堀江 久永

Ras genes are frequently mutated in many cancer types; however, there are currently no conclusively effective anticancer drugs against Ras-induced cancer. Therefore, the downstream effectors of Ras signaling need to be identified for the development of promising novel therapeutic approaches. We previously reported that oncogenic Ras induced the expression of NF-HEV/IL-33, a member of the interleukin-1 family, and showed that intracellular IL-33 was required for oncogenic Ras-induced cellular transformation. In the present study, we demonstrated that the c-Mer proto-oncogene tyrosine kinase (MerTK), a receptor tyrosine kinase, played essential roles in oncogenic Ras/IL-33 signaling. The expression of MerTK was enhanced in transformed NIH-3T3 cells by the expression of oncogenic Ras, H-Ras (G12V), in an IL-33-dependent manner. In human colorectal cancer tissues, MerTK expression also correlated with IL-33 expression. The knockdown of IL-33 or MerTK effectively attenuated the migration of NIH-3T3 cells transformed by H-Ras (G12V) and A549, LoVo, and HCT116 cells harboring an oncogenic K-Ras mutation. Furthermore, the suppression of Ras-induced cell migration by the knockdown of IL-33 was rescued by the enforced expression of MerTK. The present results also revealed that MerTK was effectively phosphorylated in NIH-3T3 cells transformed by Ras (G12V). Ras signaling was essential for the tyrosine phosphorylation of MerTK, and the kinase activity of MerTK was indispensable for accelerating cell migration. Collectively, the present results reveal a novel role for MerTK in cancer malignancy, which may be utilized to develop novel therapeutic strategies that target Ras-transformed cells.

BACKGROUND/AIMS: Recent studies have demonstrated that the populations of several microbes are significantly increased in fecal samples from patients with colorectal cancer (CRC), suggesting their involvement in the development of CRC. The aim of this study was to identify microbes which are increased in distal CRCs and to identify the specific location of microbes increased in mucosal tissue around the tumor. METHODS: Tissue specimens were collected from surgical resections of 28 distal CRCs. Five samples were collected from each specimen (location A: tumor, B: adjacent normal mucosa, C: normal mucosa 1 cm proximal to the tumor, D: normal mucosa 3 cm proximally, and E: normal mucosa 6 cm proximally). The microbiota in the sample were analyzed using 16S rRNA gene amplicon sequencing and the relative abundance (RA) of microbiota compared among the 5 locations. RESULTS: At the genus level, the RA of Fusobacterium and Streptococcus at location A was the highest among the 5 locations, significantly different from that in location E. The dominant species of each genus was Fusobacterium nucleatum and Streptococcus anginosus. The RAs of these species gradually decreased from locations B to E with a statistically significant difference in F. nucleatum. The genus Peptostreptococcus also showed a similar trend, and the RA of Peptostreptococcus stomatis in location A was significantly associated with depth of tumor invasion and tumor size. CONCLUSION: Although the clinical relevance is not clear yet, these results suggest that F. nucleatum, S. anginosus, and P. stomatis can spread to the adjacent normal tissues and may change the surrounding microenvironment to support the progression of CRC.

大腸癌の血行性転移には、肝転移、肺転移、その他(脳、骨、副腎など)がある。肝転移と肺転移は、治癒切除により予後改善効果が報告されており、多発転移であっても他臓器に転移を認めない場合は、治癒切除可能かどうかを注意深く見極めることが重要である。また近年の化学療法の進歩により、初診時には切除不能な肝転移であっても、化学療法後の縮小により切除可能となる場合がある。切除後の予後ははじめから切除可能な肝転移のそれとほぼ同等とされ、このconversion therapyは多発肝転移を有する進行大腸癌に対する治療戦略のひとつとして確立されている。肺転移についても、一定の条件を満たす症例では切除により予後の改善が報告されており、近年の胸腔鏡手術の技術や器機の進歩により、両葉や多発病変の切除も可能となっている。ただし肺転移切除の治療成績については大規模研究の報告が少なく、ほとんどが後ろ向き研究であることから、今後の研究結果の集積が待たれる。(著者抄録)

大腸癌の血行性転移には、肝転移、肺転移、その他(脳、骨、副腎など)がある。肝転移と肺転移は、治癒切除により予後改善効果が報告されており、多発転移であっても他臓器に転移を認めない場合は、治癒切除可能かどうかを注意深く見極めることが重要である。また近年の化学療法の進歩により、初診時には切除不能な肝転移であっても、化学療法後の縮小により切除可能となる場合がある。切除後の予後ははじめから切除可能な肝転移のそれとほぼ同等とされ、このconversion therapyは多発肝転移を有する進行大腸癌に対する治療戦略のひとつとして確立されている。肺転移についても、一定の条件を満たす症例では切除により予後の改善が報告されており、近年の胸腔鏡手術の技術や器機の進歩により、両葉や多発病変の切除も可能となっている。ただし肺転移切除の治療成績については大規模研究の報告が少なく、ほとんどが後ろ向き研究であることから、今後の研究結果の集積が待たれる。(著者抄録)

PURPOSE: The aim of this study was to evaluate both the intestinal mucosa staple line integrity and anastomotic leak pressure after healing in a porcine survival model. METHODS: We used two suture models using two different size staples (incomplete mucosal closure model: group G [staple height 0.75 mm], complete mucosal closure model: group B [staple height 1.5 mm]) in the porcine ileum. Five staple lines were created in each group made in the ileum for each model, and the staple sites harvested on days 0, 2, and 7. The leak pressure at the staple site was measured at each time point. RESULTS: On day 0, the leak pressure for group G (79.5 mmHg) was significantly lower than that for group B (182.3 mmHg) (p < 0.01). On days 2 and 7, there was no significant difference between groups G and B (171 mmHg and 175.5 mmHg on day 2, 175.5 mmHg and 175.5 mmHg on day 7, p > 0.05). The histological findings in both groups showed similar healing at postoperative days 2 and 7. CONCLUSION: The integrity of the mucosal staple lines was associated with the postoperative leak pressure on day 0. However, there was no association with the leak pressure at two days or more postoperatively in a porcine model.

Introduction and importance: Metastases to common iliac lymph nodes from cancer of the rectosigmoid are extremely rare. We report a patient with a right common iliac lymph node metastasis after rectosigmoid cancer resection. Case presentation: The patient is a 57-year-old woman diagnosed with rectosigmoid cancer (Stage IIIc) who underwent laparoscopic resection followed by 8 courses of adjuvant chemotherapy with capecitabine. Sixteen months after resection, an intra-abdominal mass and a left lung nodule were found on computed tomography scans, which were suspected to be recurrences. Exploratory laparoscopy showed that the abdominal lesion was an enlarged common iliac lymph node, which was completely excised. No other intraabdominal recurrences were found. Subsequently, a left upper lobe lung metastasis was resected thoracoscopically. However, multiple lung metastases developed four months after the lung resection, and systemic therapy was begun. Clinical discussion: A lower incidence of lateral lymph node metastases from cancer in the rectosigmoid has been reported. Direct lymphatic pathways from the sigmoid colon or rectosigmoid to lateral lymph nodes have been suspected, which may be associated with the poor prognosis in this patient. Conclusion: A metachronous metastasis to a common iliac lymph node from primary rectosigmoid cancer is reported. Common iliac lymph node metastases from rectosigmoid cancer might have more malignant potential, and should be treated in the same manner as peri-aortic lymph node metastases.

目的:大腸憩室出血治療の現状を調査し,外科治療必要症例の頻度や臨床的特徴を検討した.対象と方法:2010年1月から2020年4月までに当院で経験した大腸憩室出血194例を対象とし後方視的に検討した.結果:手術は7例(4%)に行われていた.手術理由は内視鏡止血困難5例,内視鏡+IVR治療困難2例,循環動態不安定3例であった(重複あり).全例とも上行結腸で,経過中にショック状態となり輸血を受けていた.手術は開腹の結腸右半切除が行われていた.左右結腸の多発例で,抗凝固薬を内服していた1例は術後3年間に3度血便を認めたが保存的に治癒した.結語:当院における憩室出血治療は概ねガイドラインに沿って行われていた.手術例では,ショック状態で輸血例であったが,周術期治療成績は良好であった.切除範囲については術後のQOLを考慮に入れた総合的な判断が必要と考えられた.(著者抄録)

Adenocarcinoma in a Meckel's diverticulum is rare and difficult to diagnose preoperatively. We report the first case of a metachronous Krukenberg tumor from adenocarcinoma in a Meckel's diverticulum. A 45-year-old woman was admitted for recurrent abdominal pain. Computed tomography scan showed a lesion with contrast enhancement, and a Meckel's diverticulum-associated tumor was suspected. Double-ballon enteroscopy revealed intestinal stenosis and biopsy showed adenocarcinoma. Operative findings showed a Meckel's diverticulum with tumor. Histopathological evaluation revealed well-differentiated adenocarcinoma, interrupted by ectopic gastric mucosa, diagnosed as adenocarcinoma in a Meckel's diverticulum. Two years postoperatively, a multi-cystic mass with contrast enhancement was observed in the pelvis on imaging evaluation and oophorectomy performed. Histological examination of the resected ovary showed proliferation of atypical glandular ducts, consistent with metastatic adenocarcinoma. This case demonstrates that adenocarcinoma in a Meckel's diverticulum may result in distant metastases and requires appropriate follow-up.

症例は48歳の男性で,約1ヵ月前に左手外傷に対して鼠径部より採皮,植皮術を施行され,退院後より腹部違和感を自覚していた.腹部症状が増悪し意識障害も出現したため前医を受診し,造影CTで広範な門脈血栓症を認め,入院となった.翌日,下部消化管出血を認め,当院転院となった.転院時造影CTで上腸間膜静脈血栓症と診断された.小腸壊死は明らかでなく,抗凝固療法を開始し,約40日の経過で血栓はほぼ消失した.経口摂取開始後に嘔吐が出現したため,小腸造影および小腸3D-CTを撮影したところ上部空腸の器質的狭窄を認めた.転院後第59病日に小腸部分切除術を施行した.病理学的には血栓形成を伴う虚血性腸炎の診断であった.術後20日目に退院し,現在も再発は認めていない.本症例では,3D-CTが遅発性小腸狭窄の範囲の推定と切除範囲の決定に有用であった.(著者抄録)

症例は48歳の男性で,約1ヵ月前に左手外傷に対して鼠径部より採皮,植皮術を施行され,退院後より腹部違和感を自覚していた.腹部症状が増悪し意識障害も出現したため前医を受診し,造影CTで広範な門脈血栓症を認め,入院となった.翌日,下部消化管出血を認め,当院転院となった.転院時造影CTで上腸間膜静脈血栓症と診断された.小腸壊死は明らかでなく,抗凝固療法を開始し,約40日の経過で血栓はほぼ消失した.経口摂取開始後に嘔吐が出現したため,小腸造影および小腸3D-CTを撮影したところ上部空腸の器質的狭窄を認めた.転院後第59病日に小腸部分切除術を施行した.病理学的には血栓形成を伴う虚血性腸炎の診断であった.術後20日目に退院し,現在も再発は認めていない.本症例では,3D-CTが遅発性小腸狭窄の範囲の推定と切除範囲の決定に有用であった.(著者抄録)

症例は37歳,女性.25歳で偶発的に膵体尾部に嚢胞性病変を指摘され,精査目的に当院消化器内科に紹介された.腹部造影CTとMRI検査では膵尾部に約5cmの嚢胞性腫瘤を認め膵粘液性嚢胞腫瘍(mucinous cystic neoplasm:MCN)が疑われたが,経過観察の方針となった.32歳時の第2子妊娠を契機に経過観察が一時中断となり,5年後の37歳に再診した.嚢胞性腫瘤は多房化し,大きさ6cmへの増大を認め,血清CA19-9の上昇を伴ったことから手術目的に消化器外科紹介となった.腹腔鏡下膵体尾部脾摘術を施行し,術後経過は良好で術後11日目に退院した.病理組織像では卵巣様間質を認め,微小浸潤を伴った膵粘液性嚢胞腺癌の診断であった.MCNの自然史を解明するには長期経過観察例の集積が必要である.(著者抄録)

症例は37歳,女性.25歳で偶発的に膵体尾部に嚢胞性病変を指摘され,精査目的に当院消化器内科に紹介された.腹部造影CTとMRI検査では膵尾部に約5cmの嚢胞性腫瘤を認め膵粘液性嚢胞腫瘍(mucinous cystic neoplasm:MCN)が疑われたが,経過観察の方針となった.32歳時の第2子妊娠を契機に経過観察が一時中断となり,5年後の37歳に再診した.嚢胞性腫瘤は多房化し,大きさ6cmへの増大を認め,血清CA19-9の上昇を伴ったことから手術目的に消化器外科紹介となった.腹腔鏡下膵体尾部脾摘術を施行し,術後経過は良好で術後11日目に退院した.病理組織像では卵巣様間質を認め,微小浸潤を伴った膵粘液性嚢胞腺癌の診断であった.MCNの自然史を解明するには長期経過観察例の集積が必要である.(著者抄録)