Homogeneity in immune features between colorectal liver metastases better identifies patients with good prognosis compared to pathological response to preoperative chemotherapy.

In colorectal cancer liver metastases (CRLM), the density of tumor-infiltrating lymphocytes, the expression of class I major histocompatibility complex (MHC-I), and the pathological response to preoperative chemotherapy have been associated with oncological outcomes after complete resection. However, the prognostic significance of the heterogeneity of these features in patients with multiple CRLMs remains under investigation. We used a tissue microarray of 220 mismatch repair-gene proficient CRLMs resected in 97 patients followed prospectively to quantify CD3+ T cells and MHC-I by immunohistochemistry. Histopathological response to preoperative chemotherapy was assessed using standard scoring systems. We tested associations between clinical, immunological, and pathological features with oncologic outcomes. Overall, 29 patients (30.2%) had CRLMs homogeneous for CD3+ T cell infiltration and MHC-I. Patients with immune homogeneous compared to heterogeneous CRLMs had longer median time to recurrence (TTR) (30 vs. 12 months, p = .0018) and disease-specific survival (DSS) (not reached vs. 48 months, p = .0009). At 6 years, 80% of the patients with immune homogeneous CRLMs were still alive. Homogeneity of response to preoperative chemotherapy was seen in 60 (61.9%) and 69 (80.2%) patients according to different grading systems and was not associated with TTR or DSS. CD3 and MHC-I heterogeneity was independent of response to pre-operative chemotherapy and of other clinicopathological variables for their association with oncological outcomes. In patients with multiple CRLMs resected with curative intent, similar adaptive immune features seen across metastases could be more informative than pathological response to pre-operative chemotherapy in predicting oncological outcomes.

Prognostic implications of adaptive immune features in MMR-proficient colorectal liver metastases classified by histopathological growth patterns.

BACKGROUND: After resection, colorectal cancer liver metastases (CRLM) surrounded by a desmoplastic rim carry a better prognosis than the metastases replacing the adjacent liver. However, these histopathological growth patterns (HGPs) are insufficient to guide clinical decision-making. We explored whether the adaptive immune features of HGPs could refine prognostication. METHODS: From 276 metastases resected in 176 patients classified by HGPs, tissue microarrays were used to assess intratumoral T cells (CD3), antigen presentation capacity (MHC class I) and CD73 expression producing immunosuppressive adenosine. We tested correlations between these variables and patient outcomes. RESULTS: The 101 (57.4%) patients with dominant desmoplastic HGP had a median recurrence-free survival (RFS) of 17.1 months compared to 13.3 months in the 75 patients (42.6%) with dominant replacement HGP (p = 0.037). In desmoplastic CRLM, high vs. low CD73 was the only prognostically informative immune parameter and was associated with a median RFS of 12.3 months compared to 26.3, respectively (p = 0.010). Only in dominant replacement CRLM, we found a subgroup (n = 23) with high intratumoral MHC-I expression but poor CD3+ T cell infiltration, a phenotype associated with a short median RFS of 7.9 months. CONCLUSIONS: Combining the assessments of HGP and adaptive immune features in resected CRLM could help identify patients at risk of early recurrence.

Outcomes of Older Patients with Resectable Colorectal Liver Metastases Cancer (CRLM): Single Center Experience.

Surgery is the only potential curative option of CRLM if resectable. The curative approach in patients over 70 years old is challenging mainly because of comorbidities and other geriatric syndromes. Herein, we report outcomes of older patients with resectable CRLM in our center. We retrospectively analyzed characteristics and outcomes of older patients with CRLM operated at "Centre Hospitalier de l'Université de Montréal" (CHUM) between 2010 and 2019. We identified 210 patients aged ≥70 years with a median age of 76 (range: 70-85). CRLM were synchronous in 56% of patients. Median disease-free survival (DFS) was 41.3 months. Median overall survival (OS) was 62.2 months and estimated 5-year survival rate was 51.5% similar to those of younger counterparts. Patients with metachronous CRLM had a trend to a higher OS compared to those with synchronous disease (67.2 vs. 58.7 months; p = 0.42). Factors associated with lower survival in the multivariate analysis were right-sided tumors and increased Charlson Comorbidity index (CCI). Survival outcomes of patients aged ≥70 years were comparable to those of younger patients and those reported in the literature. Age should not be a limiting factor in the curative management of older patients with resectable CRLM.

Effect of intraoperative hypovolemic phlebotomy on transfusion and clinical outcomes in patients undergoing hepatectomy: a retrospective cohort study.

BACKGROUND: There is no consensus on how to best achieve a low central venous pressure during hepatectomy for the purpose of reducing blood loss and red blood cell (RBC) transfusions. We analyzed the associations between intraoperative hypovolemic phlebotomy (IOHP), transfusions, and postoperative outcomes in cancer patients undergoing hepatectomy. METHODS: Using surgical and transfusion databases of patients who underwent hepatectomy for cancer at one institution (11 January 2011 to 22 June 2017), we retrospectively analyzed associations between IOHP and RBC transfusion on the day of surgery (primary outcome), and with total perioperative transfusions, intraoperative blood loss, and postoperative complications (secondary outcomes). We fitted logistic regression models by inverse probability of treatment weighting to adjust for confounders and reported adjusted odds ratio (aOR). RESULTS: There were 522 instances of IOHP performed during 683 hepatectomies, with a mean (standard deviation) volume of 396 (119) mL. The IOHP patients had a 6.9% transfusion risk on the day of surgery compared with 12.4% in non-IOHP patients (aOR, 0.53; 95% confidence interval [CI], 0.29 to 0.98; P = 0.04). Total perioperative RBC transfusion tended to be lower in IOHP patients compared with non-IOHP patients (14.9% vs 22.4%, respectively; aOR, 0.72; 95% CI, 0.44 to 1.16; P = 0.18). In patients with a predicted risk of ≥ 47.5% perioperative RBC transfusion, 24.6% were transfused when IOHP was used compared with 56.5% without IOHP. The incidence of severe postoperative complications (Clavien-Dindo scores ≥ 3) was similar in patients whether or not IOHP was performed (15% vs 16% respectively; aOR, 0.97; 95% CI, 0.53 to 1.54; P = 0.71). CONCLUSIONS: The use of IOHP during hepatectomy was associated with less RBCs transfused on the same day of surgery. Trials comparing IOHP with other techniques to reduce blood loss and transfusion are needed in liver surgery.

RéSUMé: CONTEXTE: Il n'existe pas de consensus quant à la meilleure façon d'obtenir une pression veineuse centrale basse pendant une hépatectomie dans le but de réduire les pertes et les transfusions sanguines. Nous avons analysé les associations entre la phlébotomie hypovolémique peropératoire, les transfusions, et les résultats cliniques postopératoires chez les patients qui subissent une hépatectomie pour cancer. MéTHODE: À l'aide de bases de données chirurgicales et transfusionnelles de patients ayant subi une hépatectomie pour cancer dans un seul établissement (du 11 janvier 2011 au 22 juin 2017), nous avons rétrospectivement analysé les associations entre la phlébotomie hypovolémique peropératoire et les transfusions érythrocytaires le jour de la chirurgie (critère d'évaluation principal) et avec les transfusions périopératoires totales, les pertes sanguines peropératoires, et les complications postopératoires (critères d'évaluation secondaires). Nous avons utilisé des modèles de régression logistique avec pondération de probabilité inverse de traitement afin de tenir compte des facteurs de confusion et rapporté les rapports de cotes ajustés (RCa). RéSULTATS: Il y a eu 522 phlébotomies hypovolémiques peropératoires exécutées au cours de 683 hépatectomies, avec un volume moyen (écart type) de 396 (119) mL. Les patients ayant eu une phlébotomie hypovolémique peropératoire avaient un risque transfusionnel de 6,9 % le jour de la chirurgie, comparativement à 12,4 % pour les patients sans phlébotomie (RCa, 0,53; intervalle de confiance [IC] de 95 %, 0,29 à 0,98; P = 0,04). Les transfusions périopératoires totales d'érythrocytes tendaient à être moins fréquentes chez les patients ayant subi une phlébotomie hypovolémique peropératoire par rapport aux patients sans phlébotomie (14,9 % vs 22,4 %, respectivement; RCa, 0,72; IC 95 %, 0,44 à 1,16; P = 0,18). Pour les patients présentant un risque prédit de transfusion périopératoire d'érythrocytes ≥ à 47,5 %, 24,6 % de ceux qui ont eu une phlébotomie hypovolémique peropératoire ont été transfusés, comparativement à 56,5 % sans phlébotomie. L'incidence des complications postopératoires graves (scores de Clavien-Dindo ≥ 3) était semblable chez tous les patients, avec ou sans phlébotomie hypovolémique peropératoire (15 % vs 16 % respectivement; RCa, 0,97; IC 95 %, 0,53 à 1,54; P = 0,71). CONCLUSIONS: L'utilisation de la phlébotomie hypovolémique peropératoire pendant une hépatectomie était associée à un moins grand nombre de transfusions érythrocytaires le jour de la chirurgie. Des études qui compareront la phlébotomie hypovolémique peropératoire à d'autres techniques visant à réduire les pertes et les transfusions sanguines sont nécessaires en chirurgie hépatique.

Prognostic value of CD73 expression in resected colorectal cancer liver metastasis.

Immune checkpoint blockade has not yet been effective in patients with mismatch repair proficient metastatic colorectal cancer. Targeting immunosuppressive metabolic pathways is being explored as a new immunotherapeutic approach. We assessed whether CD73, the rate limiting enzyme that catalyzes the degradation of extracellular AMP into immunosuppressive adenosine, could be an immunological determinant of colorectal liver metastases (CRLMs). By immunofluorescence on tissue microarrays, intratumoral CD73 expression (tCD73) was analyzed in 391 CRLMs resected in 215 patients, and soluble CD73 (sCD73) was measured by ELISA in the pre-operative serum of 193 patients. High tCD73 was associated with worse pathological features, such as multiple and larger CRLMs, and poorer pathologic response to pre-operative chemotherapy. The median time to recurrence and disease-specific survival after CRLM resection was significantly shorter in patients with high tCD73 (11.0 and 46.4 months, respectively) compared with low tCD73 (19.0 and 61.5 months, respectively). tCD73 was strongly associated with patient outcomes independently of clinicopathological variables. sCD73 did not correlate with tCD73. Patients with high levels of sCD73 also had shorter disease-specific survival. Our results suggested that CD73 in CRLMs may be prognostically informative and may help select patients more likely to respond to adenosine pathway blocking agents.

Portal vein embolization does not affect the long-term survival and risk of cancer recurrence among colorectal liver metastases patients: A prospective cohort study.

BACKGROUND: Previous studies comparing the survival outcomes of liver resections with and without preoperative portal vein embolization (PVE) for colorectal liver metastases (CLM) have linked PVE to higher rate of tumor progression, lower overall survival (OS) and lower disease-free survival (DFS). The lack of adjusted models to compare these outcomes is a limitation of these studies since patients requiring PVE may differ significantly from the ones receiving upfront surgery. MATERIALS AND METHODS: Prospective cohort study of 128 patients undergoing CLM resection. The OS analysis followed an intent-to-treat (ITT) approach. The adjusted impact of PVE on OS and DFS was evaluated using multivariate Cox regression models. RESULTS: Seventy-one patients underwent PVE before attempting a liver resection while 57 received upfront surgery (NoPVE). All NoPVE patients were resected while 14 PVE participants (19.7%) were not operated (tumor progression = 9/14). PVE patients had a significantly higher preoperative lesions count (3 [1.75-4] vs 1 [1-2.5]; p < 0.001), a higher prevalence of bilateral metastases (23.5% vs 8.8, p = 0.028) and a higher count of neo-adjuvant chemotherapy cycles compared to NoPVE patients. The OS of PVE patients was similar to NoPVE participants (44.7 months [26.9-69.5] vs 49.0 [24.9-64.8], p = 0.761). The DFS of resected PVE patients was higher than NoPVE patients (33.2 months [10.7-54.6] vs 23.4 months [14.1-58.1], p = 0.991). In the adjusted models, preoperative lesions count was the only significant predictor of overall mortality (HR+IC95 = 1.06 (1.02-1.11) p = 0.005) and cancer recurrence (HR+IC95 = 1.14 (1.03-1.27) p = 0.012). CONCLUSION: In the context of CLM, patients requiring PVE differ significantly from patients receiving upfront surgery. This confirms the need for adjusted models when comparing the clinical outcomes of both groups. Our adjusted analysis suggests that PVE is not a significant predictor of a lower OS or DFS. PVE allowed the resection of 80% of participants with initially unresectable CLM. INSTITUTIONAL PROTOCOL NUMBER: 12.106 STUDY REGISTRATION NUMBER: NCT03168230.

Sclerosing encapsulating peritonitis presenting as acute-on-chronic small-bowel obstruction in a patient with history of peritoneal carcinomatosis.

Sclerosing encapsulating peritonitis (SEP) is a whitish fibrous envelope that encapsulates intra-abdominal peritonealized organs. Although it pathophysiology is not well understood, several possible causes have been reported in the literature, including peritoneal dialysis, past abdominal surgeries, peritonitis, beta-blockers and peritoneal carcinomatosis (PC). Some idiopathic cases, with no apparent causes, were described. We present a SEP case in a 43-year-old woman with a surgical history of pancreatic and liver resection for metastatic pseudopapillary pancreatic tumor, followed by several peritonectomies for PC. She was admitted for acute-on-chronic small-bowel obstruction that did not resolve with conservative management. Surgical exploration revealed a fibrous sheath covering the small-bowel. Extensive dissection, along with small-bowel segmental resection and anastomosis, was performed. The specimen was cancer-free. The mechanism through which SEP develops in certain surgical patients is still unknown. This report presents a case of successful surgical management and a review of the literature.

Is intra-operative ultrasound still useful for the detection of a hepatic tumour in the era of modern pre-operative imaging?

BACKGROUND: The current role of intra-operative ultrasound (IOUS) is questioned because of recent progress in medical imaging. The aim of the present study was to determine the accuracy of IOUS in the detection of a hepatic tumour (HT) compared with a pre-operative multi-detector computed tomography (MDCT) scan and magnetic resonance imaging (MRI). METHODS: This retrospective study included 418 patients evaluated using an 8-slice MDCT scan (SCAN8), 64-slice MDCT scan (SCAN64) and MRI alone or combined with a computed tomography (CT) scan. The pathological result was used as a gold standard. RESULTS: Correlation rates for the number of detected lesions compared with pathology results were 0.627 for SCAN8, 0.785 for SCAN64, 0.657 for MRI and 0.913 for IOUS. Compared with pathology, the rate of concordance was significantly higher with IOUS (0.871) than with SCAN8 (0.736; P=0.011), SCAN64 (0.792; P<0.001) and MRI (0.742; P<0.001). IOUS was responsible for a change in operative strategy in 16.5% of patients. Surgery was extended in 12.4%, limited in 1.7% and abandoned in 2.4%. CONCLUSIONS: Compared with cross-sectional pre-operative imaging, IOUS is still superior for the detection of HT and the planning of surgery. IOUS remains recommended as a routine procedure in patients having a hepatic resection in the era of modern pre-operative imaging.

Hypertrophy of the non-embolized liver after chemotherapy.

BACKGROUND: Neoadjuvant chemotherapy (NC(+)) and portal vein embolization (PVE) enables curative resection in more patients with colorectal-liver metastases (CRLM). However, after NC(+), structural alterations have been reported with the risk of post-operative hepatic failure. We undertook to determine if NC(+) toxicity limits future remnant liver (FRL) hypertrophy after PVE. METHODS: PVE was performed in 20 patients, 13 (65%) of whom previously received a mean FOLFIRI (5-fluorouracil + leucovorin + irinotecan) regimen (NC(+)) of 6.6 cycles. The seven remaining patients served as the control group without NC (NC(-)). RESULTS: CRLM were bilateral in 69% (NC(+)) and 57% (NC(-)), and synchronous in 84% (NC(+)) and 14% (NC(-)). The FRL hypertrophy rate was 54.1% (NC(+)) and 43.7% (NC(-)) (P= 0.3). CRLM were unresectable in four of our 20 patients, i.e. group NC(+): one insufficient FRL hypertrophy and one severe steatosis; and group NC(-): two tumoral progressions. In both groups, the operative parameters were comparable except for pedicular clamping: 8 (NC(+)) and 36 min (NC(-)), respectively (P < 0.05). Also, the surgical outcome rate and hospital stay were comparable. No significant pathological difference was observed between the two groups. No mortality occurred in either group. CONCLUSION: In view of our limited experience, we conclude that hypertrophy of the non-embolized liver (FRL) is not altered after FOLFIRI-based NC.

Impact of localized congestion related to venous deprivation after hepatectomy.

OBJECTIVE: We sought to assess the impact of localized venous congestion related to venous deprivation on liver function recovery and regeneration after hepatectomy, using the living donation model. Harvesting the middle hepatic vein (MHV) optimizes the venous drainage of right grafts but could lead to donor segment IV congestion. METHODS: In a series of 44 donors, 25 underwent right liver harvesting without the MHV and 19 with the MHV. The venous drainage anatomy of segment IV was defined as type I if exclusive through the MHV and type II if shared through the left hepatic vein. We prospectively studied the occurrence, magnitude (global or partial), and regeneration impacts of segment IV congestion on computed tomography (CT) performed 1 week and 1 month after surgery. RESULTS: Early postoperative CT showed that segment IV congestion was never observed in the group without MHV harvesting, and it was present in 16 (84%) of 19 donors with MHV harvesting. Segment IV congestion was global in 9 donors, including 7 with type I anatomy. Postoperative data comparing data of the 9 donors with global congestion (GC) with other donors showed that the prothrombin time was significantly (P < .05) lower on day 1 and 5 (53% vs 63% and 76% vs 86%, respectively), and segment IV regeneration rate was lower (3.6% vs 11%) in the former group. However, a higher regeneration rate of segments II and III in the GC group (11.8% vs 3.6%) resulted in a similar regeneration rate of the remnant liver 1 month after hepatectomy (59.4 +/- 12% vs 57.8 +/- 12.4%). CONCLUSIONS: Postoperative localized venous congestion is highly related to venous anatomy and affects both early postoperative liver function and regeneration rate. Based on this living donor model, we suggest that venous anatomy evaluation of the future remnant liver parenchyma be performed systematically before extended resection of living small or diseased remnants.

Liver histology and surgical outcomes after preoperative chemotherapy with fluorouracil plus oxaliplatin in colorectal cancer liver metastases.

PURPOSE: Preoperative chemotherapy for colorectal liver metastases (CLM) can produce histologic changes in the nontumor-bearing liver (NTBL) that may impact on surgical outcomes. PATIENTS AND METHODS: From a cohort of 303 patients treated for CLM with liver resection, 92 patients (75 received preoperative chemotherapy: group C+; and 17 were chemotherapy naïve: group C-) were randomly selected for detailed pathologic analysis. Preoperative chemotherapy consisted of fluorouracil (FU)/leucovorin alone (23 patients, the majority chronomodulated) or in combination with oxaliplatin (52 patients, all chronomodulated). To determine associations between study factors, clinical and operative variables were compared with pathology data and surgical outcomes. RESULTS: Although clinical and operative factors were similarly distributed, C+ patients, compared with C- patients, were more likely to receive intraoperative RBC transfusions (mean units: 1.9 v 0.5, respectively; P = .03) and to have vascular abnormalities in the NTBL (52% v 18%, respectively; P = .01). Presence of the most severe forms of vascular alterations was closely associated with RBC transfusion requirements (P = .04). In contrast, moderate to severe steatosis was similarly distributed (C- group, 12%; C+ group, 13%). Although perioperative mortality and morbidity rates were similar in all groups, more than 12 courses of chemotherapy, compared with < or = 12 courses, predisposed patients to reoperation (11% v 0%, respectively; P = .04) and to longer hospitalization (15 v 11 days, respectively; P = .02). CONCLUSION: The main hepatic lesion induced by preoperative FU/oxaliplatin chemotherapy in patients with CLM is vascular and not steatosis. Detailed pathologic analysis determined that the most severe vascular lesions are associated with increased intraoperative transfusions. The risk for other postoperative complications is related to the duration of preoperative chemotherapy administration.

Effect of N-acetylcysteine on blood and tissue lipid peroxidation in lipopolysaccharide-induced obstructive jaundice.

In obstructive jaundice, free radical production is increased and antioxidative activity is reduced. N-Acetylcysteine (NAC) has a beneficial effect with anti-inflammatory and antioxidant activity, acting as a free radical scavenger. NAC inhibits inducible nitric oxide synthase, suppresses cytokine expression/release, and inhibits adhesion molecule expression and nuclear factor kappa B. The aim of this study was to investigate the effects of NAC on liver/renal tissue and serum lipid peroxidation in lipopolysaccharide (LPS)-induced obstructive jaundice. We randomized 60 rats into 6 groups: group 1, Sham; group 2, obstructive jaundice (OJ) induced after bile-duct ligation; group 3, OJ + NAC (100 mg kg- 1 subcutaneously); group 4, OJ + LPS (10 mg kg-1); group 5, OJ + NAC + LPS; and group 6, OJ + LPS + NAC. For each group, the biochemical markers of lipid peroxidation and the antioxidant products were measured in serum and liver/renal tissue after sacrifice. Almost all lipid peroxidation products levels were increased and antioxidant products levels were decreased in groups who received LPS (groups 4, 5, and 6), but the effect was less remarkable when NAC was administered before LPS (group 5). The same trend was seen for groups with OJ +/- LPS who did not received NAC or received it after induced toxemia (groups 2, 4, and 6) as compared to groups 1 and 3. Moreover, in the case of OJ + LPS, rats treated with NAC before LPS (group 5) had lower lipid peroxidation products levels and higher antioxidant products levels as compared to those who did not received NAC (group 4). This phenomenon was not reproducible with NAC administered after LPS (group 6). Thus, results of this study showed that NAC prevents the deleterious effects of LPS in obstructive jaundice by reducing lipid peroxidation in serum and liver/renal tissue if administered before LPS. Nonetheless, NAC failed to prevent the lipid peroxidation in the case of established endotoxemia in obstructive jaundice.

Direct bile duct visualization during the preparation of split livers.

The split-liver technique is an important means to alleviating donor shortage. Its development is, at least in part, hindered by the risk of biliary complications, particularly when splitting is performed ex situ. We present a simple technique aimed at improving the identification of the biliary anatomy at the hilar level and the safety of the procedure.

Harvesting the middle hepatic vein with a right hepatectomy does not increase the risk for the donor.

The harvesting of the middle hepatic vein (MHV) with a right hepatectomy for living-donor liver transplantation allows an optimal venous drainage for the recipient but can also have adverse effects for the donor. This study compares morbidity, early liver function, and volume regeneration in 2 groups of donors who underwent right hepatectomy with (MHV+, n = 21) or without (MHV-, n = 20) MHV harvesting during 2 successive periods. The operative time was 401 +/- 60 minutes in the MHV+ group compared with 392 +/- 63 minutes in the MHV- group, and the transection time was 152 +/- 53 minutes in the MHV+ group compared with 131 +/- 30 minutes in the MHV- group (not significant). Blood loss in the MHV+ group was 773 +/- 343 mL compared with 613 +/- 361 mL in the MHV- group (not significant). The graft weight and remnant liver volume ratio were similar in the MHV+ and MHV- groups (763 +/- 200 gm vs. 832 +/- 156 gm and 42% +/- 9.5% vs. 43% +/- 8.3%, respectively). Postoperative biologic liver function tests showed that prothrombin time (PT) ratio on postoperative days 1 and 3 were significantly lower in the MHV+ group compared with the MHV- group (53% vs. 65% and 63% vs. 72%, respectively, P <.05). There were no differences in postoperative alanine aminotransferase and aspartate aminotransferase peak levels between the MHV+ and MHV- groups (319 +/- 198 IU /L vs. 310 +/- 110 IU /L and 317 +/- 226 IU /L vs. 296 +/- 125 IU /L, respectively). Bilirubin maximal blood level was similar in the 2 groups (32 +/- 17 micromol/L in the MHV+ group vs. 43 +/- 16 micromol/L in the MHV- group, P <.05). No donor died. The overall morbidity was lower in the MHV+ group compared with the MHV- group (36% vs. 55%; P >.05, not significant). The donor's remnant liver volume regeneration, evaluated by computed tomography (CT) volumetric study on day 7, was similar in the 2 groups (97% +/- 29% in the MHV+ group and 103% +/- 39% in the MHV- group, P >.05). The results of this comparative study show that right hepatectomy with the MHV neither affects morbidity nor impairs early liver function and regeneration in donors.