Tofacitinib Is Associated With Increased Risk of Postoperative Venous Thromboembolism in Patients With Ulcerative Colitis.

BACKGROUND: In 2019, the Food and Drug Administration issued a black box warning for increased risk of venous thromboembolism in patients with rheumatoid arthritis exposed to tofacitinib. There are limited data regarding postoperative venous thromboembolism risk in patients with ulcerative colitis exposed to tofacitinib. OBJECTIVE: To assess whether preoperative exposure to tofacitinib is associated with increased odds of postoperative venous thromboembolism. DESIGN: Retrospective review. SETTINGS: Tertiary academic medical center. PATIENTS: Consecutive patients exposed to tofacitinib within 4 weeks before total abdominal colectomy or total proctocolectomy, with or without ileostomy, from 2014 to 2021, matched 1:2 for tofacitinib exposure or no exposure. INTERVENTION: Tofacitinib exposure versus no exposure. MAIN OUTCOME MEASURES: Ninety-day postoperative venous thromboembolism rate. RESULTS: Forty-two patients with tofacitinib exposure and 84 case-matched patients without tofacitinib exposure underwent surgery for medically refractory ulcerative colitis. Nine (22.0%) tofacitinib-exposed patients and 7 (8.5%) unexposed patients were diagnosed with venous thromboembolism within 90 days of surgery. In univariate logistic regression, patients exposed to tofacitinib had 3.01 times increased odds of developing venous thromboembolism within 90 days after surgery compared to unexposed patients ( p = 0.04; 95% CI, 1.03-8.79). Other venous thromboembolism risk factors were not significantly associated with venous thromboembolisms. Venous thromboembolisms in both groups were most commonly portomesenteric vein thromboses (66.7% in the tofacitinib-exposed group and 42.9% in the unexposed group) and were diagnosed at a mean of 23.2 days (range, 3-90 days) postoperatively in the tofacitinib-exposed group and 7.9 days (1-19 days) in the unexposed group. There were no statistically significant differences in location or timing between the 2 groups. LIMITATIONS: Retrospective nature of the study and associated biases. Reliance on clinically diagnosed venous thromboembolisms may underreport the true incidence rate. CONCLUSIONS: Tofacitinib exposure before surgery for medically refractory ulcerative colitis is associated with 3 times increased odds of venous thromboembolism compared with patients without tofacitinib exposure. See Video Abstract . TOFACITINIB SE ASOCIA CON UN MAYOR RIESGO DE TROMBOEMBOLISMO VENOSO POSTOPERATORIO EN PACIENTES CON COLITIS ULCEROSA: ANTECEDENTES:En 2019, la FDA emitió una advertencia de recuadro negro sobre un mayor riesgo de tromboembolismo venoso en pacientes con artritis reumatoide expuestos a tofacitinib. Hay datos limitados sobre el riesgo de tromboembolismo venoso postoperatorio en pacientes con colitis ulcerosa expuestos a tofacitinib.OBJETIVO:Evaluar si la exposición preoperatoria a tofacitinib se asocia con mayores probabilidades de tromboembolismo venoso postoperatorio.DISEÑO:Revisión retrospectiva.LUGARES:Centro médico académico terciario.PACIENTES:Pacientes consecutivos expuestos a tofacitinib dentro de las 4 semanas previas a la colectomía abdominal total o proctocolectomía total, con o sin ileostomía, entre 2014 y 2021, emparejados 1:2 para exposición a tofacitinib o ninguna exposición.INTERVENCIÓN(S):Exposición a tofacitinib versus ninguna exposición.PRINCIPALES MEDIDAS DE RESULTADO:Tasa de tromboembolismo venoso posoperatorio a los 90 días.RESULTADOS:Cuarenta y dos pacientes con exposición a tofacitinib y 84 pacientes de casos similares sin exposición a tofacitinib se sometieron a cirugía por colitis ulcerosa médicamente refractaria. Nueve (22,0%) pacientes expuestos a tofacitinib y 7 (8,5%) pacientes no expuestos fueron diagnosticados con tromboembolismo venoso dentro de los 90 días posteriores a la cirugía. En la regresión logística univariada, los pacientes expuestos a tofacitinib tuvieron 3,01 veces más probabilidades de desarrollar un tromboembolismo venoso dentro de los 90 días posteriores a la cirugía en comparación con los no expuestos ( p = 0,04, IC del 95 %: 1,03-8,79). Otros factores de riesgo de tromboembolismo venoso no se asociaron significativamente con el tromboembolismo venoso. Los tromboembolismos venosos en ambos grupos fueron más comúnmente trombosis de la vena portomesentérica (66,7% en los expuestos a tofacitinib y 42,9% en los no expuestos) y se diagnosticaron en una media de 23,2 días (rango, 3-90 días) después de la operación en los expuestos a tofacitinib y 7,9 días. (1-19 días) en los grupos no expuestos, respectivamente. No hubo diferencias estadísticamente significativas en la ubicación o el momento entre los dos grupos.LIMITACIONES:Carácter retrospectivo del estudio y sesgos asociados. La dependencia de tromboembolismos venosos diagnosticados clínicamente puede subestimar la tasa de incidencia real.CONCLUSIONES:La exposición a tofacitinib antes de la cirugía para la colitis ulcerosa médicamente refractaria se asocia con probabilidades 3 veces mayores de tromboembolismo venoso en comparación con los pacientes sin exposición a tofacitinib. (Traducción-Dr. Mauricio Santamaria ).

History and Role of Quality Accreditation.

Accreditation has played a major role in the evolution of health care quality as well as the structure and organization of American medicine. In its earliest iterations, accreditation aimed to set a minimum standard of care, and now more prominently sets standards for high quality, optimal patient care. There are several institutions that provide accreditations that are relevant to colorectal surgery including the American College of Surgeons (ACS) Commission on Cancer, National Cancer Institute Cancer Center Designation, National Accreditation Program for Rectal Cancer, and the ACS Geriatrics Verification Program. While each program has unique criteria, the aim of accreditation is to assure high-quality evidenced-based care. In addition to these benchmarks, these programs provide avenues for collaboration and research between centers and programs.

Quantitative Measure of Intestinal Permeability Using Blue Food Coloring.

BACKGROUND: Loss of intestinal barrier integrity plays a fundamental role in the pathogenesis of various gastrointestinal diseases and is implicated in the onset of sepsis and multiple organ failure. An array of methods to assess different aspects of intestinal barrier function suffers from lack of sensitivity, prolonged periods of specimen collection, or high expense. We have developed a technique to measure the concentration of the food dye FD&C Blue #1 from blood and sought to assess its utility in measuring intestinal barrier function in humans. MATERIALS AND METHODS: Four healthy volunteers and 10 critically ill subjects in the intensive care unit were recruited in accordance with an institutional review board approved protocol. Subjects were given 0.5 mg/kg Blue #1 enterally as an aqueous solution of diluted food coloring. Five blood specimens were drawn per subject: 0 h (before dose), 1, 2, 4, and 8 h. After plasma isolation, organic extracts were analyzed by high-performance liquid chromatography/mass spectrometry detecting the presence of unmodified dye. RESULTS: We found no baseline detectable absorption in healthy volunteers. After including the subjects in the intensive care unit, we compared dye absorption in the six subjects who met criteria for septic shock with the eight who did not. Septic patients demonstrated significantly greater absorption of Blue #1 after 2 h. CONCLUSIONS: We have developed a novel, easy-to-use method to measure intestinal barrier integrity using a food grade dye detectable by mass spectrometry analysis of patient blood following oral administration.

Tumor-targeting Salmonella typhimurium A1-R arrests a doxorubicin-resistant PDGFRA-amplified patient-derived orthotopic xenograft mouse model of pleomorphic liposarcoma.

Pleomorphic liposarcoma (PLPS) is a recalcitrant soft-tissue sarcoma (STS) subtype in need of transformative therapy. We have previously established a patient-derived orthotopic xenograft (PDOX) model, of PLPS with PDGFRA amplification, using surgical orthotopic implantation. In the current study, the PLPS PDOX model was randomized into 3 groups of 7 mice each: untreated control; doxorubicin (DOX)-treated; and treated with Salmonella typhimurium A1-R (S. typhimurium A1-R) expressing green fluorescent protein (GFP). Tumor volume and body weight were monitored during the treatment period. The PLPS PDOX was resistant to DOX. In contrast, the PLPS PDOX was highly sensitive to S. typhimurium A1-R. There was no significant body-weight loss among these 3 groups. Fluorescence imaging demonstrated that S. typhimurium A1-R-GFP was very effective to target the PLPS PDOX tumor. The current study demonstrates that a PLPS PDOX, resistant to first-line therapy DOX, was highly sensitive to tumor targeting S. typhimurium A1-R.

Temozolomide regresses a doxorubicin-resistant undifferentiated spindle-cell sarcoma patient-derived orthotopic xenograft (PDOX): precision-oncology nude-mouse model matching the patient with effective therapy.

Undifferentiated spindle-cell sarcoma (USCS) is a recalcitrant cancer, resistant to conventional chemotherapy. A patient with high-grade USCS from a striated muscle was implanted orthotopically in the right biceps femoris muscle of mice to establish a patient-derived orthotopic xenograft (PDOX) model. The PDOX models were randomized into the following groups when tumor volume reached 100 mm3 : G1, control without treatment; G2, doxorubicin (DOX) (3 mg/kg, intraperitoneal [i.p.] injection, weekly, for 2 weeks); G3, temozolomide (TEM) (25 mg/kg, p.o., daily, for 14 days). Tumor size and body weight were measured with calipers and a digital balance twice a week. TEM significantly inhibited tumor volume growth compared to the untreated control and the DOX-treated group on day 14 after treatment initiation: control (G1): 343 ± 78 mm3 ; DOX (G2): 308 ± 31 mm3 , P = 0.272; TEM (G3): 85 ± 21 mm3 , P < 0.0001. TEM significantly regressed the tumor volume compared to day 0 (P = 0.019). There were no animal deaths in any group. The body weight of treated mice was not significantly different in any group. Tumors treated with DOX were comprised of spindle-shaped viable cells without apparent necrosis or inflammatory changes. In contrast, tumors treated with TEM showed extensive tumor necrosis. The present study demonstrates the potential power of matching the patient with an effective drug and saving the patient needless toxicity from ineffective drugs.

Growth of doxorubicin-resistant undifferentiated spindle-cell sarcoma PDOX is arrested by metabolic targeting with recombinant methioninase.

Undifferentiated spindle-cell sarcoma (USCS) is a recalcitrant -cancer in need of individualized therapy. A high-grade USCS from a striated muscle of a patient was grown orthotopically in the right biceps femoris muscle of nude mice to establish a patient-derived orthotopic xenograft (PDOX) model. In a previous study, we evaluated the efficacy of standard first-line chemotherapy of doxorubicin (DOX), gemcitabine (GEM) combined with docetaxel (DOC), compared to pazopanib (PAZ), a multi-targeting tyrosine-kinase inhibitor, in an USCS PDOX model. In the present study, mice-bearing the USCS PDOX tumors were randomized into the following groups when tumor volume reached 100 mm3 : G1, untreated control without treatment; G2, DOX (3 mg/kg, intraperitoneal (i.p.) injection, weekly, for 2 weeks); G3, L-methionine α-deamino-γ-mercaptomethane lyase (recombinant methioninase [rMETase]) (100 U/mouse, i.p., daily, for 2 weeks). Tumor size and body weight were measured with calipers and a digital balance twice a week. The methionine level of supernatants derived from sonicated tumors was also measured. rMETase inhibited tumor growth, measured by tumor volume, compared to untreated controls and the DOX-treated group on day 14 after initiation of treatment: control (G1): 347.6 ± 88 mm3 ; DOX (G2): 329.5 ± 79 mm3 , P = 0.670; rMETase (G3): 162.6 ± 51 mm3 , P = 0.0003. The mouse body weight of the treated mice was not significantly different from the untreated controls. Tumor L-methionine levels were reduced after the rMETase-treatment compared to untreated control and pre-rMETase treatment. We previously reported efficacy of rMETase against Ewing's sarcoma and melanoma in a PDOX models. These studies suggest clinical development of rMETase, especially in recalcitrant cancers such as sarcoma.

Tumor-targeting Salmonella typhimurium A1-R is a highly effective general therapeutic for undifferentiated soft tissue sarcoma patient-derived orthotopic xenograft nude-mouse models.

Undifferentiated soft tissue sarcoma (USTS) is a recalcitrant and heterogeneous subgroup of soft tissue sarcoma with high risk of metastasis and recurrence. Due to heterogeneity of USTS, there is no reliably effective first-line therapy. We have generated tumor-targeting Salmonella typhimurium A1-R (S. typhimurium A1-R), which previously showed strong efficacy on single patient-derived orthotopic xenograft (PDOX) models of Ewing's sarcoma and follicular dendritic cell sarcoma. In the present study, tumor resected from 4 patients with a biopsy-proven USTS (2 undifferentiated pleomorphic sarcoma [UPS], 1 undifferentiated sarcoma not otherwise specified [NOS] and 1 undifferentiated spindle cell sarcoma [USS]) were grown orthotopically in the biceps femoris muscle of mice to establish PDOX models. One USS model and one UPS model were doxorubicin (DOX) resistant. One UPS and the NOS model were partially sensitive to DOX. DOX is first-line therapy for these diseases. S. typhimurium A1-R arrested tumor growth all 4 models. In addition to arresting tumor growth in each case, S. typhimurium A1-R was significantly more efficacious than DOX in each case, thereby surpassing first-line therapy. These results suggest that S. typhimurium A1-R can be a general therapeutic for USTS and possibly sarcoma in general.

A combination of irinotecan/cisplatinum and irinotecan/temozolomide or tumor-targeting Salmonella typhimurium A1-R arrest doxorubicin- and temozolomide-resistant myxofibrosarcoma in a PDOX mouse model.

Myxofibrosarcoma (MFS) is the most common sarcomas in elderly patients and is either chemo-resistant or recurs with metastasis after chemotherapy. This recalcitrant cancer in need of improved treatment. We have established a patient-derived orthotopic xenograft (PDOX) of MFS. The MFS PDOX model was established in the biceps femoris of nude mice and randomized into 7 groups of 7 mice each: control; doxorubicin (DOX); pazopanib (PAZ); temozolomide (TEM); Irinotecan (IRN); IRN combined with TEM; IRN combined with cisplatinum (CDDP) and Salmonella typhimurium A1-R (S. typhimurium A1-R). Treatment was evaluated by relative tumor volume and relative body weight. The MFS PDOX models were DOX, PAZ, and TEM resistant. IRN combined with TEM and IRN combined with CDDP were most effective on the MFS PDOX. S. typhimurium A1-R arrested the MFS PDOX tumor. There was no significant body weight loss in any group. The present study suggests that the combination of IRN with either TEM or CDDP, and S. typhimurium have clinical potential for MFS.

Combination therapy of tumor-targeting Salmonella typhimurium A1-R and oral recombinant methioninase regresses a BRAF-V600E-negative melanoma.

Melanoma is a recalcitrant cancer. To improve and individualize treatment for this disease, we previously developed a patient-derived orthotopic xenograft (PDOX) model for melanoma. We previously reported the individual efficacy of tumor-targeting Salmonella typhimurium A1-R (S. typhimurium A1-R) and recombinant methioninase (rMETase) for melanoma in the PDOX models of this disease. In the present study, we evaluated the efficacy of the combination of S. typhimurium A1-R with orally-administered rMETase (o-rMETase) for BRAF-V600E-negative melanoma in a PDOX model. Three weeks after implantation, 60 PDOX mouse models were randomized into six groups of 10 mice each: untreated control, temozolomide (TEM); o-rMETase; S. typhimurium A1-R; TEM + rMETase, S. typhimurium A1-R + rMETase. All treatments inhibited tumor growth compared to untreated control (TEM: p < 0.0001, rMETase: p < 0.0001, S. typhimurium A1-R: p < 0.0001, TEM + rMETase: p < 0.0001, S. typhimurium A1-R + rMETase: p < 0.0001). The most effective was the combination of S. typhimurium A1-R + o-rMETase which regressed this melanoma PDOX, thereby indicating a new paradigm for treatment of metastatic melanoma.

Metabolic targeting with recombinant methioninase combined with palbociclib regresses a doxorubicin-resistant dedifferentiated liposarcoma.

Liposarcoma is the most common type of soft tissue sarcoma. Among the subtypes of liposarcoma, dedifferentiated liposarcoma (DDLPS) is recalcitrant and has the lowest survival rate. The aim of the present study is to determine the efficacy of metabolic targeting with recombinant methioninase (rMETase) combined with palbociclib (PAL) against a doxorubicin (DOX)-resistant DDLPS in a patient-derived orthotopic xenograft (PDOX) model. A resected tumor from a patient with recurrent high-grade DDLPS in the right retroperitoneum was grown orthotopically in the right retroperitoneum of nude mice to establish a PDOX model. The PDOX models were randomized into the following groups when tumor volume reached 100 mm3: G1, control without treatment; G2, DOX; G3, PAL; G4, recombinant methioninase (rMETase); G5, PAL combined with rMETase. Tumor length and width were measured both pre- and post-treatment. On day 14 after initiation, all treatments significantly inhibited tumor growth compared to the untreated control except DOX. PAL combined with rMETase was significantly more effective than both DOX, rMETase alone, and PAL alone. Combining PAL and rMETase significantly regressed tumor volume on day 14 after initiation of treatment and was the only treatment to do so. The relative body weight on day 14 compared with day 0 did not significantly differ between each treatment group. The results of the present study indicate the powerful combination of rMETase and PAL should be tested clinically against DDLPS in the near future.

Trabectedin arrests a doxorubicin-resistant PDGFRA-activated liposarcoma patient-derived orthotopic xenograft (PDOX) nude mouse model.

BACKGROUND: Pleomorphic liposarcoma (PLPS) is a rare, heterogeneous and an aggressive variant of liposarcoma. Therefore, individualized therapy is urgently needed. Our recent reports suggest that trabectedin (TRAB) is effective against several patient-derived orthotopic xenograft (PDOX) mouse models. Here, we compared the efficacy of first-line therapy, doxorubicin (DOX), and TRAB in a platelet-derived growth factor receptor-α (PDGFRA)-amplified PLPS. METHODS: We used a fresh sample of PLPS tumor derived from a 68-year-old male patient diagnosed with a recurrent PLPS. Subcutaneous implantation of tumor tissue was performed in a nude mouse. After three weeks of implantation, tumor tissues were isolated and cut into small pieces. To match the patient a PDGFRA-amplified PLPS PDOX was created in the biceps femoris of nude mice. Mice were randomized into three groups: Group 1 (G1), control (untreated); Group 2 (G2), DOX-treated; Group 3 (G3), TRAB-treated. Measurement was done twice a week for tumor width, length, and mouse body weight. RESULTS: The PLPS PDOX showed resistance towards DOX. However, TRAB could arrest the PLPS (p < 0.05 compared to control; p < 0.05 compared to DOX) without any significant changes in body-weight. CONCLUSIONS: The data presented here suggest that for the individual patient the PLPS PDOX model could specifically distinguish both effective and ineffective drugs. This is especially crucial for PLPS because effective first-line therapy is harder to establish if it is not individualized.

Rescue Diverting Loop Ileostomy: An Alternative to Emergent Colectomy in the Setting of Severe Acute Refractory IBD-Colitis.

BACKGROUND: Severe acute refractory colitis has traditionally been an indication for emergent colectomy in IBD, yet under these circumstances patients are at elevated risk for complications because of their heightened inflammatory state, nutritional deficiencies, and immunocompromised state. OBJECTIVE: We hypothesized that rescue diverting loop ileostomy may be a viable alternative to emergent colectomy, providing the opportunity for colonic healing and patient optimization before more definitive surgery. DESIGN: This was a retrospective case series. SETTINGS: The study was conducted at a single academic center. PATIENTS: Patients with severe acute medically refractory IBD-related colitis were included. INTERVENTION: Rescue diverting loop ileostomy was the intervening procedure. MAIN OUTCOME MEASURES: The primary outcome was avoidance of urgent/emergent colectomy. The secondary outcome was efficacy, defined by 3 clinical aims: 1) reduced steroid dependence or opportunity for bridge to medical rescue, 2) improved nutritional status, and 3) ability to undergo an elective laparoscopic definitive procedure or ileostomy reversal with colon salvage. RESULTS: Among 33 patients, 14 had Crohn's disease and 19 had ulcerative colitis. Three patients required urgent/emergent colectomy, 2 with ulcerative colitis and 1 with Crohn's disease. Across both disease cohorts, >80% of patients achieved each clinical aim for efficacy: 88% reduced their steroid dependence or were able to bridge to medical rescue, 87% improved their nutritional status, and 82% underwent an elective laparoscopic definitive procedure or ileostomy reversal. A total of 4 patients (11.7%) experienced a postoperative complication following diversion, including 3 surgical site infections and 1 episode of acute kidney injury. LIMITATIONS: The study was limited by being a single-center, retrospective series. CONCLUSIONS: Rescue diverting loop ileostomy in the setting of severe, refractory IBD-colitis is a safe and effective alternative to emergent colectomy. This procedure has acceptably low complication rates and affords patients time for medical and nutritional optimization before definitive surgical intervention. See Video Abstract at http://links.lww.com/DCR/A520.

An Enhanced Recovery After Surgery (ERAS) Protocol for Ambulatory Anorectal Surgery Reduced Postoperative Pain and Unplanned Returns to Care After Discharge.

BACKGROUND: Ambulatory surgery for anorectal procedures has been proven to be safe and effective. Specific perioperative pathways combining multiple interventions have been shown to optimize recovery and outcomes associated with inpatient colorectal surgery. However, there are no major studies describing and evaluating a standardized protocol for ambulatory anorectal surgery. The purpose of this study was to evaluate the outcomes of a modified enhanced recovery after surgery (ERAS) protocol for ambulatory anorectal surgery. METHODS: This was a retrospective review of prospectively collected data from 14 Southern California Kaiser Permanente medical centers. An eight-item protocol including: preoperative education, preoperative distribution of prescriptions, preoperative carbohydrate treatment, multimodal analgesia, preferential use of monitored anesthesia care (MAC), routine use of local anesthesia/regional blocks, intraoperative restriction of intravenous fluids, and post-discharge phone call. Postoperative pain scores and preventable returns to the emergency department or urgent care were assessed. RESULTS: Postoperative pain scores were reduced when all eight elements of the protocol were delivered (p = 0.005). On multivariate analysis, there was reduced postoperative pain when preoperative carbohydrate treatment was completed (p = 0.002), with MAC (p = 0.003), and when multimodal analgesia was used (p = 0.02). There were decreased preventable returns to the emergency department or urgent care when MAC was used (p = 0.03); there were more returns for constipation (p = 0.04) but fewer returns for pain (p = 0.002) after preoperative carbohydrate treatment. Local anesthesia was associated with fewer returns for constipation (p = 0.01). CONCLUSIONS: Implementation of a standardized ERAS protocol for ambulatory anorectal surgery decreased postoperative pain and unplanned return visits to emergency care.

Can We Do That Here? Establishing the Scope of Surgical Practice at a New Safety-Net Community Hospital Through a Transparent, Collaborative Review of Physician Privileges.

PROBLEM DEFINITION: Stewarding of physician privileges wisely is imperative, but no guidelines exist for how to incorporate system-level factors in privileging decisions. A newly opened, safety-net community hospital tailored the scope of surgical practice through review of physician privileges. Martin Luther King, Jr. Community Hospital is a public-private partnership, safety-net institution in South Los Angeles that opened in July 2015. It has 131 beds, including a 28-bed emergency department, a 20-bed ICU, and 5 operating rooms. Staff privileging decisions were initially based only on physicians' training and experience, but this resulted in several cases that tested the boundaries of what a small community hospital was prepared to handle. ITERATION AND PIVOTS: A collaborative, transparent process to review physician privileges was developed. This began with physician-only review of procedure lists, followed by a larger, multidisciplinary group to assess system-level factors. Specific questions were used to guide discussion, and unanimous approval from all stakeholders was required to include a procedure. An initial list of 558 procedures across 11 specialties was reduced to 321 (57.5%). No new cases that fall outside these new boundaries have arisen. KEY INSIGHTS: An inclusive process was crucial for obtaining buy-in and establishing cultural norms. Arranging transfer agreements remains a significant challenge. NEXT STEPS: Accumulation of institutional experience continues through regular performance reviews. As this hospital's capabilities mature, a blueprint has been established for expanding surgical scope of practice based explicitly on system-level factors.

Tumor-Targeting Salmonella typhimurium A1-R Sensitizes Melanoma With a BRAF-V600E Mutation to Vemurafenib in a Patient-Derived Orthotopic Xenograft (PDOX) Nude Mouse Model.

Previously, a BRAF-V600E-mutant melanoma obtained from the right chest wall of a patient was grown orthotopically in the right chest wall of nude mice to establish a patient-derived orthotopic xenograft (PDOX) model. Trametinib (TRA), an MEK inhibitor, caused tumor regression. In contrast, another MEK inhibitor, cobimetinib (COB) could slow but not arrest growth or cause regression of the melanoma PDOX. First-line therapy temozolomide (TEM) could slow but not arrest tumor growth or cause regression. In addition, vemurafenib (VEM) was not effective even though VEM is supposed to target the BRAF-V600E mutation. We also previously demonstrated that tumor-targeting with S. typhimurium A1-R combined with TEM was significantly more effective than either S. typhimurium A1-R alone or TEM alone on the melanoma PDOX with the BRAF-V600E mutation. The present study used this PDOX model of melanoma to test its sensitivity to VEM combined with S. typhimurium A1-R compared to VEM alone and VEM combined with COB. VEM combined with S. typhimurium A1-R was significantly more effective than VEM alone or VEM combined with COB (P = 0.0216) which is currently first line therapy for advanced melanoma with a BRAF-V600E mutation. J. Cell. Biochem. 118: 2314-2319, 2017. © 2017 Wiley Periodicals, Inc.

Peritransplant pancreatitis: A marker of high mortality and graft failure in liver transplant patients.

Perioperative pancreatitis is a significant comorbid condition in surgical patients. However, the degree to which pancreatitis affects graft and overall survival in liver transplant recipients has not been evaluated. This study assesses the impact of pancreatitis on graft and patient survival in adult orthotopic liver transplantation (OLT). All patients undergoing OLT at a single academic institution from 2007 to 2015 were reviewed. Pancreatitis was classified by method of diagnosis (intraoperative/radiographic [IO/R] versus isolated serologic diagnosis) and timing (preoperative versus postoperative diagnosis). Twenty-three patients were identified with peritransplant pancreatitis (within 30 days preoperatively or postoperatively). A control group of patients without pancreatitis undergoing OLT was composed of 775 patients. Graft failure/death rates for patients with versus without pancreatitis were 7.4% versus 7.4% at 30 days, 33.3% versus 12.6% at 90 days, and 44.4% versus 26.9% at 12 months. Four patients with pancreatitis (17.4%) required emergent retransplantation and subsequently died within 90 days of their second transplant. Overall, 6 patients with pancreatitis (26.1%) died within 90 days of transplantation. Patients with pancreatitis had a hazard ratio (HR) for death or graft failure of 2.28 as compared with controls (P < 0.01). The effect of pancreatitis is most pronounced among those diagnosed by IO/R findings, with an adjusted HR of 2.53 (P < 0.01) and those diagnosed in the postoperative period, adjusted HR of 2.57 (P = 0.01). In conclusion, perioperative pancreatitis is associated with early graft failure and patient mortality, regardless of the method or timing of the diagnosis. Given these results, IO/R findings of pancreatitis should induce caution and potentially preclude OLT until resolved. Liver Transplantation 23 925-932 2017 AASLD.

Pneumonia after liver transplantation.

PURPOSE OF REVIEW: Pneumonia occurs in 8-23% of patients after liver transplantation and contributes considerably to their morbidity and mortality. With the increasing acuity of liver transplantation patients in the current era, pneumonias, particularly ventilator-associated pneumonias, and multidrug-resistant pathogens, are of growing concern. RECENT FINDINGS: Postliver transplantation pneumonia cause varies with the timing of infection. In the early period (<1 month postliver transplantation), nosocomial pneumonias, including ventilator-associated pneumonias and multidrug-resistant species are most common. During the intermediate period (1-6 months postliver transplantation), opportunistic infections predominate as intensive immunosuppression persists. In the late period (>6 months postliver transplantation), community-acquired bacterial and viral pneumonias arise, as immunosuppression is reduced. Numerous risk factors have been implicated in postliver transplantation pneumonias. Prevention is aimed at reducing bacterial colonization, preventing aspiration events, and utilizing surveillance and targeted antibiotics. Novel studies have also shown reduced risk of infection with personalized immunosuppression regimens guided by an immune function assay. SUMMARY: The etiologic patterns, risk factors, and preventive measures for postliver transplantation pneumonia must be understood to minimize patient exposure to modifiable risks and optimize recipient status in the perioperative period. Prevention is multifaceted and may be enhanced by personalization of immune therapy based on predisposition to infection and graft rejection.

Changes in surgical mortality during COVID-19 pandemic by patients' race, ethnicity and socioeconomic status among US older adults: a quasi-experimental event study model.

OBJECTIVES: To examine changes in the 30-day surgical mortality rate after common surgical procedures during the COVID-19 pandemic and investigate whether its impact varies by urgency of surgery or patient race, ethnicity and socioeconomic status. DESIGN: We used a quasi-experimental event study design to examine the effect of the COVID-19 pandemic on surgical mortality rate, using patients who received the same procedure in the prepandemic years (2016-2019) as the control, adjusting for patient characteristics and hospital fixed effects (effectively comparing patients treated at the same hospital). We conducted stratified analyses by procedure urgency, patient race, ethnicity and socioeconomic status (dual-Medicaid status and median household income). SETTING: Acute care hospitals in the USA. PARTICIPANTS: Medicare fee-for-service beneficiaries aged 65-99 years who underwent one of 14 common surgical procedures from 1 January 2016 to 31 December 2020. MAIN OUTCOME MEASURES: 30-day postoperative mortality rate. RESULTS: Our sample included 3 620 689 patients. Surgical mortality was higher during the pandemic, with peak mortality observed in April 2020 (adjusted risk difference (aRD) +0.95 percentage points (pp); 95% CI +0.76 to +1.26 pp; p<0.001) and mortality remained elevated through 2020. The effect of the pandemic on mortality was larger for non-elective (vs elective) procedures (April 2020: aRD +0.44 pp (+0.16 to +0.72 pp); p=0.002 for elective; aRD +1.65 pp (+1.00, +2.30 pp); p<0.001 for non-elective). We found no evidence that the pandemic mortality varied by patients' race and ethnicity (p for interaction=0.29), or socioeconomic status (p for interaction=0.49). CONCLUSIONS: 30-day surgical mortality during the COVID-19 pandemic peaked in April 2020 and remained elevated until the end of the year. The influence of the pandemic on surgical mortality did not vary by patient race and ethnicity or socioeconomic status, indicating that once patients were able to access care and undergo surgery, surgical mortality was similar across groups.

Defining a threshold for intervention in breast cancer-related lymphedema: what level of arm volume increase predicts progression?

The purpose of this study is to evaluate arm volume measurements and clinico-pathologic characteristics of breast cancer patients to define a threshold for intervention in breast cancer-related lymphedema. We prospectively performed arm volume measurements on breast cancer patients using a Perometer. Arm measurements were performed pre- and post-operatively, and change in arm volume was quantified using a relative volume change (RVC) equation. Patient and treatment risk factors were evaluated. Cox proportional hazards models with time-dependent covariates for RVC were used to evaluate whether RVC elevations of ≥3 to <5 % or ≥5 to <10 % occurring ≤3 months or >3 months after surgery were associated with progression to ≥10 % RVC. 1,173 patients met eligibility criteria with a median of 27 months post-operative follow-up. The cumulative incidence of ≥10 % RVC at 24 months was 5.26 % (95 % CI 4.01-6.88 %). By multivariable analysis, a measurement of ≥5 to <10 % RVC occurring >3 months after surgery was significantly associated with an increased risk of progression to ≥10 % RVC (HR 2.97, p < 0.0001), but a measurement of ≥3 to <5 % RVC during the same time period was not statistically significantly associated (HR 1.55, p = 0.10). Other significant risk factors included a measurement ≤3 months after surgery with RVC of ≥3 to <5 % (p = 0.007), ≥5 to <10 % (p < 0.0001), or ≥10 % (p = 0.023), axillary lymph node dissection (ALND) (p < 0.0001), and higher BMI at diagnosis (p = 0.0028). Type of breast surgery, age, number of positive or number of lymph nodes removed, nodal radiation, chemotherapy, and hormonal therapy were not significant (p > 0.05). Breast cancer patients who experience a relative arm volume increase of ≥3 to <5 % occurring >3 months after surgery do not have a statistically significant increase in risk of progression to ≥10 %, a common lymphedema criterion. Our data support utilization of a ≥5 to <10 % threshold for close monitoring or intervention, warranting further assessment. Additional risk factors for progression to ≥10 % include ALND, higher BMI, and post-operative arm volume elevation.

Foot and shoe size mismatch in three different New York City populations.

Proper shoe size is an important element of foot health, especially in the elderly and diabetic populations. An improper fit can lead to pain, functional limitations, and falls. The aim of the present study was to determine the proportion of adults who are unaware of their own shoe size in 3 different New York City populations: a foot specialist private practice, an academic diabetic foot and ankle clinic, and a charity care center, the Bowery clinic, serving the homeless. A shoe size mismatch was defined as a difference of at least 0.5 in size between the measured foot and the shoe size. Demographic data were collected during the examination and retrospectively by chart review. A total of 235 volunteers participated in our study. A significant difference in the prevalence of the measured foot and shoe size mismatch was found between the cohort from the private practice compared with both the diabetic foot and ankle clinic and the Bowery clinic (P < .01 and P < .01, respectively). A significant difference was also detected (P < .05) between the private practice and the Bowery mission cohort when a difference of at least 1.5 sizes was present between the measured foot and the shoe size. Of those with a foot to shoe size mismatch, 60% had a difference of more than 0.5 in the shoe size between their right and left foot. In conclusion, our findings suggest that proper footwear sizing is lacking among a large proportion of our patients and that an adequate shoe size can be achieved with proper counseling.