Publications by authors named "Thomas Boerner"

26 Publications

  • Page 1 of 1

Diaphragm hernia after debulking surgery in patients with ovarian cancer.

Gynecol Oncol Rep 2021 May 31;36:100759. Epub 2021 Mar 31.

Gynecology Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA.

Over 80% of patients with epithelial ovarian cancer present with advanced disease, FIGO stage III or IV at the time of diagnosis. The majority require extensive upper abdominal surgery to obtain complete gross resection. This may include splenectomy, distal pancreatectomy, partial hepatectomy, cholecystectomy, and usually diaphragmatic peritonectomy or resection. Following surgery, diaphragmatic hernia-a very rare but serious complication-may occur. We describe four cases of left-sided diaphragmatic hernia resulting after debulking surgery, which included left diaphragm peritonectomy and splenectomy, in patients with advanced ovarian cancer. In association with the current shift towards more extensive debulking surgery for ovarian cancer, more patients may present with postoperative left-sided diaphragm hernia, making the prevention, diagnosis, and management of this complication important to practicing gynecologic oncologists. Intraoperatively the diaphragm should be checked thoroughly to rule out any defects, which should be closed. A diaphragmatic hernia may be easily misdiagnosed because the patient can present with various symptoms. While rare, these hernias require prompt identification, intervention and surgical correction to avoid serious complications.
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http://dx.doi.org/10.1016/j.gore.2021.100759DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8042427PMC
May 2021

Genetic Determinants of Outcome in Intrahepatic Cholangiocarcinoma.

Hepatology 2021 Mar 25. Epub 2021 Mar 25.

Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA.

Background/aims: Genetic alterations in intrahepatic cholangiocarcinoma (iCCA) are increasingly well-characterized, but their impact on outcome and prognosis remain unknown.

Approach/results: This bi-institutional study of patients with confirmed iCCA (n=412) used targeted next-generation sequencing of primary tumors to define associations among genetic alterations, clinicopathological variables, and outcome. The most common oncogenic alterations were IDH1 (20%), ARID1A (20%), TP53 (17%), CDKN2A (15%), BAP1 (15%), FGFR2 (15%), PBRM1 (12%), and KRAS (10%). IDH1/2 mutations (mut) were mutually exclusive with FGFR2 fusions (fus), but neither was associated with outcome. For all patients, TP53 (p<0.0001), KRAS (p=0.0001), and CDKN2A (p<0.0001) alterations predicted worse overall survival (OS). These high-risk alterations were enriched in advanced disease but adversely impacted survival across all stages, even when controlling for known correlates of outcome (multifocal disease, lymph node involvement, bile duct type, periductal infiltration). In resected patients (n=209), TP53mut (HR=1.82, 95%CI=1.08-3.06, p=0.03) and CDKN2A deletions (del) (HR=3.40, 95%CI=1.95-5.94, p<0.001) independently predicted shorter OS, as did high-risk clinical variables (multifocal liver disease [p<0.001]; regional lymph node metastases [p<0.001]), whereas KRASmut (HR=1.69, 95%CI=0.97-2.93, p=0.06) trended toward statistical significance. The presence of both or neither high-risk clinical or genetic factors represented outcome extremes (median OS=18.3 vs. 74.2 months, p<0.001), with high-risk genetic alterations alone (median OS=38.6 months, 95%CI=28.8-73.5) or high-risk clinical variables alone (median OS=37.0 months, 95%CI=27.6-NA) associated with intermediate outcome. TP53mut, KRASmut, and CDKN2Adel similarly predicted worse outcome in patients with unresectable iCCA. CDKN2Adel tumors with high-risk clinical features were notable for limited survival and no benefit of resection over chemotherapy.

Conclusions: TP53, KRAS, and CDKN2A alterations were independent prognostic factors in iCCA when controlling for clinical and pathologic variables, disease stage, and treatment. Since genetic profiling can be integrated into pre-treatment therapeutic decision-making, combining clinical variables with targeted tumor sequencing may identify patient subgroups with poor outcome irrespective of treatment strategy.
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http://dx.doi.org/10.1002/hep.31829DOI Listing
March 2021

Voltage-independent GluN2A-type NMDA receptor Ca signaling promotes audiogenic seizures, attentional and cognitive deficits in mice.

Commun Biol 2021 Jan 8;4(1):59. Epub 2021 Jan 8.

Departments Molecular Neurobiology and Physiology at the Max Planck Institute for Medical Research, Jahnstr. 29, 69120, Heidelberg, Germany.

The NMDA receptor-mediated Ca signaling during simultaneous pre- and postsynaptic activity is critically involved in synaptic plasticity and thus has a key role in the nervous system. In GRIN2-variant patients alterations of this coincidence detection provoked complex clinical phenotypes, ranging from reduced muscle strength to epileptic seizures and intellectual disability. By using our gene-targeted mouse line (Grin2a), we show that voltage-independent glutamate-gated signaling of GluN2A-containing NMDA receptors is associated with NMDAR-dependent audiogenic seizures due to hyperexcitable midbrain circuits. In contrast, the NMDAR antagonist MK-801-induced c-Fos expression is reduced in the hippocampus. Likewise, the synchronization of theta- and gamma oscillatory activity is lowered during exploration, demonstrating reduced hippocampal activity. This is associated with exploratory hyperactivity and aberrantly increased and dysregulated levels of attention that can interfere with associative learning, in particular when relevant cues and reward outcomes are disconnected in space and time. Together, our findings provide (i) experimental evidence that the inherent voltage-dependent Ca signaling of NMDA receptors is essential for maintaining appropriate responses to sensory stimuli and (ii) a mechanistic explanation for the neurological manifestations seen in the NMDAR-related human disorders with GRIN2 variant-meidiated intellectual disability and focal epilepsy.
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http://dx.doi.org/10.1038/s42003-020-01538-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7794508PMC
January 2021

Exploring the clinical significance of serous tubal intraepithelial carcinoma associated with advanced high-grade serous ovarian cancer: A Memorial Sloan Kettering Team Ovary Study.

Gynecol Oncol 2021 Mar 30;160(3):696-703. Epub 2020 Dec 30.

Gynecology Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA; Department of OB/GYN, Weill Cornell Medical College, New York, NY, USA. Electronic address:

Objective: To evaluate the clinical significance and genomic associations of concurrent serous tubal intraepithelial carcinoma (STIC) with high-grade serous carcinoma (HGSC) of the ovary in women undergoing primary debulking surgery (PDS).

Methods: All patients who underwent PDS for HGSC between 01/2015 and 12/2018 were captured in a prospectively maintained institutional database. Patients were categorized based on the presence or absence of concurrent STIC noted on final pathology. Demographic, perioperative, and outcomes data were collected, and groups were compared using standard statistical tests. Progression-free survival (PFS) and overall survival (OS) were evaluated using the Kaplan-Meier method. For comparison of differences in somatic alterations between the two cohorts, specimens were sequenced using MSK-IMPACT.

Results: Of 306 eligible patients, 87 (28%) had a concurrent STIC lesion (+STIC) and 219 (72%) did not (no-STIC). Demographics and clinicopathological factors were similar between the two cohorts, except for a significantly higher median preoperative CA-125 level in the no-STIC group (423 U/mL vs. 321 U/mL; p=0.029). There were no significant differences in median PFS (22.7 months [95%CI: 18.9-28.4] vs. 27.7 months [95%CI: 25.5-30.5]; p=0.126) and 3- year OS rate (81% [95%CI: 70-88%] vs. 85% [95%CI: 78-90%]; p=0.392) between +STIC and no-STIC patients, respectively. Targeted DNA-sequencing via MSK-IMPACT showed a similar distribution of driver mutations or structural genetic alterations, and affected genetic signaling pathways were similar between the cohorts.

Conclusions: There were no identifiable clinical and genetic differences in patients with HGSC and concurrent STIC. These data suggest a comparable, if not identical, disease process.
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http://dx.doi.org/10.1016/j.ygyno.2020.12.022DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7902425PMC
March 2021

Survival outcomes of acute normovolemic hemodilution in patients undergoing primary debulking surgery for advanced ovarian cancer: A Memorial Sloan Kettering Cancer Center Team Ovary study.

Gynecol Oncol 2021 Jan 17;160(1):51-55. Epub 2020 Nov 17.

Gynecology Service, Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, NY, USA; Joan & Sanford I. Weill Medical College of Cornell University, New York, NY, USA. Electronic address:

Objective: To describe oncologic outcomes after using acute normovolemic hemodilution (ANH) to reduce requirement for allogenic red blood cell transfusions (ABT) in patients undergoing primary debulking surgery (PDS) for advanced ovarian cancer.

Methods: We performed a post-hoc analysis of a recent prospective trial investigating the safety and feasibility of ANH during PDS for advanced ovarian cancer. We report long-term survival outcomes. We compared demographics, clinicopathological characteristics, survival outcomes in this cohort of Stage IIIB-IVB high-grade serous ovarian cancer patients undergoing ANH (ANH group), with a retrospective cohort of all other patients (standard group) undergoing PDS during the same time period (01/2012-04/2017). Standard statistical tests were used.

Results: There were no demographic or clinicopathological differences between ANH (n = 33) and standard groups (n = 360), except for higher median age at diagnosis (57 vs. 62 years, respectively; p = 0.044) and shorter operative time (357 vs. 446 min, respectively; p < 0.001) in the standard group. Cytoreductive outcomes (ANH vs. standard): 0 mm, 69.7 vs. 63.9%; gross residual disease (RD) ≤1 cm, 21.2 vs. 26.9%; >1 cm, 9.1 vs. 9.2% (p = 0.78). RD after PDS was the only independent factor associated with worse progression-free survival (PFS) on multivariable analysis (p < 0.001). Patients with BRCA mutations trended towards improved PFS (p = 0.057). Significant factors for overall survival (OS) on multivariable analysis: preoperative CA125 (p = 0.004), ascites (p = 0.018), RD after PDS (p = 0.04), BRCA mutation status (p < 0.001). After adjustment for potential confounders, ANH was not independently associated with PFS or OS [PFS: HR 0.928 (0.618-1.395); p = 0.721; OS: HR 0.588 (95%CI: 0.317-1.092); p = 0.093].

Conclusions: ANH is an innovative approach in intraoperative management. It was previously proven to decrease need for ABT while maintaining the ability to achieve complete gross resection and associated benefits.
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http://dx.doi.org/10.1016/j.ygyno.2020.10.042DOI Listing
January 2021

Salpingectomy for the Risk Reduction of Ovarian Cancer: Is It Time for a Salpingectomy-alone Approach?

J Minim Invasive Gynecol 2021 Mar 8;28(3):403-408. Epub 2020 Oct 8.

Gynecology Service, Department of Surgery, Memorial Sloan Kettering Cancer Center (all authors); Department of Obstetrics and Gynecology, Weill Cornell Medical College (Dr. Long Roche), New York, New York. Electronic address:

Objective: To summarize published evidence supporting current strategies for the prevention of epithelial ovarian cancer in women with a genetic, elevated risk for the development of this disease, as well as the emerging data on the novel salpingectomy with delayed oophorectomy (SDO) strategy. Furthermore, we will explore whether salpingectomy alone is a viable risk-reducing strategy for these women. We will also discuss current national guidelines for risk-reducing surgery based on patients' individual genetic predisposition.

Data Sources: MEDLINE, PubMed, EMBASE, and the Cochrane Database, with a focus on randomized controlled trials and large prospective, observational studies.

Methods Of Study Selection: The key search terms for our review included Medical Subject Headings: "salpingectomy," "ovarian cancer," and "risk-reducing surgery."

Tabulation, Integration, And Results: The fallopian tube is now well established as the site of origin for most ovarian cancers, particularly high-grade serous carcinomas. This finding has led to the development of new preventive surgical techniques, such as SDO, which may be associated with fewer side effects. However, until the results of ongoing trials are reported and the impact of SDO on ovarian cancer risk reduction is established, it should not be recommended outside of clinical trials, and bilateral salpingo-oophorectomy remains the treatment of choice for risk-reducing surgery, especially in women with a genetic, high risk for ovarian cancer.

Conclusion: The decision to undergo risk-reducing surgery among women with an elevated risk for ovarian cancer should be made after comprehensive consultation and individually based on genetic predisposition, childbearing status, and personal preference.
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http://dx.doi.org/10.1016/j.jmig.2020.09.020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7954812PMC
March 2021

Extrahepatic recurrence rates in patients receiving adjuvant hepatic artery infusion and systemic chemotherapy after complete resection of colorectal liver metastases.

J Surg Oncol 2020 Dec 25;122(8):1536-1542. Epub 2020 Sep 25.

Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York, USA.

Background: This study investigated the effect of the reduced dose of systemic chemotherapy (SYS) on recurrence patterns in patients receiving adjuvant hepatic artery infusion (HAI) chemotherapy after complete colorectal liver metastases (CRLM) resection.

Methods: Patients undergoing complete CRLM resection between 2000 and 2007 were selected from a prospectively maintained database and categorized as receiving SYS or HAI + SYS. Those with pre and/or intraoperative extrahepatic disease, documented death, or recurrence within 30 days of CRLM resection were excluded. Competing risk, Fine and Gray's tests were used to compare SYS versus HAI + SYS for time-to-organ recurrence.

Results: Of 361 study patients, 153 (42.4%) received SYS and 208 (57.6%) received HAI + SYS. The median follow-up for survivors was 100 (range = 12-185) and 156 months (range = 18-217) for SYS and HAI + SYS, respectively. The 5-year cumulative incidence (CI) of any liver recurrence was greater for those receiving SYS (SYS = 41.9% vs. HAI + SYS = 28.6%, p = .005). The 5-year CI of developing any lung or extrahepatic recurrence for SYS patients was 36.2% and 47.9% compared with 44.5% (p = .242) and 51.7% (p = .551), respectively, in patients receiving HAI + SYS.

Conclusion: Despite the reduced dose of SYS, adjuvant HAI + SYS after CRLM resection is not associated with a significantly increased risk of extrahepatic recurrence.
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http://dx.doi.org/10.1002/jso.26221DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7938716PMC
December 2020

Early liver metastases after "failure" of adjuvant chemotherapy for stage III colorectal cancer: is there a role for additional adjuvant therapy?

HPB (Oxford) 2021 Apr 14;23(4):601-608. Epub 2020 Sep 14.

Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA. Electronic address:

Background: The utility of adjuvant chemotherapy after resection of colorectal liver metastasis (CLM) in patients with rapid recurrence after adjuvant chemotherapy for their primary tumor is unclear. The aim of this study was to evaluate the oncologic benefit of adjuvant hepatic arterial plus systemic chemotherapy (HAIC + Sys) in patients with early CLM.

Methods: A retrospective analysis of patients with early CLM (≤12 months of adjuvant chemotherapy for primary tumor) who received either HAIC + Sys, adjuvant systemic chemotherapy alone (Sys), or active surveillance (Surgery alone) following resection of CLM was performed. Recurrence and survival were compared between treatment groups using Kaplan-Meier methods and Cox proportional hazards models.

Results: Of 239 patients undergoing resection of early CLM, 79 (33.1%) received HAIC + Sys, 77 (32.2%) received Sys, and 83 (34.7%) had Surgery alone. HAIC + Sys was independently associated with reduced risk of RFS events (adjusted hazard ratio [HRadj]: 0.64, 95%CI:0.44-0.94, p = 0.022) and all-cause mortality (HRadj: 0.54, 95%CI:0.36-0.81, p = 0.003) compared to Surgery alone patients. Largest tumor >5 cm (HRadj: 2.03, 95%CI: 1.41-2.93, p < 0.001) and right-sided colon tumors (HRadj: 1.93, 95%CI: 1.29-2.89, p = 0.002) were independently associated with worse OS.

Conclusion: Adjuvant HAIC + Sys after resection of early CLM that occur after chemotherapy for node-positive primary is associated with improved outcomes.
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http://dx.doi.org/10.1016/j.hpb.2020.08.018DOI Listing
April 2021

Video-assisted thoracic surgery in the primary management of advanced ovarian carcinoma with moderate to large pleural effusions: A Memorial Sloan Kettering Cancer Center Team Ovary Study.

Gynecol Oncol 2020 10 10;159(1):66-71. Epub 2020 Aug 10.

Gynecology Service, Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, NY, USA; Joan and Sanford I. Weill Medical College of Cornell University, New York, NY, USA. Electronic address:

Objectives: We assessed the utility of video-assisted thoracic surgery (VATS) in defining extent of intrathoracic disease in advanced ovarian carcinoma with moderate-to-large pleural effusions.

Methods: Beginning in 2001, VATS was performed on all patients with suspected advanced ovarian carcinoma and moderate-to-large pleural effusions, evaluating for macroscopic intrathoracic disease. The algorithm recommended primary debulking surgery (PDS) for ≤1 cm, neoadjuvant chemotherapy (NACT)/interval debulking surgery (IDS) for >1 cm intrathoracic disease. We reviewed records of patients undergoing VATS from 10/01-01/19. Differences between treatment groups were tested using standard statistical techniques.

Results: One-hundred patients met eligibility criteria (median age, 60; median CA-125 level, 1158 U/mL; medium serum albumin, 3.8 g/dL). Macroscopic pleural disease was found in 70 (70%). After VATS, 50 (50%) underwent attempted PDS (PDS group), 50 (50%) received NACT (NACT/IDS group). Forty-seven (94%) underwent IDS. Median overall survival (OS) for the entire cohort (n = 100) was 44.5 months (95% CI: 37.8-51.7). The PDS group had significantly longer survival than the NACT/IDS group [45.8 (95% CI: 40.5-87.8) vs. 37.4 months (95% CI: 33.3-45.2); p = .016]. On multivariable analysis, macroscopic intrathoracic disease (HR 2.18, 95% CI: 1.14-4.18; p = .019) and age ≥ 65 (HR 1.98, 95% CI: 1.16-3.40; p = .013) were independently associated with elevated death risk. Patients with the best outcome had no macroscopic disease at VATS and underwent PDS (median OS, 87.8 months).

Conclusions: VATS is useful in therapeutic decision-making for PDS vs. NACT/IDS in advanced ovarian cancer with moderate-to-large pleural effusions.
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http://dx.doi.org/10.1016/j.ygyno.2020.07.101DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7541719PMC
October 2020

Association of RAS Mutation Location and Oncologic Outcomes After Resection of Colorectal Liver Metastases.

Ann Surg Oncol 2021 Feb 18;28(2):817-825. Epub 2020 Jul 18.

Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA.

Background: RAS mutations are prognostic for patients with metastatic colorectal cancer (mCRC). We investigated clinical, pathologic, and survival differences based on RAS exon for patients with colorectal liver metastases (CRLM).

Methods: This retrospective, single-center study included patients with R0/R1 resection of CRLM from 1992 to 2016. Patients with unresected extrahepatic disease or liver-first resection were excluded. Overall survival (OS) and recurrence-free survival were assessed and stratified by mutation status and location. Fisher's exact test, Wilcoxon rank-sum test, and log-rank test were used, where appropriate.

Results: A total of 938 mCRC patients were identified with median age of 57 (range 19-91). Of the 445 patients with KRAS mutations, 407 (91%) had a mutation in exon 2, 14 (3%) exon 3, and 24 (5%) exon 4. Median OS was 71.4 months (95% confidence interval [CI] 66.1-76.5). Patients with KRAS mutations had worse OS compared with KRAS wild-type patients (median 55.5 vs. 91.3 months, p < 0.001). While there was no significant difference in OS based on the exon mutated (p = 0.12), 5-year OS was higher for patients with exon 4 mutations [68.8% (95% CI 0.45-0.84)] compared with those with mutations in exon 2 [45.7% (95% CI 0.40-0.51)] or exon 3 [39.1% (95% CI: 0.11-0.68)]. Patients with NRAS mutant tumors also had worse OS compared with NRAS wild-type patients (median 50.9 vs. 73.3 months, p = 0.03).

Conclusions: NRAS and KRAS exon 3/4 mutations are present in a minority of mCRC patients. Patients with exon 4 mutant tumors may have a more favorable prognosis, although the difference in oncologic outcomes based on mutated exon appears to be smaller than previously reported.
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http://dx.doi.org/10.1245/s10434-020-08862-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7854850PMC
February 2021

Recurrence After Liver Resection of Colorectal Liver Metastases: Repeat Resection or Ablation Followed by Hepatic Arterial Infusion Pump Chemotherapy.

Ann Surg Oncol 2021 Feb 9;28(2):808-816. Epub 2020 Jul 9.

Department of Surgery, Memorial Sloan Kettering Cancer Center, New York City, NY, USA.

Background: The aim of this study was to investigate the effectiveness of adjuvant hepatic arterial infusion pump (HAIP) chemotherapy after complete resection or ablation of recurrent colorectal liver metastases (CRLM).

Methods: A retrospective cohort study was conducted of patients from two centers who were treated with resection and/or ablation of recurrent CRLM only between 1992 and 2018. Overall survival (OS) and hepatic disease-free survival (hDFS) were estimated using the Kaplan-Meier method. The Cox regression method was used to calculate hazard ratios (HRs) with corresponding 95% confidence intervals (CI).

Results: Of 374 eligible patients, 81 (22%) were treated with adjuvant HAIP chemotherapy. The median follow-up for survivors was 65 months (IQR 32-118 months). Patients receiving adjuvant HAIP were more likely to have multifocal disease and receive perioperative systemic chemotherapy at time of resection for recurrence. A median hDFS of 46 months (95% CI 29-81 months) was found in patients treated with adjuvant HAIP compared with 18 months (95% CI 15-26 months) in patients treated with resection and/or ablation alone (p = 0.001). The median OS and 5-year OS were 89 months (95% CI 52-126 months) and 66%, respectively, in patients treated with adjuvant HAIP compared with 57 months (95% CI 47-67 months) and 47%, respectively, in patients treated with resection and/or ablation only (p = 0.002). Adjuvant HAIP was associated with superior hDFS (adjusted HR 0.599, 95% CI 0.38-0.93, p = 0.02) and OS (adjusted HR 0.59, 95% CI 0.38-0.92, p = 0.02) in multivariable analysis.

Conclusion: Adjuvant HAIP chemotherapy after resection and/or ablation of recurrent CRLM is associated with superior hDFS and OS.
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http://dx.doi.org/10.1245/s10434-020-08776-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7801355PMC
February 2021

Addition of adjuvant hepatic artery infusion to systemic chemotherapy following resection of colorectal liver metastases is associated with reduced liver-related mortality.

J Surg Oncol 2020 Jun 31;121(8):1314-1319. Epub 2020 Mar 31.

Department of Surgery, Memorial Sloan Kettering Cancer Center, New York City, New York.

Background: After resection of colorectal liver metastases (CRLM), recurrent disease in the liver is a major cause of death but may be reduced with the addition of adjuvant hepatic arterial infusion (HAI) chemotherapy to systemic chemotherapy (SYS).

Objective: This study investigates organ-specific causes of death in patients receiving adjuvant HAI and SYS compared to adjuvant SYS alone.

Methods: Between 2000 and 2007, patients undergoing complete CRLM resection were identified from a prospectively maintained liver resection database and categorized as receiving HAI + SYS or SYS only. Using newly constructed definitions, mortality was attributed to specific organs (liver, lung, peritoneum, and brain) or infection. Univariate models and cumulative incidence functions were generated using competing risk methods.

Results: Of 361 eligible patients, 208 (57.6%) received HAI + SYS and 153 (42.4%) received SYS. The median follow up among survivors was 142 months (range = 12-217 months). Ten-year overall survival was 50.6% in the HAI + SYS group compared to 30.9% in those receiving SYS (P = .004). The 5-year cumulative incidence of liver-related mortality was 6.8% in the HAI + SYS group compared to 14.3% in the SYS group (P = .007).

Conclusion: The addition of HAI to SYS after CRLM resection is associated with a 50% reduction in liver-related mortality at 5 years.
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http://dx.doi.org/10.1002/jso.25916DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7927157PMC
June 2020

The impact of hepatic arterial infusion pump chemotherapy on hepatic recurrences and survival in patients with resected colorectal liver metastases.

HPB (Oxford) 2020 Sep 27;22(9):1271-1279. Epub 2019 Dec 27.

Department of Surgery, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, 10065 NY, New York, United States. Electronic address:

Background: The objective was to investigate the impact of adjuvant hepatic arterial infusion pump (HAIP) chemotherapy on the rates and patterns of recurrence and survival in patients with resected colorectal liver metastases (CRLM).

Methods: Recurrence rates, patterns, and survival were compared between patients treated with and without adjuvant HAIP using competing risk analyses.

Results: 2128 patients were included, of which 601 patients (28.2%) received adjuvant HAIP and systemic chemotherapy (HAIP + SYS). The overall recurrence rate was similar with HAIP + SYS or SYS (63.5% versus 64.2%,p = 0.74). The 5-year cumulative incidence of initial intrahepatic recurrences was lower with HAIP + SYS (22.9% versus 38.4%,p < 0.001). The 5-year cumulative incidence of initial extrahepatic recurrences was higher with HAIP + SYS (48.5% versus 40.3%,p = 0.005), because patients remained at risk for extrahepatic recurrence in the absence of intrahepatic recurrence, which was largely attributable to more pulmonary recurrences with HAIP + SYS (33.6% versus 23.7%,p < 0.001). HAIP was an independent prognostic factor for DFS (adjusted HR 0.69, 95% CI 0.60-0.79, p < 0.001), and OS (adjusted HR 0.67, 95% CI 0.57-0.78,p < 0.001).

Conclusion: Adjuvant HAIP chemotherapy is associated with lower intrahepatic recurrence rates and better DFS and OS after resection of CRLM.
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http://dx.doi.org/10.1016/j.hpb.2019.11.013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7890567PMC
September 2020

Long-Term and Oncologic Outcomes of Robotic Versus Laparoscopic Liver Resection for Metastatic Colorectal Cancer: A Multicenter, Propensity Score Matching Analysis.

World J Surg 2020 03;44(3):887-895

Division of Surgical Oncology, Department of Surgery, The Ohio State University Wexner Medical Center, N924 Doan Hall, 410 West 10th Ave, Columbus, OH, 43210, USA.

Background: To assess long-term oncologic outcomes of robotic-assisted liver resection (RLR) for colorectal cancer (CRC) metastases as compared to a propensity-matched cohort of laparoscopic liver resections (LLR). Although safety and short-term outcomes of RLR have been described and previously compared to LLR, long-term and oncologic data are lacking.

Methods: A retrospective study was performed of all patients who underwent RLR and LLR for CRC metastases at six high-volume centers in the USA and Europe between 2002 and 2017. Propensity matching was used to match baseline characteristics between the two groups. Data were analyzed with a focus on postoperative and oncologic outcomes, as well as long-term recurrence and survival.

Results: RLR was performed in 115 patients, and 514 patients underwent LLR. Following propensity matching 115 patients in each cohort were compared. Perioperative outcomes including mortality, morbidity, reoperation, readmission, intensive care requirement, length-of-stay and margin status were not statistically different. Both prematching and postmatching analyses demonstrated similar overall survival (OS) and disease-free survival (DFS) between RLR and LLR at 5 years (61 vs. 60% OS, p = 0.87, and 38 vs. 31% DFS, p = 0.25, prematching; 61 vs. 60% OS, p = 0.78, and 38 vs. 44% DFS, p = 0.62, postmatching).

Conclusions: Propensity score matching with a large, multicenter database demonstrates that RLR for colorectal metastases is feasible and safe, with perioperative and long-term oncologic outcomes and survival that are largely comparable to LLR.
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http://dx.doi.org/10.1007/s00268-019-05270-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7700440PMC
March 2020

Assessment of Hepatic Arterial Infusion of Floxuridine in Combination With Systemic Gemcitabine and Oxaliplatin in Patients With Unresectable Intrahepatic Cholangiocarcinoma: A Phase 2 Clinical Trial.

JAMA Oncol 2019 Oct 31. Epub 2019 Oct 31.

Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York.

Importance: Unresectable intrahepatic cholangiocarcinoma (IHC) carries a poor prognosis, with a median overall survival (OS) of 11 months. Hepatic arterial infusion (HAI) of high-dose chemotherapy may have potential benefit in these patients.

Objective: To evaluate clinical outcomes when HAI chemotherapy is combined with systemic chemotherapy in patients with unresectable IHC.

Design, Setting, And Participants: A single-institution, phase 2 clinical trial including 38 patients was conducted with HAI floxuridine plus systemic gemcitabine and oxaliplatin in patients with unresectable IHC at Memorial Sloan Kettering Cancer Center between May 20, 2013, and June 27, 2019. A confirmatory phase 1/2 study using the same therapy was conducted during the same time period at Washington University in St Louis. Patients with histologically confirmed, unresectable IHC were eligible. Resectable metastatic disease to regional lymph nodes and prior systemic therapy were permitted. Patients with distant metastatic disease were excluded.

Interventions: Hepatic arterial infusion of floxuridine and systemic administration of gemcitabine and oxaliplatin.

Main Outcomes And Measures: The primary outcome was progression-free survival (PFS) of 80% at 6 months.

Results: For the phase 2 clinical trial at Memorial Sloan Kettering Cancer Center, 42 patients with unresectable IHC were included and, of these, 38 patients were treated (13 [34%] men; median [range] age at diagnosis, 64 [39-81] years). The median follow-up was 30.5 months. Twenty-two patients (58%) achieved a partial radiographic response, and 32 patients (84%) achieved disease control at 6 months. Four patients had sufficient response to undergo resection, and 1 patient had a complete pathologic response. The median PFS was 11.8 months (1-sided 90% CI, 11.1) with a 6-month PFS rate of 84.1% (90% CI, 74.8%-infinity), thereby meeting the primary end point (6-month PFS rate, 80%). The median OS was 25.0 months (95% CI, 20.6-not reached), and the 1-year OS rate was 89.5% (95% CI, 80.2%-99.8%). Patients with resectable regional lymph nodes (18 [47%]) showed no difference in OS compared with patients with node-negative disease (24-month OS: lymph node negative: 60%; 95% CI, 40%-91% vs lymph node positive: 50%; 95% CI, 30%-83%; P = .66). Four patients (11%) had grade 4 toxic effects requiring removal from the study (1 portal hypertension, 2 gastroduodenal artery aneurysms, 1 infection in the pump pocket). Subgroup analysis showed significant improvement in survival in patients with IDH1/2 mutated tumors (2-year OS, 90%; 95% CI, 73%-99%) vs wild-type (2-year OS, 33%; 95% CI, 18%-63%) (P = .01). In the Washington University in St Louis confirmatory cohort, 9 patients (90%) achieved disease control at 6 months; the most common grade 3 toxic effect was elevated results of liver function tests, and median PFS was 12.8 months (1-sided 90% CI, 6.4).

Conclusions And Relevance: Hepatic arterial infusion plus systemic chemotherapy appears to be highly active and tolerable in patients with unresectable IHC; further evaluation is warranted.
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http://dx.doi.org/10.1001/jamaoncol.2019.3718DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6824231PMC
October 2019

Recurrence Patterns After Resection of Colorectal Liver Metastasis are Modified by Perioperative Systemic Chemotherapy.

World J Surg 2020 03;44(3):876-886

Department of Surgery, Erasmus MC Cancer Institute, Erasmus University, Dr. Molewaterplein 40, 3015 GD, Rotterdam, The Netherlands.

Background: This study investigated the impact of perioperative systemic chemotherapy on the recurrence rate and pattern following resection of colorectal liver metastases.

Methods: A retrospective cohort study was conducted in two centers. Rates and patterns of recurrence and overall survival (OS) were compared between patients treated with and without perioperative systemic chemotherapy. The clinical risk score (CRS) was used to stratify patients in low risk (CRS 0-2) and high risk (CRS 3-5) of recurrence.

Results: A total of 2020 patients were included, of whom 1442 (71%) received perioperative systemic chemotherapy. The median follow-up was 88 months, and 1289 patients (64%) developed a recurrence. The recurrence pattern was independent of chemotherapy in low-risk patients: intrahepatic recurrences (30% vs. 30%, p = 0.97) and extrahepatic recurrences (38% vs. 39%, p = 0.52). In high-risk patients, no difference in intrahepatic recurrences was found (48% vs. 50%, p = 0.59). However, a lower rate of extrahepatic recurrences (43% vs. 55%, p = 0.007) was observed with perioperative systemic chemotherapy, mainly due to a reduction in pulmonary recurrences (25% vs. 35%, p = 0.007). In competing risk analysis, the cumulative incidence of extrahepatic recurrence was significantly lower with perioperative systemic chemotherapy in high-risk patients only (5-year cumulative incidence 44% vs. 59%, p < 0.001). Perioperative chemotherapy was associated with improved OS in high-risk patients (adjusted HR 0.73, 95% CI 0.57-0.94, p = 0.02), but not in low-risk patients (adjusted HR 0.99, 95% CI 0.82-1.19, p = 0.90).

Conclusions: Perioperative systemic chemotherapy had no association with intrahepatic recurrence, but was associated with fewer pulmonary recurrences and superior OS in high-risk patients only.
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http://dx.doi.org/10.1007/s00268-019-05121-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7668197PMC
March 2020

Distinct histomorphological features are associated with IDH1 mutation in intrahepatic cholangiocarcinoma.

Hum Pathol 2019 09 21;91:19-25. Epub 2019 May 21.

Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, 10065 USA. Electronic address:

Intrahepatic cholangiocarcinoma has known histological heterogeneity. Mutations in IDH1 (mIDH1) define a molecular subclass of intrahepatic cholangiocarcinoma and IDH-targeted therapies are in development. Characterizing mIDH1 ICC histomorphology is of clinical interest for efficient identification. Resected ICCs with targeted next-generation sequencing by MSK-IMPACT were selected. Clinical data were obtained. By slide review, blinded to IDH status, data were collected for histology type, mucin production, necrosis, fibrosis, cytoplasm cell shape (low cuboidal, plump cuboidal/polygonal, and columnar), and architectural pattern (anastomosing, tubular, compact tubular, and solid). A tumor was considered architecturally heterogeneous if no dominant pattern represented ≥75% of the tumor. Parameters were compared between mIDH1and IDH wild-type controls. In the examined cohort (113 ICC: 29 mIDH1 and 84 IDH wild-type), all IDH1-mutant tumors were of small duct-type histology, thus analysis was limited to 101 small duct-type tumors. mIDH1cases were more likely to have plump cuboidal/polygonal shape (P = .014) and geographic-type fibrosis (P = .005), while IDH1 wild-type were more likely to have low cuboidal shape (P = .005). Both groups were predominantly architecturally heterogeneous with no significant difference in the distribution of architectural patterns. Plump cuboidal/polygonal cell shape and a geographic-type pattern of intra-tumoral fibrosis are more often seen in mIDH1compared to IDH wild-type tumors; however, IDH1 mutation is not associated with a distinct histoarchitectural pattern.
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http://dx.doi.org/10.1016/j.humpath.2019.05.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6744317PMC
September 2019

Robotic Versus Open Minor Liver Resections of the Posterosuperior Segments: A Multinational, Propensity Score-Matched Study.

Ann Surg Oncol 2019 Feb 17;26(2):583-590. Epub 2018 Oct 17.

Department of Surgery, City of Hope National Medical Center, City of Hope Hospital Duarte, Duarte, CA, USA.

Background: Minor liver resections of posterosuperior segments (1, 4A, 7, 8) are challenging to perform laparoscopically and are mainly performed using an open approach. We determined the feasibility of robotic resections of posterosuperior segments and compared short-term outcomes with the open approach.

Methods: Data on open and robotic minor (≤ 3 segments) liver resections including the posterosuperior segments, performed between 2009 and 2016, were collected retrospectively from four hospitals. Robotic and open liver resections were compared, before and after propensity score matching.

Results: In total, 51 robotic and 145 open resections were included. After matching, 31 robotic resections were compared with 31 open resections. Median hospital stay was 4 days (interquartile range [IQR] 3-7) for the robotic group, versus 8 days (IQR 6-10) for the open group (p < 0.001). Median operative time was 222 min (IQR 164-505) for robotic cases versus 231 min (IQR 190-301) for open cases (p = 0.668). Median estimated blood loss was 200 mL (IQR 100-400) versus 300 mL (IQR 125-750), respectively (p = 0.212). In the robotic group, one patient (3%) had a major complication, versus three patients (10%) in the open group (p = 0.612). Readmissions were similar-10% in the robotic group versus 6% in the open group (p > 0.99). There was no mortality in either group.

Conclusion: Minor robotic liver resections of the posterosuperior segments are safe and feasible and display a shorter length of stay than open resections in selected patients at expert centers.
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http://dx.doi.org/10.1245/s10434-018-6928-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7883340PMC
February 2019

Intrahepatic Cholangiocarcinomas Have Histologically and Immunophenotypically Distinct Small and Large Duct Patterns.

Am J Surg Pathol 2018 10;42(10):1334-1345

Departments of Pathology.

Intrahepatic cholangiocarcinomas are histologically heterogenous. Using a cohort of 184 clinically defined, resected intrahepatic cholangiocarcinomas, we retrospectively classified the histology into 4 subtypes: large duct (LD), small duct (SD) (predominantly tubular [SD1] or predominantly anastomosing/cholangiolar, [SD2]), or indeterminate. Then, we tested the 4 subtypes for associations with risk factors, patient outcomes, histology, and immunophenotypic characteristics. SD was the most common (84%; 24% SD1 and 60% SD2) with lower proportions of LD (8%), and indeterminate (8%). Primary sclerosing cholangitis was rare (2%), but correlated with LD (P=0.005). Chronic hepatitis, frequent alcohol use, smoking, and steatosis had no histologic association. LD was associated with mucin production (P<0.001), perineural invasion (P=0.002), CA19-9 staining (P<0.001), CK7, CK19, CD56 immunophenotype (P=0.005), and negative albumin RNA in situ hybridization (P<0.001). SD was histologically nodular (P=0.019), sclerotic (P<0.001), hepatoid (P=0.042), and infiltrative at the interface with hepatocytes (P<0.001). Albumin was positive in 71% of SD and 18% of LD (P=0.0021). Most albumin positive tumors (85%) lacked extracellular mucin (P<0.001). S100P expression did not associate with subtype (P>0.05). There was no difference in disease-specific or recurrence-free survival among the subtypes. Periductal infiltration and American Joint Committee on Cancer eighth edition pT stage predicted survival by multivariable analysis accounting for gross configuration, pT stage, and histologic type. pT2 had worse outcome relative to other pT stages. Significant differences in histology and albumin expression distinguish LD from SD, but there is insufficient evidence to support further subclassification of SD.
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http://dx.doi.org/10.1097/PAS.0000000000001118DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6657522PMC
October 2018

Is Hepatectomy Justified for BRAF Mutant Colorectal Liver Metastases?: A Multi-institutional Analysis of 1497 Patients.

Ann Surg 2020 01;271(1):147-154

Department of Hepatobiliary Surgery, Memorial Sloan Kettering Cancer Center, New York, NY.

Objective: To analyze clinical outcomes and prognostic variables of patients undergoing hepatic resection for BRAF mutant (BRAF-mut) colorectal liver metastases (CRLM).

Background: Outcomes following hepatectomy for BRAF-mut CRLM have not been well studied.

Methods: All patients who underwent hepatectomy for CRLM with complete resection and known BRAF status during 2001 to 2016 at 3 high-volume centers were analyzed.

Results: Of 4124 patients who underwent hepatectomy for CRLM, 1497 had complete resection and known BRAF status. Thirty-five (2%) patients were BRAF-mut, with 71% of V600E mutation. Compared with BRAF wild-type (BRAF-wt), BRAF-mut patients were older, more commonly presented with higher ASA scores, synchronous, multiple and smaller CRLM, underwent more major hepatectomies, but had less extrahepatic disease. Median overall survival (OS) was 81 months for BRAF-wt and 40 months for BRAF-mut patients (P < 0.001). Median recurrence-free survival (RFS) was 22 and 10 months for BRAF-wt and BRAF-mut patients (P < 0.001). For BRAF-mut, factors associated with worse OS were node-positive primary tumor, carcinoembryonic antigen (CEA) >200 μg/L, and clinical risk score (CRS) ≥4. Factors associated with worse RFS were node-positive primary tumor, ≥4 CRLM, and positive hepatic margin. V600E mutations were not associated with worse OS or RFS. A case-control matching analysis on prognostic clinicopathologic factors confirmed shorter OS (P < 0.001) and RFS (P < 0.001) in BRAF-mut.

Conclusions: Patients with resectable BRAF-mut CRLM are rare among patients selected for surgery and more commonly present with multiple synchronous tumors. BRAF mutation is associated with worse prognosis; however, long-term survival is possible and associated with node-negative primary tumors, CEA ≤ 200 μg/L and CRS < 4.
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http://dx.doi.org/10.1097/SLA.0000000000002968DOI Listing
January 2020

Long-Term Oncologic Outcomes Following Robotic Liver Resections for Primary Hepatobiliary Malignancies: A Multicenter Study.

Ann Surg Oncol 2018 Sep 9;25(9):2652-2660. Epub 2018 Jul 9.

Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, University of Pittsburgh Medical Center, Pittsburgh, PA, USA.

Objective: Robotic liver surgery (RLS) has emerged as a feasible alternative to laparoscopic or open resections with comparable perioperative outcomes. Little is known about the oncologic adequacy of RLS. The purpose of this study was to investigate the long-term oncologic outcomes for patients undergoing RLS for primary hepatobiliary malignancies.

Methods: We performed an international, multicenter, retrospective study of patients who underwent RLS for hepatocellular carcinoma (HCC), cholangiocarcinoma (CC), or gallbladder cancer (GBC) between 2006 and 2016. Age, gender, histology, resection margin status, extent of surgical resection, disease-free survival (DFS), and overall survival (OS) were retrospectively collected and analyzed.

Results: Of the 61 included patients, 34 (56%) had RLS performed for HCC, 16 (26%) for CC, and 11 (18%) for GBC. The majority of resections were nonanatomical or segmental resections (39.3%), followed by central hepatectomy (18%), left-lateral sectionectomy (14.8%), left hepatectomy (13.1%), right hepatectomy (13.1%), and right posterior segmentectomy (1.6%). R0 resection was achieved in 94% of HCC, 68% of CC, and 81.8% of GBC patients. Median hospital stay was 5 days, and conversion to open surgery was needed in seven patients (11.5%). Grade III-IV Dindo-Clavien complications occurred in seven patients with no perioperative mortality. Median follow-up was 75 months (95% confidence interval 36-113), and 5-year OS and DFS were 56 and 38%, respectively. When stratified by tumor type, 3-year OS was 90% for HCC, 65% for GBC, and 49% for CC (p = 0.01).

Conclusions: RLS can be performed for primary hepatobiliary malignancies with long-term oncologic outcomes comparable to published open and laparoscopic data.
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http://dx.doi.org/10.1245/s10434-018-6629-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6133735PMC
September 2018

Unresectable Colorectal Liver Metastases: When Definitions Matter to Appropriately Assess Extreme Liver Resection Techniques.

Ann Surg 2018 12;268(6):e82-e83

Department of Digestive and Hepatobiliary Surgery, University Hospital of Clermont-Ferrand, Clermont-Ferrand, France U1071 INSERM/Clermont Auvergne University, Clermont-Ferrand, France Liverpool Hepatobiliary Center, Aintree University Hospital, Liverpool, UK Department of Surgery, Memorial Sloan Kettering Cancer Center, New York City, NY Department of Digestive and Hepatobiliary Surgery, University Hospital of Clermont-Ferrand, Clermont-Ferrand, France Department of Surgical Oncology, Léon Bérard Cancer Center, Lyon, France.

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http://dx.doi.org/10.1097/SLA.0000000000002677DOI Listing
December 2018

Laparoscopy as a useful selection tool for patients with prior surgery and peritoneal metastases suitable for multimodality treatment strategies.

Surg Endosc 2018 05 7;32(5):2288-2294. Epub 2017 Dec 7.

Department of Surgery, University of Regensburg Medical Center, Regensburg, Germany.

Background: Complete macroscopic cytoreduction in patients with peritoneal carcinomatosis (PC) is the basic requirement for long-term survival. Diagnostic laparoscopy (DL) can be difficult and of limited clinical value secondary to postoperative or tumor-induced adhesions. The aim of this study was to evaluate the role of DL in patients with prior surgery and PC.

Methods: The database of the surgical department of the University Medical Center of Regensburg was reviewed (9/2010-10/2014) selecting for DL in patients with PC. The operative report had a standardized format allowing for the determination of the extent of the intra-abdominal visible area and the extent of tumor on the surface of the small intestine. For the classification we used our own developed score.

Results: DL was performed in 102 patients. The complete abdominal cavity was evaluable in 48%. At least two quadrants and the largest part of the small intestine could be assessed in 70%. 37% of the patients had massive tumor manifestation on the small intestine or its mesentery. PCI (Peritoneal Cancer Index) could not be calculated in 71% of the patients due to incomplete visualization of the abdominal cavity and/or multiple tumor manifestations on the small intestine. 54% of patients were classified as non-resectable and 85% who seemed suitable for cytoreductive surgery underwent a CCR-0 resection and HIPEC.

Conclusions: In spite of prior surgery and PC, DL is frequently possible and a useful tool to define the extent of tumor spread. Lots of patients can be prevented from needless open laparotomy. The extent of tumor involvement of the small intestine seems to be more relevant than calculation of the PCI to determine the potential for complete resection. Therefore, in the presence of adhesions, inspection of the complete abdominal cavity does not offer added clinical benefit and further adhesiolysis can be avoided.
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http://dx.doi.org/10.1007/s00464-017-5923-0DOI Listing
May 2018

The group II metabotropic glutamate receptor agonist LY354740 and the D2 receptor antagonist haloperidol reduce locomotor hyperactivity but fail to rescue spatial working memory in GluA1 knockout mice.

Eur J Neurosci 2017 04 4;45(7):912-921. Epub 2017 Mar 4.

Department of Psychology, Durham University, Science Site, South Road, Durham, DH1 3LE, UK.

Group II metabotropic glutamate receptor agonists have been suggested as potential anti-psychotics, at least in part, based on the observation that the agonist LY354740 appeared to rescue the cognitive deficits caused by non-competitive N-methyl-d-aspartate receptor (NMDAR) antagonists, including spatial working memory deficits in rodents. Here, we tested the ability of LY354740 to rescue spatial working memory performance in mice that lack the GluA1 subunit of the AMPA glutamate receptor, encoded by Gria1, a gene recently implicated in schizophrenia by genome-wide association studies. We found that LY354740 failed to rescue the spatial working memory deficit in Gria1 mice during rewarded alternation performance in the T-maze. In contrast, LY354740 did reduce the locomotor hyperactivity in these animals to a level that was similar to controls. A similar pattern was found with the dopamine receptor antagonist haloperidol, with no amelioration of the spatial working memory deficit in Gria1 mice, even though the same dose of haloperidol reduced their locomotor hyperactivity. These results with LY354740 contrast with the rescue of spatial working memory in models of glutamatergic hypofunction using non-competitive NMDAR antagonists. Future studies should determine whether group II mGluR agonists can rescue spatial working memory deficits with other NMDAR manipulations, including genetic models and other pharmacological manipulations of NMDAR function.
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http://dx.doi.org/10.1111/ejn.13539DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5396315PMC
April 2017

Decreased striatal dopamine in group II metabotropic glutamate receptor (mGlu2/mGlu3) double knockout mice.

BMC Neurosci 2013 Sep 22;14:102. Epub 2013 Sep 22.

Department of Psychiatry, University of Oxford, Warneford Hospital, Oxford OX3 7JX, UK.

Background: Group II metabotropic glutamate receptors (mGlu2 and mGlu3, encoded by Grm2 and Grm3) have been the focus of attention as treatment targets for a number of psychiatric conditions. Double knockout mice lacking mGlu2 and mGlu3 (mGlu2/3-/-) show a subtle behavioural phenotype, being hypoactive under basal conditions and in response to amphetamine, and with a spatial memory deficit that depends on the arousal properties of the task. The neurochemical correlates of this profile are unknown. Here, we measured tissue levels of dopamine, 5-HT, noradrenaline and their metabolites in the striatum and frontal cortex of mGlu2/3-/- double knockout mice, using high performance liquid chromatography. We also measured the same parameters in mGlu2-/- and mGlu3-/- single knockout mice.

Results: mGlu2/3-/-mice had reduced dopamine levels in the striatum but not in frontal cortex, compared to wild-types. In a separate cohort we replicated this deficit and, using tissue punches, found it was more prominent in the nucleus accumbens than in dorsolateral striatum. Noradrenaline, 5-HT and their metabolites were not altered in the striatum of mGlu2/3-/- mice, although the noradrenaline metabolite MHPG was increased in the cortex. In mGlu2-/- and mGlu3-/- single knockout mice we found no difference in any monoamine or metabolite, in either brain region, compared to their wild-type littermates.

Conclusions: Group II metabotropic glutamate receptors impact upon striatal dopamine. The effect may contribute to the behavioural phenotype of mGlu2/3-/- mice. The lack of dopaminergic alterations in mGlu2-/- and mGlu3-/- single knockout mice reveals a degree of redundancy between the two receptors. The findings support the possibility that interactions between mGlu2/3 and dopamine may be relevant to the pathophysiology and therapy of schizophrenia and other disorders.
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http://dx.doi.org/10.1186/1471-2202-14-102DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3857325PMC
September 2013