Prediction model of the risk for lateral local recurrence in locally advanced rectal cancer without enlarged lateral lymph nodes: Lessons from a Japanese multicenter pooled analysis of 812 patients.

Aim: Although the oncological impact of lateral lymph node dissection on enlarged lateral lymph nodes has been gradually accepted over the last decade, that on lateral lymph nodes without swelling remains doubtful. This study aimed to develop a prediction model for the future risk of lateral local recurrence and to clarify the value of adding lateral lymph node dissection in locally advanced rectal cancer without enlarged lateral lymph nodes. Methods: This retrospective, multi-institutional study recruited 812 patients with cStage II/III low rectal cancer without enlarged lateral lymph nodes <7 mm. Total lateral local recurrence was a hypothetical value of future risk of lateral local recurrence when lateral lymph node dissection was never performed. Results: Overall, total lateral local recurrences were observed in 67 patients (8.3%). In the multivariate analyses, the strongest risk factor for total local recurrences was no preoperative chemoradiotherapy (odds ratio [OR][95%Cl]: 33.2 [4.56-241.7], P < 0.001), followed by tumor distance ≤40 mm (OR [95%Cl]: 2.71 [1.51-4.86], P < 0.001) and lateral lymph node 5-7 mm (OR[95%Cl]: 2.38 [1.26-4.48], P = 0.007). In patients with lateral lymph nodes of 5-7 mm, the total lateral recurrence rate was 4.8% after preoperative chemoradiotherapy. Lateral lymph node dissection could reduce from a total lateral local recurrence of 21.6% to an actual lateral local recurrence of 8.0% in patients without preoperative treatment. Conclusion: We introduce a novel prediction model of future risk of lateral local recurrences, which has the potential to enable us to indicate lateral lymph node dissection selectively according to the patients' risks.

Trefoil factor 1 suppresses stemness and enhances chemosensitivity of pancreatic cancer.

BACKGROUND AND AIMS: Pancreatic cancer is one of the most lethal malignancies, partly due to resistance to conventional chemotherapy. The chemoresistance of malignant tumors is associated with epithelial-mesenchymal transition (EMT) and the stemness of cancer cells. The aim of this study is to investigate the availability and functional mechanisms of trefoil factor family 1 (TFF1), a tumor-suppressive protein in pancreatic carcinogenesis, to treat pancreatic cancer. METHODS: To investigate the role of endogenous TFF1 in human and mice, specimens of human pancreatic cancer and genetically engineered mouse model of pancreatic cancer (KPC/TFF1KO; Pdx1-Cre/LSL-KRASG12D/LSL-p53R172H/TFF1-/-) were analyzed by immunohistochemistry (IHC). To explore the efficacy of extracellular administration of TFF1, recombinant and chemically synthesized TFF1 were administered to pancreatic cancer cell lines, a xenograft mouse model and a transgenic mouse model. RESULTS: The deficiency of TFF1 was associated with increased EMT of cancer cells in mouse models of pancreatic cancer, KPC. The expression of TFF1 in cancer cells was associated with better survival rate of the patients who underwent chemotherapy, and loss of TFF1 deteriorated the benefit of gemcitabine in KPC mice. Extracellular administration of TFF1 inhibited gemcitabine-induced EMT, Wnt pathway activation and cancer stemness, eventually increased apoptosis of pancreatic cancer cells in vitro. In vivo, combined treatment of gemcitabine and subcutaneous administration of TFF1 arrested tumor growth in xenograft mouse model and resulted in the better survival of KPC mice by inhibiting EMT and cancer stemness. CONCLUSION: These results indicate that TFF1 can contribute to establishing a novel strategy to treat pancreatic cancer patients by enhancing chemosensitivity.

TLK1 Inhibition Enhances the Anticancer Effect of Deep UV Irradiation Through CHK1 Activation.

BACKGROUND/AIM: A deep ultraviolet (DUV) light-emitting diode (LED) is a device that can irradiate electromagnetic waves from 250 nm to 350 nm. Tousled-like kinase 1 (TLK1) encodes a nuclear serine/threonine kinase, which is thought to influence the effects of DUV irradiation in cancer. The aim of this study was to clarify the interaction of TLK1 with DUV irradiation-induced DNA damage in cancer cells. MATERIALS AND METHODS: Pancreatic cancer cell lines were treated with or without DUV. TLK1 expression and phosphorylation in the two groups were examined. Then, these cancer cell lines were treated with thioridazine (THD), DUV or both. Thereafter, cytomorphology and apoptosis were assessed. Several proteins related to DNA damage, were analyzed in cancer cells treated with DUV and THD. Tumors in a subcutaneous xenograft model were treated with THD, DUV, or both for six weeks. RESULTS: DUV irradiation induced the phosphorylation of TLK1 in pancreatic cancer cell lines. Cytomorphology was significantly changed in pancreatic cancer cells treated with DUV and THD. TLK1 inhibition enhanced DUV irradiation-induced apoptosis in cancer cells. Interestingly, CHK1 and pCHK1 expression was suppressed after TLK1 inhibition. In addition, inhibition of MRE11 led to a decrease in the expression of CHK1 and pCHK1, accompanied by a notable increase in apoptosis. In the subcutaneous xenograft models, the tumor volume in the DUV and THD groups was lower than that in the other groups. CONCLUSION: TLK1 phosphorylation is an important event in DUV irradiation. DUV irradiation combined with TLK1 inhibition has therapeutic potential in pancreatic cancer cells.

Neuro-mesenchymal interaction mediated by a ß2 adrenergic-nerve growth factor feedforward loop promotes colorectal cancer progression.

Cancer-associated fibroblasts (CAFs) and nerves, components of the tumor microenvironment, have each been shown to directly promote gastrointestinal cancers. However, it remains unknown whether these cells interact with each other to regulate cancer progression. We found that in colorectal cancer (CRC) norepinephrine induces ADRB2-dependent nerve growth factor (NGF) secretion from CAFs, which in turn increases intra-tumor sympathetic innervation and norepinephrine accumulation. Adrenergic stimulation accelerates CRC growth through ADRA2A/Gi-mediated activation of Yes-Associated Protein (YAP). NGF from CAFs directly enhances CRC cell growth via the PI3K/AKT pathway. Treatment with a tropomyosin receptor kinase (Trk) inhibitor decreased YAP and AKT activation and CRC progression in mice. In human CRC, high NGF expression is associated with the mesenchymal-like tumor subtype and poor patient survival. These findings suggest a central role for reciprocal CAF-nerve crosstalk in promoting CRC progression. Blocking this feedforward loop with a Trk inhibitor may represent a potential therapeutic approach for CRC.

Complete mitochondrial genome sequences of two ground crickets, Dianemobius fascipes nigrofasciatus and Polionemobius taprobanensis (Orthoptera: Grylloidea: trigonidiidae).

The authors sequenced the complete mitochondrial (mt) genomes of the band-legged ground cricket (Dianemobius fascipes nigrofasciatus Matsumura, 1904) and a temperate form of the lawn ground cricket (Polionemobius taprobanensis Walker, 1869), collected in Japan. The length of the mt genome sequences was 15,354 bp in D. fascipes nigrofasciatus and 16,063 bp in P. taprobanensis. Annotation of the mt genome sequences revealed 13 protein-coding genes, two rRNA genes, and 22 tRNA genes. The orientation of the genes was the same as in other Grylloidea species, and the order was the same as in other Trigonidiidae species. In our phylogenetic analysis, D. fascipes nigrofasciatus formed a clade with D. fascipes collected in China, and the temperate form of P. taprobanensis formed a clade with P. taprobanensis collected in China. Comparison of the numbers of positions with different amino acid residues encoded by the protein-coding genes implied the separate species status of each member of each of the two pairs of ground crickets. The mt genome sequences of D. fascipes nigrofasciatus and P. taprobanensis will contribute to phylogenetic and taxonomic studies of the Trigonidiidae.