rates of morbidity and mortality. The aim of this retrospective study is to identify risk factors for overall mortality after colon cancer resection with a special focus on nonelective resection. METHOD: Data were obtained from the Dutch Surgical Colorectal Audit. Patients undergoing colon cancer resection in the Netherlands between January 2009 and December 2013 were included. Patient, treatment and tumour factors were analysed in relation to the urgency of surgery. The primary outcome was 30-day postoperative mortality. RESULTS: The study included 30 907 patients. A nonelective colon cancer resection was performed in 5934 (19.2%) patients. There was a 4.4% overall mortality rate, with significantly more deaths after nonelective surgery (8.5% vs 3.4%, P < 0.001). Older patients, male patients and patients with high comorbidity, advanced tumours, perforated tumours, a tumour in the right or transverse colon and postoperative anastomotic leakage were at risk of postoperative death. In nonelective resections, a right-sided tumour and postoperative anastomotic leakage were associated with high mortality. CONCLUSION: Nonelective colon cancer resection is associated with high mortality. In particular, right-sided resections and patients with tumour perforation are at particularly high risk. The optimization of patients prior to surgery and expeditious operation after diagnosis might prevent the need for a nonelective resection.

Cost-effectiveness of a carcinoembryonic antigen (CEA) based follow-up programme for colorectal cancer (the CEA Watch trial).

AIM: The study CEA Watch (Netherlands Trial Register 2182) has shown that an intensified follow-up schedule with more frequent carcinoembryonic antigen (CEA) measurements but fewer outpatient visits detects more curable recurrences compared with the usual follow-up protocol in colorectal cancer (CRC) patients. The aim of the study was to compare the cost and cost-effectiveness between various follow-up programmes. METHOD: In total, 3223 patients with stage I-III CRC were followed between October 2010 and October 2012. Direct medical costs were calculated per patient adding the costs for all visits, CEA measurements and imaging. Productivity losses and travel expenses were calculated using answers from questionnaires. The cost-effectiveness displayed the additional costs per additional patient with recurrent disease and used an incremental cost-effectiveness ratio (ICER) to compare them. RESULTS: The mean yearly cost per patient was €548 in the intensified protocol and €497 in the control protocol. The ICER was €94 (95% CI €76-€157) per cent; to detect one additional patient with a recurrence in the intervention protocol compared with the control protocol would require an additional €9400. For curable recurrences, the ICER was €607 (95% CI €5695-€5728). Annual patient-reported costs were €509 per year in the intervention protocol and €488 in the control protocol. CONCLUSION: The current study demonstrates that the direct medical and patient-reported cost of a newly introduced, safe and effective way of CRC follow-up was comparable to that of standard care. The ICER per curable recurrence was considered acceptably low.

Intensified follow-up in colorectal cancer patients using frequent Carcino-Embryonic Antigen (CEA) measurements and CEA-triggered imaging: Results of the randomized "CEAwatch" trial.

AIM: The value of frequent Carcino-Embryonic Antigen (CEA) measurements and CEA-triggered imaging for detecting recurrent disease in colorectal cancer (CRC) patients was investigated in search for an evidence-based follow-up protocol. METHODS: This is a randomized-controlled multicenter prospective study using a stepped-wedge cluster design. From October 2010 to October 2012, surgically treated non-metastasized CRC patients in follow-up were followed in eleven hospitals. Clusters of hospitals sequentially changed their usual follow-up care into an intensified follow-up schedule consisting of CEA measurements every two months, with imaging in case of two CEA rises. The primary outcome measures were the proportion of recurrences that could be treated with curative intent, recurrences with definitive curative treatment outcome, and the time to detection of recurrent disease. RESULTS: 3223 patients were included; 243 recurrences were detected (7.5%). A higher proportion of recurrences was detected in the intervention protocol compared to the control protocol (OR = 1.80; 95%-CI: 1.33-2.50; p = 0.0004). The proportion of recurrences that could be treated with curative intent was higher in the intervention protocol (OR = 2.84; 95%-CI: 1.38-5.86; p = 0.0048) and the proportion of recurrences with definitive curative treatment outcome was also higher (OR = 3.12, 95%-CI: 1.25-6.02, p-value: 0.0145). The time to detection of recurrent disease was significantly shorter in the intensified follow-up protocol (HR = 1.45; 95%-CI: 1.08-1.95; p = 0.013). CONCLUSION: The CEAwatch protocol detects recurrent disease after colorectal cancer earlier, in a phase that a significantly higher proportion of recurrences can be treated with curative intent.

Risk factors for anastomotic leakage and leak-related mortality after colonic cancer surgery in a nationwide audit.

BACKGROUND: Surgical resection with restoration of bowel continuity is the cornerstone of treatment for patients with colonic cancer. The aim of this study was to identify risk factors for anastomotic leakage (AL) and subsequent death after colonic cancer surgery. METHODS: Data were retrieved from the Dutch Surgical Colorectal Audit. Patients undergoing colonic cancer resection with creation of an anastomosis between January 2009 to December 2011 were included. Outcomes were AL requiring reintervention and postoperative mortality following AL. RESULTS: AL occurred in 7·5 per cent of 15 667 patients. Multivariable analyses identified male sex, high American Society of Anesthesiologists (ASA) fitness grade, extensive tumour resection, emergency surgery, and surgical resection types such as transverse resection, left colectomy and subtotal colectomy as independent risk factors for AL. A defunctioning stoma was created in a small group of patients, leading to a lower risk of leakage. The mortality rate was 4·1 per cent overall, and was significantly higher in patients with AL than in those without leakage (16·4 versus 3·1 per cent; P < 0·001). Multivariable analyses identified older age, high ASA grade, high Charlson score and emergency surgery as independent risk factors for death after AL. The adjusted risk of death after AL was twice as high following right compared with left colectomy. CONCLUSION: The elderly and patients with co-morbidity have a higher risk of death after AL. Accurate preoperative patient selection, intensive postoperative surveillance for AL, and early and aggressive treatment of suspected leakage is important, especially in patients undergoing right colectomy.

Changing patterns of recurrent disease in colorectal cancer.

BACKGROUND: Due to changes in staging, (neo)-adjuvant treatment and surgical techniques for colorectal cancer (CRC), it is expected that the recurrence pattern will change as well. This study aims to report the current incidence of, and time to recurrent disease (RD), further the localization(s) and the eligibility for successive curative treatment. METHODS: A consecutive cohort of CRC patients, whom were routinely staged with CT and underwent curative treatment according to the national guidelines, was analyzed (n = 526). RESULTS: After a mean and median FU of 39 months, 20% of all patients and 16% of all AJCC stage 0-III patients had developed RD. The annual incidences were the highest in the first two years but tend to retain in the succeeding years for stage 0-III patients. The majority of RD was confined to one organ (58%) and 28% of these patients were again treated with curative intent. CONCLUSIONS: In follow-up nowadays, less recurrences are found than reported in historical studies but these can more often be treated with curative intent. A main cause for the decreased incidence of RD, next to improvements in treatment, is probably stage shift elicited by pre-operative staging. The outcomes support continuation of follow-up in colorectal cancer.

Results of a national survey among Dutch surgeons treating patients with colorectal carcinoma. Current opinion about follow-up, treatment of metastasis, and reasons to revise follow-up practice.

OBJECTIVE: Follow-up after curative resection of colorectal carcinoma (CRC) has been subjected to debate concerning its effectiveness to reduce cancer mortality. Current national and international guidelines advise CEA measurements every 3 months during 3 years after surgery. The common clinical practice and opinion about follow-up for colorectal carcinoma, was evaluated by means of a survey among Dutch general surgeons. METHOD: A web-based survey of follow-up after treatment of CRC was sent to all registered Dutch general surgeons. A reply from 246 surgeons treating patients for colorectal carcinoma in 105 out of 118 hospitals was received (response rate 91%). Questions related to actual follow-up protocol, opinion about serum CEA monitoring, liver and/or lung metastasectomy, and motivation to participate in a new trial concerning follow-up. RESULTS: For the majority of surgeons the length of follow-up was influenced by age of the patient (62%) and physical condition (76%) prohibiting hepatic metastasectomy. The generally accepted follow-up protocol consisted of CEA measurements every 3 months in the first year and six-monthly thereafter, and ultrasound examination of the liver every 6 months. Nearly all surgeons (92%) were willing to participate in a new study of follow-up protocol. CONCLUSION: The adherence to national guidelines for the follow-up of colorectal carcinoma is low. The indistinctness about follow-up after curative treatment of colorectal carcinoma also affects clinical practice. Recent advancements in imaging techniques, liver and lung surgery have changed circumstances, which are not yet anticipated upon in current guidelines. Renewal of follow-up based upon scientific evidence is required.

Carcinoembryonic antigen (CEA) measurement during follow-up for rectal carcinoma is useful even if normal levels exist before surgery. A retrospective study of CEA values in the TME trial.

BACKGROUND: Carcinoembryonic antigen (CEA) as a marker in the follow-up after curative resection of colorectal carcinoma (CRC) is often omitted from follow-up despite guideline recommendations. One reason is the assumption that when a normal CEA value exists before curative resection of CRC, it will neither rise during follow-up. This study investigates this relationship. METHOD: Data were derived from a study initiated to evaluate treatment regimes for rectal carcinoma (Dutch TME trial, n=1861) from which 954 were eligible for analysis. Recurrent disease occurred in 272 of these patients (29.5%). The pre-operative CEA value was compared to CEA values during follow-up, using threshold values of 2.5 and 5.0 ng/ml. RESULTS: Normal pre-operative CEA values were present in 63% (CEA<5.0) and 39% (CEA<2.5) of patients with recurrent disease. Patients with a normal pre-operative CEA and recurrent disease had elevated CEA values during follow-up in 41% (CEA<5.0), 50% (CEA<2.5) and in 60% with both threshold values when the last measurement was done within 3 months before recurrent disease was diagnosed. CONCLUSION: A normal pre-operative CEA is common in patients with rectal carcinoma. CEA does rise due to recurrent disease in at least 50% of patients with normal pre-operative values. Serial post-operative CEA testing cannot be discarded based on a normal pre-operative serum CEA.

A metabolic network analysis & NMR experiment design tool with user interface-driven model construction for depth-first search analysis.

A Windows program for metabolic engineering analysis and experimental design has been developed. A graphical user interface enables the pictorial, "on-screen" construction of a metabolic network. Once a model is composed, balance equations are automatically generated. Model construction, modification and information exchange between different users is thus considerably simplified. For a given model, the program can then be used to predict all the extreme point flux distributions that optimize an objective function while satisfying balances and constraints by using a depth-first search strategy. One can also find the minimum reaction set that satisfies different conditions. Based on the identified flux distributions or linear combinations, the user can simulate the NMR and GC/MS spectra of selected signal molecules. Alternately, spectra vectorization allows for the automated optimization of labeling experiments that are intended to distinguish between different, yet plausible flux extreme point distributions. The example provided entails predicting the flux distributions associated with deleting pyruvate kinase and designing 13C NMR experiments that can maximally discriminate between the flux distributions.

Interactions between artificial saliva and 20 aroma compounds in water and oil model systems.

The interactions between saliva components and 20 aroma compounds in water and oil model systems were systematically evaluated as a function of saliva composition and saliva/model system ratio. Air/liquid partition coefficients of dimethyl sulfide, 1-propanol, diacetyl, 2-butanone, ethyl acetate, 1-butanol, 2-pentanol, propyl acetate, 3-methyl-1-butanol, ethyl butyrate, hexanal, butyl acetate, 1-hexanol, 2-heptanone, heptanal, alpha-pinene, 2-octanone, octanal, 2-nonanol, and 2-decanone were determined by static headspace gas chromatography. Chain length of compounds within the homologous series determined the extent of interactions with the model system or saliva. Salts in the artificial saliva hardly interacted with aroma compounds. On the other hand, saliva proteins lowered retention of highly volatile compounds and increased retention of less volatile, hydrophobic compounds. Significant differences in volatility of compounds when artificial saliva or water was added indicated that saliva could not be sufficiently replaced by water. The model system/saliva ratio influenced air/liquid partitioning of the aroma compounds significantly for both model systems. Although saliva composition affected volatility of the aroma compounds, the saliva/model system ratio was of much greater influence.

A MILP-based flux alternative generation and NMR experimental design strategy for metabolic engineering.

A mixed-integer linear program (MILP) is described that can enumerate all the ways fluxes can distribute in a metabolic network while still satisfying the same constraints and objective function. The multiple solutions can be used to (1) generate alternative flux scenarios that can account for limited experimental observations, (2) forecast the potential responses to mutation (e.g., new reaction pathways may be used), and (3) (as illustrated) design (13)C NMR experiments such that different potential flux patterns in a mutant can be distinguished. The experimental design is enabled by using the MILP results as an input to an isotopomer mapping matrices (IMM)-based program, which accounts for the network circulation of (13)C from a precursor such as glucose. The IMM-based program can interface to common plotting programs with the result that the user is provided with predicted NMR spectra that are complete with splittings and Lorentzian line-shape features. The example considered is the trafficking of carbon in an Escherichia coli mutant, which has pyruvate kinase activity deleted for the purpose of eliminating acetate production. Similar yields and extracellular measurements would be manifested by the flux alternatives. The MILP-IMM results suggest how NMR experiments can be designed such that the spectra of glutamate for two flux distribution scenarios differ significantly.

Prevention of osteonecrosis following renal transplantation by using vitamin D2 (ergocalciferol).

Osteonecrosis is a frequently disabling complication of renal transplantation. Thirty-one of 244 patients (12.7%), who received cadaver renal transplants from 1968 to 1978 developed an osteonecrosis. An analysis of 14 possible risk factors suggested that only the following were significantly more frequent in the osteonecrosis group: greater than 3 pulse doses of 1.2 g prednisolone, serum creatinine greater than 133 mumol/L, steroid-induced diabetes mellitus and second and subsequent transplantation. An important decline in the incidence of osteonecrosis (26.7 per cent to 6.5 per cent) was seen with prophylactic vitamin D2 treatment and the onset of osteonecrosis was on average one year later. Dangerous side effects of the large doses of vitamin D2 were minimal. Hypercalcaemia due to overdosage with vitamin D2 during simultaneous prednisolone therapy was usually mild and returned to normal in a few days by dose reduction.