Comparative Cost Analysis Between Endoscopic Resection and Surgery for Submucosal Colorectal Cancer.

BACKGROUND: There are few studies analyzing the cost of endoscopic resection and surgical resection in the treatment of submucosal colorectal cancer. OBJECTIVE: The objective was to perform a detailed cost analysis of endoscopic resection and surgical resection for submucosal colorectal cancer. DESIGN: This was a retrospective observational study. SETTING: This study was conducted at a tertiary academic center. PATIENTS: Medical records of 484 patients with submucosal colorectal cancer who underwent endoscopic resection or surgical resection between July 2003 and July 2015 were reviewed. MAIN OUTCOME MEASUREMENTS: The total costs during index admission and follow-up as well as clinical outcomes between the 2 groups were compared in the whole cohort and propensity score-matched cohort. RESULTS: In the propensity score-matched analysis ( n = 155 in each group), the endoscopic resection and surgical resection groups did not show significant differences in the rates of procedure-related adverse events (6.5% vs 3.9%; p = 0.304) and recurrence (0.6% vs 1.3%; p > 0.99). Readmission was more common in the endoscopic resection group (40.6% vs 11.0%; p < 0.001) because 64 (41.3%) patients underwent additional surgery for endoscopic noncurative resection. The endoscopic resection group had a lower cost during the index admission (1335.6 vs 6698.4 USD; p < 0.001), whereas the surgical resection group had a lower cost during follow-up (2488.7 vs 5035.7 USD; p < 0.001). The total cumulative cost was lower in the endoscopic resection group (6371.3 vs 9187.1 USD; p < 0.001). The same trend was observed in the whole cohort without propensity score matching. LIMITATIONS: A limitation of this study was the retrospective nature of analysis. CONCLUSIONS: The total cumulative cost for treatment and follow-up for submucosal colorectal cancer was lower in the endoscopic resection group, which had comparable oncologic outcomes as the surgical resection group. Endoscopic resection can be considered a cost-effective option for initial treatment for submucosal colorectal cancer. See Video Abstract at http://links.lww.com/DCR/B881 . ANLISIS COMPARATIVO DE COSTOS ENTRE LA RESECCIN ENDOSCPICA Y LA CIRUGA PARA EL CNCER COLORRECTAL SUBMUCOSO: ANTECEDENTES: Existen pocos estudios que analizan el costo de la resección endoscópica y la resección quirúrgica en el tratamiento del cáncer colorrectal submucoso.OBJETIVO: El objetivo fue realizar un análisis detallado de costos tanto de la resección endoscópica y la resección quirúrgica para el cáncer colorrectal submucoso.DISEÑO: Este fue un estudio observacional retrospectivo.AJUSTE: Este estudio se realizó en un centro académico terciario.PACIENTES: Se revisaron las historias clínicas de 484 pacientes con cáncer colorrectal submucoso que fueron sometidos a resección endoscópica o resección quirúrgica entre julio de 2003 y julio de 2015.PRINCIPALES MEDICIONES DE RESULTADOS: Los costos totales durante la admisión índice y el seguimiento, así como los resultados clínicos entre los dos grupos, fueron comparados en toda la cohorte y la cohorte emparejada por puntuación de propensión.RESULTADOS: En el análisis emparejado por puntuación de propensión ( n = 155 en cada grupo), los grupos de resección endoscópica y resección quirúrgica no mostraron diferencias significativas en las tasas de eventos adversos relacionados con el procedimiento (6,5% vs 3,9%, p = 0,304) y recurrencia (0,6% vs 1,3%, p > 0,99). La readmisión fue más común en el grupo de resección endoscópica (40,6% vs 11,0%, p < 0,001) porque 64 (41,3%) pacientes fueron sometidos a una cirugía adicional para lograr la resección en aquellos casos en que la resección endoscópica no fue curativa. El grupo de resección endoscópica tuvo un costo menor durante el ingreso índice (1335.6 vs 6698.4 USD, p < 0.001), mientras que el grupo de resección quirúrgica tuvo un costo menor durante el seguimiento (2488.7 vs 5035.7 USD, p < 0.001). El costo total acumulado fue menor en el grupo de resección endoscópica (6371,3 vs 9187,1 USD, p < 0,001). La misma tendencia se observó en toda la cohorte sin emparejamiento por puntuación de propensión.LIMITACIONES: La naturaleza retrospectiva del análisis.CONCLUSIONES: El costo total acumulado para el tratamiento y seguimiento del cáncer colorrectal submucoso fue menor en el grupo de resección endoscópica, que tuvo resultados oncológicos comparables a los del grupo de resección quirúrgica. La resección endoscópica puede considerarse una opción rentable para el tratamiento inicial del cáncer colorrectal submucoso. Consulte Video Resumen en http://links.lww.com/DCR/B881 . (Traducción-Dr Osvaldo Gauto ).

Combined Endoscopic and Radiologic Healing Is Associated With a Better Prognosis Than Endoscopic Healing Only in Patients With Crohn's Disease Receiving Anti-TNF Therapy.

INTRODUCTION: Although endoscopic healing (EH) is recommended as the therapeutic goal in patients with Crohn's disease (CD), combined EH and radiologic healing (RH) could be a more ideal therapeutic goal considering the transmural nature of CD. We compared the prognosis of patients with CD who achieved EH, RH, both EH and RH (deep healing; DH), or no healing under treatment with anti-tumor necrosis factor (TNF) agents. METHODS: We analyzed 392 patients with CD who received anti-TNF treatment for more than 1 year and evaluated with CT enterography or magnetic resonance enterography together with colonoscopy within 3 months between July 2017 and December 2018. Major outcomes (anti-TNF dose intensification, switch to other biologics, CD-related bowel resection, and hospitalization) were compared according to the EH and RH status. RESULTS: During the follow-up (median 18 months; interquartile range, 15-21), the DH group showed a better rate of major outcome-free survival compared with other groups (P < 0.001). In multivariable analysis, elevated C-reactive protein (adjusted hazard ratio [aHR], 2.166; 95% confidence interval [CI], 1.508-3.110; P < 0.001), EH-only (aHR, 3.903; 95% CI, 1.635-9.315; P = 0.002), RH-only (aHR, 3.843; 95% CI, 1.545-9.558; P = 0.004), and no healing (aHR, 8.844; 95% CI, 4.268-18.323; P < 0.001) were associated with increased risks of major outcomes. DISCUSSION: Patients with CD who achieved DH under anti-TNF therapy showed a better prognosis compared with those who only achieved EH. The possibility of DH being used as a new therapeutic target for patients with CD should be investigated in further studies.

Tip-in versus conventional endoscopic mucosal resection for flat colorectal neoplasia 10 mm or larger in size.

PURPOSE: A modified endoscopic mucosal resection (EMR) technique, Tip-in EMR, was recently introduced to enhance the complete resection of colorectal neoplasia (CRN). We aimed to evaluate the feasibility of Tip-in EMR for flat CRNs. METHODS: From January to September 2018, conventional or Tip-in EMR was consecutively performed for 112 flat CRNs ≥ 10 mm in diameter. Tip-in EMR was performed when en bloc snaring was impossible with conventional EMR or when a lesion was inadequately lifted owing to a previous forceps biopsy. We retrospectively collected the clinical, procedural, and histologic data of the conventional and Tip-in EMR groups and compared the en bloc resection rate, complete resection rate, and complications between the two groups. RESULTS: Among 112 flat CRNs of 80 patients, conventional EMR and Tip-in EMR were performed for 74 and 38 lesions, respectively. The median lesion size was 12 (10-27) mm. Tip-in EMR was superior to conventional EMR in terms of en bloc resection (94.7% vs. 77.0%, p = 0.018) and histologic complete resection (76.3% vs. 54.1%, p = 0.022). There was no difference in postprocedural bleeding between the two groups; however, overall adverse events, including bleeding and postpolypectomy electrocoagulation syndrome, were more frequent in the Tip-in EMR group. CONCLUSIONS: Tip-in EMR is a feasible technique for flat colorectal lesions ≥ 10 mm and is superior to conventional EMR with respect to en bloc and complete resection rates. The safety profiles of Tip-in EMR and conventional EMR should be compared via large-scale prospective studies.

Association of Faecal Calprotectin Level and Combined Endoscopic and Radiological Healing in Patients With Crohn's Disease Receiving Anti-tumour Necrosis Factor Therapy.

BACKGROUND AND AIMS: Combined endoscopic and radiological healing, or deep healing, is associated with favourable outcomes in patients with Crohn's disease; thus, a non-invasive biomarker for predicting deep healing would be invaluable. We evaluated the usefulness of faecal calprotectin for predicting deep healing in patients with Crohn's disease receiving anti-tumour necrosis factor [TNF] therapy. METHODS: We analysed the records of patients with Crohn's disease who received anti-tumour necrosis factor therapy and underwent endoscopic evaluation, radiological evaluation, and faecal calprotectin measurement within a period of 3 months between August 2017 and November 2018. Results of endoscopic and radiological studies were independently reviewed by two gastrointestinal endoscopists and a gastrointestinal radiologist, respectively. Serum C-reactive protein and albumin were also measured. RESULTS: Out of 268 patients analysed, 77 [28.7%] had deep healing, 36 [13.4%] had endoscopic healing only, 36 [13.4%] had radiological healing only, and 119 [44.4%] had neither. The median duration of anti-TNF treatment was 40.0 months. The deep healing group had the lowest median faecal calprotectin level [56.5 mg/kg] among the four groups [p <0.001]. The faecal calprotectin cutoff level of 81.1 mg/kg showed a sensitivity of 0.623 and a specificity of 0.817 in predicting deep healing (area under the receiver operating characteristic curve [AUROC], 0.767; 95% confidence interval, 0.702-0.832). Adding serum C-reactive protein and serum albumin to faecal calprotectin further increased the AUROC to 0.805 [95% confidence interval, 0.752-0.858]. CONCLUSIONS: Faecal calprotectin, when combined with serum C-reactive protein and albumin, showed acceptable performance in predicting deep healing in patients with Crohn's disease.

Endoscopic Vacuum-Assisted Closure Therapy in Patients with Anastomotic Leakage after Esophagectomy: A Single-Center Experience.

AIM: To study the efficacy of E-VAC therapy for patients with anastomotic leakage after esophagectomy. METHODS: Between January 2013 and April 2017, 12 patients underwent E-VAC therapy for the management of postoperative leakage. Their clinical features and endoscopic procedure details, therapy results, adverse events, and survival were investigated. RESULTS: All 12 patients were male and the median age was 57 years (interquartile range 51.5-62.8 years). The reasons for esophageal surgery were esophageal cancer (83.3%), gastrointestinal stromal tumor (8.3%), and esophageal diverticulum (8.3%). Prior to E-VAC therapy, 6 patients had undergone failed primary surgical repair and the median duration from esophagectomy to leakage discovery was 13.5 days (IQR 6-207 days). The median duration of E-VAC therapy was 25 days (IQR 13.5-34.8 days) and the average sponge exchange rate was 2.7 times during the treatment period. After E-VAC therapy, 8 patients (66.7%) had complete leakage closure, 3 (25%) had a decreased leakage size, and 1 (8.3%) was unchanged. The three patients with a decreased leakage size after E-VAC therapy were treated with endoscopic and conservative management without further surgery. CONCLUSION: With proper patient selection, E-VAC therapy is a feasible and safe method for the treatment of anastomotic leakage after esophagectomy.

[Clinical Outcomes of Angiography and Transcatheter Arterial Embolization for Acute Gastrointestinal Bleeding: Analyses according to Bleeding Sites and Embolization Types].

Background/Aims: The clinical outcomes of angiography and transcatheter arterial embolization (TAE) for acute gastrointestinal bleeding (GIB) have not been completely assessed, especially according to bleeding sites. This study aimed to assess the efficacy of angiography and safety of TAE in acute GIB. Methods: This was a retrospective study evaluating the records of 321 patients with acute GIB who underwent angiography with or without TAE. Targeted TAE was conducted in 134 patients, in whom angiography showed bleeding sources. Prophylactic TAE was performed in 29 patients when the bleeding source was not detected but a specific vessel was strongly suspected by other examinations. The rate of technical success, clinical success, and complications were analyzed. Results: The detection rate of bleeding source via angiography was 50.8% (163/321), which was not different according to the bleeding sites. The detection rate was higher if the probable bleeding source had already been found by another investigation (59.7% vs. 35.8%, p<0.001). TAE sites were upper GIB in 67, mid GIB in 74, and lower GIB in 22. The technical success rate was 99.3% (133/134), and the clinical success rate was 63.0% (104/163). The prophylactic embolization group showed lower clinical success rate than the targeted embolization group (44.8% vs. 67.9%, p=0.06). The TAE-related complication rate was 12.9% (21/163). Ischemia and/or infarction was more common after TAE for mid and lower GIB than for upper GIB (15.6% vs. 3.0%, p=0.007). Conclusions: Angiography with or without TAE was an effective method for acute GIB. Targeted embolization should be performed if possible given that it has a higher clinical success rate.

Comprehensive characterization of glutamine synthetase-mediated selection for the establishment of recombinant CHO cells producing monoclonal antibodies.

To characterize a glutamine synthetase (GS)-based selection system, monoclonal antibody (mAb) producing recombinant CHO cell clones were generated by a single round of selection at various methionine sulfoximine (MSX) concentrations (0, 25, and 50 µM) using two different host cell lines (CHO-K1 and GS-knockout CHO). Regardless of the host cell lines used, the clones selected at 50 µM MSX had the lowest average specific growth rate and the highest average specific production rates of toxic metabolic wastes, lactate and ammonia. Unlike CHO-K1, high producing clones could be generated in the absence of MSX using GS-knockout CHO with an improved selection stringency. Regardless of the host cell lines used, the clones selected at various MSX concentrations showed no significant difference in the GS, heavy chain, and light chain gene copies (P > 0.05). Furthermore, there was no correlation between the specific mAb productivity and these three gene copies (R2 ≤ 0.012). Taken together, GS-mediated gene amplification does not occur in a single round of selection at a MSX concentration up to 50 µM. The use of the GS-knockout CHO host cell line facilitates the rapid generation of high producing clones with reduced production of lactate and ammonia in the absence of MSX.

Anti-Apoptosis Engineering for Improved Protein Production from CHO Cells.

Improving the time integral of viable cell concentration by overcoming cell death, namely apoptosis, is one of the widely used strategies for efficient production of therapeutic proteins. By establishing stable cell lines that overexpress anti-apoptotic genes or down-regulate pro-apoptotic genes, the final product yields can be enhanced as cells become more resistance to environmental stresses. From the selection of high-expressing clones to verification of anti-apoptotic activity, the method to construct a stable anti-apoptotic cell line is discussed in this chapter.

Reduction of ammonia and lactate through the coupling of glutamine synthetase selection and downregulation of lactate dehydrogenase-A in CHO cells.

Chinese hamster ovary (CHO) cell cultivation for production of therapeutic proteins is accompanied by production of metabolic wastes, mostly ammonia and lactate. To reduce ammonia production, the glutamine synthetase (GS) system was used to develop therapeutic monoclonal antibody (mAb)-producing CHO cells (SM-0.025). Additionally, the lactate dehydrogenase-A (LDH-A) was downregulated with shRNA to reduce lactate production in SM-0.025. The resulting mAb-producing cell lines (#2, #46, and #52) produced less ammonia than the host cell line during the exponential phase due to GS protein overexpression. LDH-A downregulation in SM-0.025 not only reduced lactate production but also further reduced ammonia production. Among the three LDH-A-downregulated clones, clone #2 had the highest mAb production along with significantly reduced specific lactate and ammonia production rates compared to those in SM-0.025. Waste reduction increased the galactosylation level of N-glycosylation, which improved mAb quality. LDH-A downregulation was also successfully applied to the host cell lines (CHO K1 and GS knockout CHO-K1). However, LDH-A downregulated host cells could not survive the pool-selection process wherein glutamine was excluded and methionine sulfoximine was added to the media. Taken together, LDH-A downregulation in the mAb-producing cell line generated with the GS system successfully reduced both ammonia and lactate levels, improving mAb galactosylation. However, LDH-A downregulation could not be applied to host cell lines because it hampered the selection process of the GS system.

Limitations to the development of recombinant human embryonic kidney 293E cells using glutamine synthetase-mediated gene amplification: Methionine sulfoximine resistance.

To investigate the feasibility of glutamine synthetase (GS)-mediated gene amplification in HEK293 cells for the high-level stable production of therapeutic proteins, HEK293E cells were transfected by the GS expression vector containing antibody genes and were selected at various methionine sulfoximine (MSX) concentrations in 96-well plates. For a comparison, CHOK1 cells were transfected by the same GS expression vector and selected at various MSX concentrations. Unlike CHOK1 cells, HEK293E cells producing high levels of antibodies were not selected at all. For HEK293E cells, the number of wells with the cell pool did not decrease with an increase in the concentration of MSX up to 500µM MSX. A q-RT-PCR analysis confirmed that the antibody genes in the HEK293E cells, unlike the CHOK1 cells, were not amplified after increasing the MSX concentration. It was found that the GS activity in HEK293E cells was much higher than that in CHOK1 cells (P<0.05). In a glutamine-free medium, the GS activity of HEK293E cells was approximately 4.8 times higher than that in CHOK1 cells. Accordingly, it is inferred that high GS activity of HEK293E cells results in elevated resistance to MSX and therefore hampers GS-mediated gene amplification by MSX. Thus, in order to apply the GS-mediated gene amplification system to HEK293 cells, the endogenous GS expression level in HEK293 cells needs to be minimized by knock-out or down-regulation methods.

Valeric acid induces cell cycle arrest at G1 phase in CHO cell cultures and improves recombinant antibody productivity.

To find a more effective chemical reagent for improved monoclonal antibody (mAb) production, eight chemical reagents (curcumin, quercein, DL-sulforaphane, thymidine, valeric acid, phenyl butyrate, valproic acid, and lithium chloride) known to induce cell cycle arrest were examined individually as chemical additives to recombinant CHO (rCHO) cell cultures producing mAb. Among these chemical additives, valeric acid showed the best production performance. Valeric acid decreased specific growth rate (µ), but increased culture longevity and specific mAb productivity (qmAb ) in a dose-dependent manner. The beneficial effect of valeric acid on culture longevity and qmAb outweighed its detrimental effect on µ, resulting in 2.9-fold increase in the maximum mAb concentration when 1.5 mM valeric acid was added to the cultures. Furthermore, valeric acid did not negatively affect the mAb quality attributes with regard to aggregation, charge variation, and galactosylation. Unexpectedly, galactosylation of the mAb increased by the 1.5 mM valeric acid addition. Taken together, the results obtained here demonstrate that valeric acid is an effective chemical reagent to increase mAb production in rCHO cells.