Background
The National Comprehensive Cancer Network (NCCN) guidelines for colon cancer recently added the following footnote regarding the therapeutic strategy for peritoneal metastases: “If R0 ...resection can be achieved, surgical resection of isolated peritoneal disease may be considered at experienced centers.” This study investigated the efficacy of R0 resection of peritoneal metastasis from colorectal cancer without cytoreductive surgery or hyperthermic intraperitoneal chemotherapy (HIPEC).
Methods
This retrospective cohort study was conducted at a single-institution tertiary care cancer center. Among 496 consecutive M1c colorectal cancer patients, R0 resection was achieved for 94 patients (19%). The subjects were 78 consecutive patients with colorectal cancer and simultaneous peritoneal metastasis but no other distant metastases who underwent R0 resection at the National Cancer Center Hospital from 1971 to 2016 (16% of all M1c patients). Overall survival (OS) was investigated, and clinicopathologic variables were analyzed for prognostic significance.
Results
No perioperative mortality was noted. The 3-year OS rate was 45%, and the 5-year OS rate was 28.7%. The median survival time was 33.4 months. Notably, 17 patients survived for more than 5 years, and 9 of these patients did not receive any chemotherapy. Multivariate analysis showed cancer location in the colon and harvesting of 12 or more lymph nodes to be independent factors associated with a better prognosis.
Conclusions
From the perspective of long-term outcomes and no perioperative mortality, R0 resection of peritoneal metastasis from colorectal cancer, without complete peritonectomy or HIPEC, appeared to be an acceptable therapeutic option for some patients with peritoneal metastasis.
Background and Aims
Activation of the antitumor immune response using programmed death receptor‐1 (PD‐1) blockade showed benefit only in a fraction of patients with hepatocellular carcinoma (HCC). ...Combining PD‐1 blockade with antiangiogenesis has shown promise in substantially increasing the fraction of patients with HCC who respond to treatment, but the mechanism of this interaction is unknown.
Approach and Results
We recapitulated these clinical outcomes using orthotopic—grafted or induced—murine models of HCC. Specific blockade of vascular endothelial receptor 2 (VEGFR‐2) using a murine antibody significantly delayed primary tumor growth but failed to prolong survival, while anti‐PD‐1 antibody treatment alone conferred a minor survival advantage in one model. However, dual anti‐PD‐1/VEGFR‐2 therapy significantly inhibited primary tumor growth and doubled survival in both models. Combination therapy reprogrammed the immune microenvironment by increasing cluster of differentiation 8–positive (CD8+) cytotoxic T cell infiltration and activation, shifting the M1/M2 ratio of tumor‐associated macrophages and reducing T regulatory cell (Treg) and chemokine (C‐C motif) receptor 2–positive monocyte infiltration in HCC tissue. In these models, VEGFR‐2 was selectively expressed in tumor endothelial cells. Using spheroid cultures of HCC tissue, we found that PD‐ligand 1 expression in HCC cells was induced in a paracrine manner upon anti‐VEGFR‐2 blockade in endothelial cells in part through interferon‐gamma expression. Moreover, we found that VEGFR‐2 blockade increased PD‐1 expression in tumor‐infiltrating CD4+ cells. We also found that under anti‐PD‐1 therapy, CD4+ cells promote normalized vessel formation in the face of antiangiogenic therapy with anti‐VEGFR‐2 antibody.
Conclusions
We show that dual anti‐PD‐1/VEGFR‐2 therapy has a durable vessel fortification effect in HCC and can overcome treatment resistance to either treatment alone and increase overall survival in both anti‐PD‐1 therapy–resistant and anti‐PD‐1 therapy–responsive HCC models.
Sorafenib, a broad tyrosine kinase inhibitor, is the only approved systemic therapy for advanced hepatocellular carcinoma (HCC) but provides limited survival benefits. Recently, immunotherapy has ...emerged as a promising treatment strategy, but its role remains unclear in HCCs, which are associated with decreased cytotoxic CD8+ T‐lymphocyte infiltration in both murine and human tumors. Moreover, in mouse models after sorafenib treatment intratumoral hypoxia is increased and may fuel evasive resistance. Using orthotopic HCC models, we now show that increased hypoxia after sorafenib treatment promotes immunosuppression, characterized by increased intratumoral expression of the immune checkpoint inhibitor programmed death ligand‐1 and accumulation of T‐regulatory cells and M2‐type macrophages. We also show that the recruitment of immunosuppressive cells is mediated in part by hypoxia‐induced up‐regulation of stromal cell–derived 1 alpha. Inhibition of the stromal cell–derived 1 alpha receptor (C‐X‐C receptor type 4 or CXCR4) using AMD3100 prevented the polarization toward an immunosuppressive microenvironment after sorafenib treatment, inhibited tumor growth, reduced lung metastasis, and improved survival. However, the combination of AMD3100 and sorafenib did not significantly change cytotoxic CD8+ T‐lymphocyte infiltration into HCC tumors and did not modify their activation status. In separate experiments, antibody blockade of the programmed death ligand‐1 receptor programmed death receptor‐1 (PD‐1) showed antitumor effects in treatment‐naive tumors in orthotopic (grafted and genetically engineered) models of HCC. However, anti‐PD‐1 antibody treatment had additional antitumor activity only when combined with sorafenib and AMD3100 and not when combined with sorafenib alone. Conclusion: Anti‐PD‐1 treatment can boost antitumor immune responses in HCC models; when used in combination with sorafenib, anti‐PD‐1 immunotherapy shows efficacy only with concomitant targeting of the hypoxic and immunosuppressive microenvironment with agents such as CXCR4 inhibitors. (Hepatology 2015;61:1591–1602)
Thermally activated delayed fluorescence (TADF) benzyl cellulose derivatives (TBC-X ), which contained both carbazole (host) and phthalimide-based TADF dye (guest) moieties, were prepared from ...2,3-di-O-benzyl cellulose in high yields. The TBC-X samples were soluble in common organic solvents such as CH2Cl2, CHCl3, THF, and toluene. The photoluminescence spectra of TBC-X spin-coated films had a single emission peak derived only from guest moieties, which indicated efficient energy transfer from the host to guest moieties. The TBC-10 (with a content of host and guest moieties of 93 and 7, respectively) in a spin-coated film had the highest photoluminescence quantum yield of 55.3% and TADF characteristics. A nondoped organic light-emitting diode with TBC-10 as the emitting layer showed green emission (λEL = 517 nm) and achieved a maximum external quantum efficiency of 5.9%.
Protein–protein (e.g., antibody–antigen) interactions comprise multiple weak interactions. We have previously reported that lipid nanoparticles (LNPs) bind to and neutralize target toxic peptides ...after multifunctionalization of the LNP surface (MF-LNPs) with amino acid derivatives that induce weak interactions; however, the MF-LNPs aggregated after target capture and showed short blood circulation times. Here we optimized polyethylene glycol (PEG)-modified MF-LNPs (PEG-MF-LNPs) to inhibit the aggregation and increase the blood circulation time. Melittin was used as a target toxin, and MF-LNPs were prepared with negatively charged, hydrophobic, and neutral amino-acid-derivative-conjugated functional lipids. In this study, MF-LNPs modified with only PEG5k (PEG5k-MF-LNPs) and with both PEG5k and PEG2k (PEGmix-MF-LNPs) were prepared, where PEG5k and PEG2k represent PEG with a molecular weight of 5000 and 2000, respectively. PEGylation of the MF-LNPs did not decrease the melittin neutralization ability of nonPEGylated MF-LNPs, as tested by hemolysis assay. The PEGmix-MF-LNPs showed better blood circulation characteristics than the PEG5k-MF-LNPs. Although the nonPEGylated MF-LNPs immediately aggregated when mixed with melittin, the PEGmix-MF-LNPs did not aggregate. The PEGmix-MF-LNPs dramatically increased the survival rate of melittin-treated mice, whereas the nonPEGylated MF-LNPs increased slightly. These results provide a fundamental strategy to improve the in vivo toxin neutralization ability of MF-LNPs.
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•Multifunctionalization of LNP (MF-LNP) neutralizes target toxic peptides.•PEGylation improved MF-LNP blood circulation time without diminishing their toxin neutralization effect.•PEGylated MF-LNP did not aggregate after target capture.•PEGylated MF-LNPs dramatically increased the survival rate of toxin-treated mice.
Background Controversy remains around whether the addition of lateral lymph node dissection to total mesorectal excision offers benefits in terms of survival or local control to patients with low ...rectal cancer. This study aimed to examine the impact of lateral lymph node dissection in the treatment of low rectal cancer on prognosis and local control and to identify patients who might benefit from lateral lymph node dissection at 2 high-volume centers in Japan that employ different policies with regard to adopting lateral lymph node dissection. Methods We reviewed outcomes from a total of 1,191 consecutive patients with low rectal cancer (rectal cancer distal to the peritoneal reflection) who underwent total mesorectal excision plus lateral lymph node dissection at 2 high-volume centers (the National Cancer Center and Aichi Cancer Center) in Japan. To assess the therapeutic outcomes of the respective node dissections, we applied an index calculated by multiplying the incidence by the 5-year overall survival of patients with metastasis in the respective lateral node stations. Multivariate analyses were performed to determine independent risk factors for local recurrence and prognostic factors. Results Outcomes according to the presence or absence of lateral nodal metastases showed long-term survival with lateral dissection, even in patients with lateral nodal metastases (5-year overall survival: 53.1% at the National Cancer Center vs 45.2% at Aichi Cancer Center), while stage I to III patients with no lateral nodal metastases had very good prognoses at both centers (5-year overall survival: 81.7% at the National Cancer Center vs 81.0% at Aichi Cancer Center). According to the index of estimated benefit from lateral lymph node dissection, dissection of the distal internal iliac nodes and obturator nodes yielded the greatest therapeutic benefit in patients at both centers. Compared to patients with bilateral lateral lymph node dissection, the relative risk for local recurrence was 2.0 for those with unilateral lateral lymph node dissection. Conclusion Lateral lymph node dissection outcomes observed at the 2 high-volume centers in Japan demonstrate high reproducibility with good results in terms of prognosis. Differences in policies concerning the adoption of lateral lymph node dissection affected local recurrence rate.
The clinical benefit of extended lymphadenectomy for synchronous extraregional lymph node metastasis, such as para-aortic lymph node (PALN) metastasis in colorectal cancer, remains highly ...controversial.
To evaluate the clinical benefit of PALN dissection in colorectal cancer patients with synchronous PALN metastasis with or without multiorgan metastases.
Thirty-six patients with pathologically positive PALN metastasis below the renal veins who underwent concurrent PALN dissection and primary colorectal cancer resection from January 1984 through September 2011 at the National Cancer Center Hospital in Tokyo, Japan, were included in this retrospective cohort study. We examined 5-year recurrence-free survival (RFS) rates in patient groups depending on the number of nodes involved (≤2 and ≥3 nodes) and on the presence or absence of other organ involvement (M1a and M1b,c categories in TNM staging).
The 5-year RFS rate was significantly different depending on the number of metastatic PALNs (42.1 and 0.6% for PALN ≤2 and ≥3, respectively, p = 0.01). The 5-year RFS rate was significantly better in patients in the M1a category than in patients in the M1b and M1c categories (27.6 and 0.0%, respectively, p < 0.01). Twenty-nine patients (80.6%) experienced recurrence after PALN dissection. Postoperative complications were seen in 14 (38.9%) patients.
PALN dissection below the renal veins for patients with isolated PALN metastasis with 2 or fewer involved PALNs may be effective in improving prognosis in colorectal cancer.
Recurrent laryngeal nerve paralysis (RLNP) after esophagectomy is a common complication and associated with aspiration pneumonia. In this study, we assessed the risk of RLNP and the usefulness of ...immediate reconstruction of recurrent laryngeal nerve (RLN) to prevent respiratory complications after esophagectomy. Seven hundred and eighty-two consecutive patients underwent an esophagectomy with three-field lymph node dissection, simultaneous gastric conduit reconstruction, and cervical anastomosis. Vocal cord function was observed using a flexible laryngoscope. Reconstruction between RLN and ipsilateral vagus nerve was performed during esophagectomy. RLNP was observed in 229 (29.3%) of the patients after esophagectomy: 198 unilateral and 31 bilateral cases. Of the 198 unilateral RLNP, vocal cord paralysis was observed predominantly on the left side (82.7%). RLNP was significantly associated with postoperative respiratory complications (P < 0.001) requiring a tracheotomy (P < 0.001) and mechanical ventilation (P < 0.001) and was also associated with esophagogastric anastomotic leakage (P = 0.015); consequently, the postoperative hospital stay was longer for patients with RLNP (P < 0.001). A longer operation time (P < 0.001) and advanced age (P = 0.038) were identified as significant independent predictors of RLNP. Resection of the RLN together with metastatic nodes was performed in 29 cases. The patients underwent RLN reconstruction (n = 11) had a significantly shorter postoperative hospital stay than those without RLN reconstruction (n = 18) (P = 0.019). In conclusion, RLNP was related to a poorer postoperative course among patients undergoing an esophagectomy. New surgical technologies are recommended for prevention of RLNP.
Background
The benefits that palliative resection of the primary tumor offers patients with unresectable stage 4 colorectal cancer, specifically with regard to overall survival, are controversial, ...and the issue is complicated by marked differences in patient backgrounds and characteristics.
Methods
The study enrolled 770 consecutive patients with unresectable stage 4 colorectal cancer referred to the divisions of surgery or gastrointestinal oncology at the National Cancer Center Hospital from 1997 to 2013. Of these patients, 429 (56 %) underwent palliative resection of the primary tumor, whereas 341 (44 %) did not. To lessen the effects of confounding factors between the groups, including age, year, severe symptoms, number of organs involved by metastases, primary tumor site, and carcinoembryonic antigen (CEA) value, propensity score analyses were used for regression adjustment, stratification, and matching, with overall survival as the primary end point.
Results
The regression adjustment including the propensity score as a linear predictor in the model showed that palliative resection was associated with a significantly improved overall survival (hazard ratio HR 0.60; 95 % confidence interval CI 0.50–0.71;
p
< 0.01). Stratification analysis showed that in all five strata, palliative resection was associated with better overall survival (HR 0.43–0.73). Similarly, the propensity score-matched cohort (267 matched pairs) yielded an HR of 0.58 (95 % CI 0.48–0.70;
p
< 0.01).
Conclusions
The findings suggest that palliative resection of the primary tumor may be associated with improved overall survival. Further investigations such as prospective randomized trials are needed to confirm this result.
Abstract
Ceramide, the central molecule in sphingolipid synthesis, is a bioactive lipid that serves as a regulatory molecule in the anti-inflammatory responses, apoptosis, programmed necrosis, ...autophagy, and cell motility of cancer cells. In particular, the authors have reported differences in sphingolipid content in colorectal cancer tissues. The associations among genetic mutations, clinicopathological factors, and sphingolipid metabolism in colorectal cancer (CRC) have not been investigated. The objective of this study is to investigate the association between genes associated with sphingolipid metabolism, genetic variations in colorectal cancer (CRC), and clinicopathological factors in CRC patients. We enrolled 82 consecutive patients with stage I–IV CRC who underwent tumor resection at a single institution in 2019–2021. We measured the expression levels of genes related to sphingolipid metabolism and examined the relationships between CRC gene mutations and the clinicopathological data of each individual patient. The relationship between CRC gene mutations and expression levels of ceramide synthase (
CERS
),
N
-acylsphingosine amidohydrolase (
ASAH)
, and alkaline ceramidase (
ACER
) genes involved in sphingolipid metabolism was examined CRES4 expression was significantly lower in the CRC
KRAS
gene mutation group (p = 0.004); vascular invasion was more common in colorectal cancer patients with high CERS4 expression (p = 0.0057). By examining the correlation between sphingolipid gene expression and clinical factors, we were able to identify cancer types in which sphingolipid metabolism is particularly relevant.
CERS4
expression was significantly reduced in
KRAS
mutant CRC. Moreover, CRC with decreased
CERS4
showed significantly more frequent venous invasion.
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