18F-Fluorodeoxyglucose Positron Emission Tomography/Magnetic Resonance Imaging-Defined Extramural Venous Invasion Predicts Distant Metastasis and Reflects Strong Tumor Invasiveness in Rectal Cancer.

INTRODUCTION: Extramural vascular invasion in patients with rectal cancer is a poor prognostic factor associated with distant metastasis; thus, accurate preoperative diagnosis is important. However, the accurate detection of extramural vascular invasion using magnetic resonance imaging (MRI) is difficult, and an improved diagnostic modality is required. In addition, the factors involved in the formation of extramural venous invasion (EMVI) remain unclear. In this study, we aimed to examine the ability of 18F-fluorodeoxyglucose positron emission tomography/MRI ([18F] FDG PET/MRI) to detect EMVI and elucidate the factors involved in EMVI. METHODS: Thirty-one patients with rectal cancer were enrolled in this study between 2017 and 2021. We preoperatively evaluated the pelvic [18F] FDG PET/MRI to detect extramural vascular invasion ([18F] FDG PET/MRI-defined EMVI: pmrEMVI). To investigate the factors related to pmrEMVI, we confirmed the desmoplastic reaction (DR) and TWIST expression in the primary lesions of rectal cancer and examined its relationship with pmrEMVI. RESULTS: Six of the 31 patients were pmrEMVI positive. Four pmrEMVI-positive patients had distant metastases. The levels of immature DR and TWIST1 expression were significantly higher in cases with pmrEMVI positivity. CONCLUSION: pmrEMVI is a useful biomarker for predicting distant metastasis. In addition, pmrEMVI was significantly correlated with factors related to tumor invasiveness.

Follicular cholangitis mimicking a common bile duct cancer: a case report.

BACKGROUND: Follicular cholangitis (FC) is a benign bile duct disease that was first reported 2003. Pathologically, it is characterized by lymphoplasmacytic infiltration with multiple lymphoid follicle formations under the mucosal layer of the biliary tract. However, as this disease is extremely rare, little is known about its etiology and pathogenesis. CASE PRESENTATION: A 77-year-old woman was diagnosed with middle bile duct stenosis and potential increases in alkaline phosphatase (ALP) and γ-glutamyl transpeptidase levels (γ-GTP). Carcinoembryonic antigen (CEA), carbohydrate antigen 19-9 (CA19-9) and IgG4 levels were all within the normal limits. Contrast-enhanced computed tomography (CE-CT) and magnetic resonance imaging (MRI) revealed bile duct dilation from intrahepatic to upper common bile duct and an irregular mass lesion in distal bile duct. Additionally, multiple overlapping leaf-like folds were detected. 18F-fluorodeoxyglucose positron emission tomography-computed tomography (18F-FDG-PET/CT) did not demonstrate fluorodeoxyglucose uptake. Subtotal stomach-preserving pancreaticoduodenectomy with regional lymph node dissection was performed because common bile duct cancer could not be ruled out. The resected specimen showed diffuse homogeneous middle bile duct wall thickening. Microscopically, the lesion exhibited thick fibrosis with several invaded lymphoplasmacytic cells, and lymphoid follicle formations were detected under the mucosal layer. Immunohistochemical staining (IHC) revealed positive for CD3, CD4, CD20 and CD79a, and these findings led to a final diagnosis of FC. The patient has not experienced recurrence to date (42 months postoperatively). CONCLUSIONS: Currently, accurate preoperative diagnosis of FC is difficult. More cases must be accumulated to generate additional knowledge on its precise diagnosis and proper treatment.

[Short-Term Outcomes of Neoadjuvant Chemoradiotherapy for Locally Advanced Rectal Cancer].

In recent years, an increasing number of reports have demonstrated the usefulness of neoadjuvant chemoradiotherapy (NACRT). In our department, we consider cT3-4 and/or cN-positive locally advanced rectal cancer as an indication for NACRT. We have retrospectively evaluated the efficacy and safety of NACRT in 11 patients who underwent NACRT from November 2018 to July 2022. All patients were male, with a median age of 69 years, and cStage was Ⅱa: 1, Ⅱc: 1, Ⅲb: 5, Ⅲc: 3, and Ⅳa: 1. All patients completed NACRT, and there were no cases of CTCAE Grade 3 or higher adverse events or treatment interruptions. The response rate was 72.7%, and histological response grade were Grade 3: 1(9.1%), 2: 4 (36.4%), 1b: 6(54.5%), and surgical margin was negative in all cases. Pathological down stage was obtained in 45.5% of cases, and pCR was obtained in 1 case(9.1%). The median observation period was 17 months, and during the period, 2 cases(18.2%)developed recurrence, both of which were pulmonary metastases, and no local recurrence including pelvic lymph node recurrence was observed. NACRT for locally advanced rectal cancer is considered a relatively safe and highly locally controllable preoperative treatment.

[A Case of BRAF V600E-Mutant Colorectal Cancer Treated Effectively by Encorafenib, Binimetinib, and Cetuximab Triple Therapy].

A 76-year-old woman was diagnosed with left-sided transverse colon cancer invading the pancreatic tail with multiple liver metastases and peritoneal dissemination. Preoperative diagnosis was cT4b(SI)N2aM1c(H3, P1), cStage Ⅳc, harboring BRAF V600E mutation. Transverse colostomy was performed, and FOLFOXIRI plus bevacizumab(BEV)was administered. After 12 chemotherapy cycles, the primary tumor and metastatic lesions showed partial response. Because of CEA elevating after 5-FU plus LV plus BEV as maintenance therapy was changed, the regimen was switched to encorafenib plus binimetinib plus cetuximab as the second-line chemotherapy. The patient developed dermatitis around the colostomy after the start of the second-line chemotherapy, resulting in temporally cetuximab monotherapy. After improvement of dermatitis, the patient resumed encorafenib plus binimetinib, improving liver metastases. Eight months after the start of the second- line, the patient has been administered with triple therapy and had stable disease status.

Stage IV anal canal squamous cell carcinoma with long-term survival: a case report.

BACKGROUND: Currently, no established standard treatment exists for metastatic anal squamous cell carcinoma. We report a case of complete response in a patient with stage IV anal squamous cell carcinoma after undergoing multidisciplinary treatment. CASE PRESENTATION: A 62-year-old woman visited a nearby doctor with a chief concern of severe pain associated with a firm mass in the anus. The patient was diagnosed with anal canal squamous cell carcinoma and liver metastases and referred to First Department of Surgery Faculty of Medicine University of Fukui for treatment. The patient received a TNM classification of T4N0M1 and stage IV. Rectal amputation was performed; however, postoperative complications hindered immediate anticancer therapy and the liver metastases exacerbated. Radiofrequency hyperthermia and systemic chemotherapy were performed 3 months postoperatively. A prominent reduction in the liver metastasis was observed. Lung metastases appeared during the course of systemic chemotherapy. Radiotherapy was performed to treat the lung lesion and resolved. Radiotherapy was also performed for liver metastasis. The lesion in the liver showed resolution after 54 months postoperatively, and treatment with the anticancer drug was discontinued. Ten-year follow-up findings suggested complete resolution of the lesion in response to the treatment protocol followed in this case. This long-term survival was achieved through a multidisciplinary treatment. CONCLUSIONS: The present case suggests that multidisciplinary treatment approach is effective for resolving stage IV anal squamous cell carcinoma, and addition of new anticancer drug therapy may improve the overall prognosis of squamous cell carcinoma.

Feasibility of [18F]FDG PET/MRI with Early-Delayed and Extended PET as One-Stop Imaging for Staging and Predicting Metastasis in Rectal Cancer.

BACKGROUND: We aimed to evaluate the diagnostic accuracy of 2-[18F]-fluoro-2-deoxy-D-glucose positron emission tomography/magnetic resonance imaging ([18F]FDG PET/MRI) for preoperative staging and usefulness of the detection of extramural vascular invasion (EMVI) for predicting metastasis in rectal cancer. METHODS: Twenty-three patients underwent pretreatment [18F]FDG PET/MRI, including early-delayed and extended PET and dedicated pelvic MRI without using anticonvulsant or contrast agents. Seven patients received preoperative treatment and all subsequently underwent surgery. Clinical cancer stages were evaluated using postoperative histopathology as a reference. PET/MR-defined EMVI (pmrEMVI) and pathological (p) TN stages were correlated with disease progression for a maximum of 2 years. RESULTS: Of 16 patients without preoperative treatment, 10 had pT3, 4 tumors, 7 had pN1-3 lymph nodes, and 5 had synchronous metastases (SM; liver, lung, inguinal node). The sensitivity, specificity, and accuracy of PET/MRI were 90%, 67%, and 81% for T staging (T1, 2 vs. T3, 4), and 89%, 100%, and 94% for N staging (N0 vs. N1-3), respectively. Patient-based accuracy for SM staging was 100% (4/4). Of 23 patients, 6 were positive for pmrEMVI and 4 had metachronous metastases or local recurrence (MM; pelvic node, brain, lung, skin) during the follow-up periods. Five of the 6 pmrEMVI-positive patients had SM and/or MM (odds ratio = 37.5). Among pT, pN, and pmrEMVI, pmrEMVI-positivity was the only significant predictor for poorer progression-free survival (p < 0.05). CONCLUSIONS: [18F]FDG PET/MRI according to our suggested protocol is a one-stop, non-contrast, and valid diagnostic method for rectal cancer staging, and pmr-EMVI can be used as an imaging biomarker for predicting metastases.

Plasma Prokineticin 1, a prognostic biomarker in colorectal cancer patients with curative resection: a retrospective cohort study.

BACKGROUND: Prokineticin 1 (PROK1) was reported as an angiogenic factor, which is associated with tumor progression, cell invasion, and metastasis in colorectal cancer. Although the association between PROK1 expression in primary cancer lesion and patient prognosis was reported, it is unclear whether plasma PROK1 concentration may be a predictive factor in colorectal cancer patients. This study investigated the association between PROK1 concentration in plasma and prognosis in colorectal cancer patients. METHODS: We measured preoperative PROK1 plasma levels using ELISA method, while PROK1 expression in primary cancer lesion was evaluated using immunohistochemistry (IHC). The association between plasma PROK1 levels and cancer-related survival rate (CRS) was evaluated. Additionally, we examined whether simultaneous PROK1 expression in both primary cancer lesions and plasma was correlated with CRS. The cancer-related survival rate was calculated using the Kaplan-Meier method, and survival estimates were compared using the log-rank test. RESULTS: We have gathered eligible 130 CRC patients retrospectively. Out of 130 patients, 61 (46.9%) were positive on IHC in primary cancer, and 69 (53.1%) were negative, while 43 (33.1%) had high-value PROK1 in plasma. Out of these 43, 30 (25.4%) also had concomitant higher IHC expression in primary cancer. The plasma PROK1 levels tended to increase with advancing stages. The plasma PROK1-positive group had a lower 5-year CRS than the negative group (63.6% vs. 88.2%; P = 0.006). Additionally, simultaneous PROK1 expression was associated with a more significant decrease of 5-year CRS than both negative groups in all stages (76.2% vs. 92.5%; P = 0.003) and stage III (59.3% vs. 84.5%; P = 0.047). Multivariate analysis showed simultaneous PROK1 expression was independently associated with worse CRS (HR, 1.97; 95% CI 1.20­3.24, P < 0.01). CONCLUSION: PROK1 expression in preoperative plasma reflects poor prognosis in patients undergoing curative resection for colorectal cancer. The plasma PROK1 level may be a potential predictive marker, especially in stage III colorectal cancer patients.

[A Long Term Survival Case of Gastric Cancer with Peritoneal Dissemination Responding to Intraperitoneal Chemotherapy].

A 32-year-old woman was admitted our hospital due to epigastric discomfort. The patient diagnosed as having scirrhous carcinoma of the stomach by upper gastrointestinal scope. Peritoneal dissemination and ovarian metastasis were confirmed by the diagnostic laparoscopy. Therefore, combination chemotherapy with S-1 and intraperitoneal chemotherapy(ip)with docetaxel (DTX) was started. After 2 courses chemotherapy, laparoscopy was performed again. Peritoneal dissemination was scarred, but biopsy showed altered AE1/AE3 positive cells, and increased left ovarian metastasis, so systemic chemotherapy was changed to DCS chemotherapy and added DTX ip. After 4 courses chemotherapy and 7 months after the first diagnosis, subtotal gastrectomy, hysterectomy and bilateral adnexectomy were performed because the cytology and tumor marker remained within normal range. In histopathological diagnosis, the effect of chemotherapy was Grade 2 at the primary site and Grade 3 at the metastatic site. Nine years have passed since the initial diagnosis and she has no relapse with postoperative adjuvant chemotherapy.

[Examination of Prognosis and Adjuvant Chemotherapy in Stage â ¡ and Stage â ¢ Resected Colorectal Cancer in the 9th Edition Japanese Classification of Colorectal Carcinoma].

In the 9th edition Japanese Classification of Colorectal Carcinoma, Stage Ⅱ and Stage Ⅲ colorectal cancer(CRC)were subdivided by TNM classification on invasion and number of lymph node metastases. We studied prognostic comparison and relation of adjuvant chemotherapy at the new classification. We included 400 cases with resected Ⅱ and Ⅲ CRC from 2007 to 2014. Ⅱa/Ⅱb/Ⅱc/Ⅲa/Ⅲb/Ⅲc were 97/68/20/24/124/67 cases. Adjuvant chemotherapy was performed at 19/32/45/66/59/70% in Ⅱa/Ⅱb/Ⅱc/Ⅲa/Ⅲb/Ⅲc, with or without adjuvant chemotherapy at each stage survival rates were compared. In Ⅱa/Ⅱb/Ⅱc, DSS was 97/97/82% and DFS was 89/88/76%, and the prognosis of Ⅱc was significantly worse. In Ⅲa/Ⅲb/Ⅲc, DSS was 95/86/57% and DFS was 82/77/41%. By the presence or absence of adjuvant chemotherapy, significantly differences were obtained at Ⅲb and Ⅲc. Prognosis of Ⅱc was almost same as Ⅲb, and prognosis of Ⅲa was almost same as Ⅱb. Therefore, we considered adjuvant chemotherapy with oxaliplatin should be performed to Ⅱc, Ⅲb, and Ⅲc.

Acute Small Bowel Perforation Caused by Obstruction of a Novel Tag-Less AgileTM Patency Capsule.

A 74-year-old man visited our hospital complaining of abdominal pain. An abdominal computed tomography scan showed multiple wall thickness of the small bowel. Capsule endoscopy was recommended for further evaluation, and patency capsule examination was performed. Eighteen hours after patency capsule ingestion, he experienced small bowel perforation with severe peritonitis caused by intestinal pressure rising because of the patency capsule trapped in his terminal ileum. An ileocolic resection was performed, including the removal of the sclerotic ileum as an emergency surgery. A pathological examination showed transmural inflammation and multiple ulcers with perforation of the small intestine, consistent with Crohn's disease. Here, we report a rare and valuable case of novel tag-less AgileTM patency capsule (Given Imaging Ltd., Yoqneam, Israel) retention leading to small bowel perforation.

Prokineticin 2 expression as a novel prognostic biomarker for human colorectal cancer.

Molecular tumor biomarkers hold considerable promise for accurately predicting colorectal cancer (CRC) recurrence and progression. Prokineticin 2 (PROK2) may be associated with angiogenesis and tumor formation in some malignant tumors. However, its prognostic value remains unknown. We focused on the association between PROK2 expression and clinical characteristics of CRC to assess value of PROK2 as a potential biomarker for stage I-III CRC patients prognosis. Between 1992 and 2006, 436 consecutive patients with stage I-III CRC treated with curative resection were included. PROK2 expression in primary tumors was investigated using immunohistochemistry. An animal model of liver metastasis was used to assess the role of PROK2. Positive PROK2 expression in primary tumors was found in 222 of 436 (50.9%) human CRC specimens and was significantly associated with lymphatic invasion, lymph node metastasis, clinical stage, and postoperative liver recurrence rate. Recurrence-free survival was significantly shorter in patients with positive PROK2 expression than in those with negative PROK2 expression. PROK2 expression was an independent unfavorable prognostic indicator for CRC [hazards ratio, 2.119; 95% confidence interval, 1.315-3.415; p = 0.002]. PROK2 overexpression promoted liver metastasis in vivo. We suggest that positive PROK2 expression is observed in CRC primary tissues; thus, PROK2 may be a useful predictor for liver recurrence and prognosis in CRC.

Long-term survival in a patient with Virchow's lymph node metastasis of cecal cancer.

The patient was a 53-year-old male with a chief complaint of bloody stool. To treat the cecal colon cancer, right hemicolectomy was performed. Histological examination showed moderately differentiated adenocaricinoma, SE, N3, H0, P0, M0 Stage IIIb by Japanese Classification of the Colorectal Carcinoma. After the operation, the patient received a chemotherapy with 6 cycles of Capecitabine regimen. After 1 year later, computed tomography detected swelling of Virchow's lymph node and tumor in the thyroid gland. By fine-needle aspiration cytology, thyroid gland tumor was diagnosed as papillary cancer and Virchow's lymph node was detected adenocarcinoma which was metastasis of cecal cancer. Total thyroidectomy and cervical lymph node dissection were performed. After the operation, the patient received chemotherapy with 6 cycles of FOLFOX regimen. And the patient had taken UFT/LV for 30 months. Now he has no recurrence and keeps his quality of life high. He has been alive for 80 months since the first operation. Virchow lymph node dissection can be one of the options of treatment of metastasis.

Favorable response of colonic mixed adenoneuroendocrine carcinoma to streptozocin monotherapy.

Mixed adenoneuroendocrine carcinoma (MANEC) of the colon is rare and has a poor prognosis. Here, we report a case of MANEC in the ascending colon, in which streptozocin monotherapy achieved a partial response. A 36-year-old woman underwent right hemicolectomy for colonic polyposis, which included ascending colon cancer. Pathological examination revealed that some mucosal polyps were adenocarcinoma while one submucosal polyp was neuroendocrine carcinoma. Adjuvant chemotherapy was not administered, and 5 months after the operation, multiple liver metastases were identified. She was started on modified (5-FU, leucovorin, oxaliplatin) followed by XELOX (capecitabine, oxaliplatin) plus bevacizumab. Although these regimens helped achieve stable disease, computed tomography showed that the hepatic metastatic lesions had enlarged 4 months later. Subsequently, the regimen was changed to streptozocin monotherapy (1000 mg/m2, weekly). After 5 cycles, the regimen achieved partial response and was continued for a total of 17 courses without significant adverse events until progressive disease. As a third-line chemotherapy regimen, cisplatin plus etoposide (EP) was administered. The EP regimen reduced the size of the hepatic and ovarian metastatic lesions but severe neutropenia and anemia was observed. Amrubicin monotherapy was also administered as fourth-line chemotherapy but a good clinical response was not detected, and the patient died 20 months after the operation. Streptozocin monotherapy has the potential to be a therapeutic option for mixed adenoneuroendocrine carcinoma of the colon.

Expression of prokineticin-receptor2(PK-R2) is a new prognostic factor in human colorectal cancer.

The increased invasiveness of colorectal cancer cells is important for progression and metastasis to the surrounding organs. According to recent molecular biological studies, signaling through transmembrane Prokineticin-Receptor2(PK-R2) is likely involved in the ability of tumor cell to invade. However, no studies have evaluated the relationship between PK-R2 expression, ability of cancer to invade/metastasize, and patient prognosis in cases of resected colorectal cancer. Accordingly, we have examined these factors in the present study.Immunohistochemical staining was performed to detect PK-R2 in the primary lesion and adjacent normal large intestine mucosa of 324 colorectal cancer patients who underwent resection surgery at our department. Additionally, we conducted clinicopathologic examinations and analyzed patient prognoses with the Kaplan-Meier method. Further, multivariate analysis was conducted using a cox-proportional hazard model.PK-R2 expression was observed on the cellular membrane of the primary lesion in 147 of 324 cases (45.3%) of human colorectal cancer. PK-R2 expression was associated with a higher incidence of vascular invasion, lymph node metastasis, hepatic metastasis, and hematogenous metastasis. Further, prevalence of PK-R2 expression increased as tumor stage increased. In stage III curative resection cases, where recurrence is the most serious problem, cases that expressed PK-R2 had a significantly lower 5-year survival rate (82.1% versus 66.8%) and higher recurrence compared to those cases with no PK-R2 expression. In the multivariate analysis for prognosis, PK-R2 expression was found to be an independent factor(ratio2.621).PK-R2 expression could be one of the new prognostic factors in human colorectal cancer.

Prokineticin 2 (PROK2) is an important factor for angiogenesis in colorectal cancer.

The Prokineticin 2 (PROK2) is correlated with indispensable in maintaining the homeostasis of healthy human tissues. Herein, we examined the role of PROK2 in human colorectal cancer.After total RNA extraction from 6 colorectal cancer cell lines, we examined the expression of PROK2 mRNA. For investigating angiogenesis and tumor growth in mice, the PROK2 gene was transfected into colorectal cancer cell lines having low PROK2 mRNA expression. In addition, small interfering RNA (siRNA) was transfected into colorectal cancer cell lines having high PROK2 mRNA expression for investigation of angiogenesis and tumor growth in mice.From 6 colorectal cancer cell lines studied, PROK2 mRNA expression was increased in 3 cell lines. When the PROK2 gene was transfected into the colorectal cancer cell line with low PROK2 mRNA expression, angiogenesis and tumor growth in mice increased significantly compared to the cell line with the control vector.When PROK2 siRNA was transfected into colorectal cancer cell lines with high PROK2 mRNA expression, angiogenesis and tumor growth in mice were suppressed significantly compared to the cell line with siRNA (control).This is the first report of the association of PROK2 as an angiogenic growth factor in colorectal cancer.

Cancer stem cell marker in circulating tumor cells: expression of CD44 variant exon 9 is strongly correlated to treatment refractoriness, recurrence and prognosis of human colorectal cancer.

BACKGROUND/AIM: The expression of the CD44 variant exon 9 (CD44v9) was investigated in order to elucidate its significance for cancer stem cells in circulating human colorectal cancer cells (CTCs). MATERIALS AND METHODS: After peripheral blood was drawn from patients with colorectal cancer, CTCs were collected. Using the reverse transcription-polymerase chain reaction method, we examined the relationship between expression of CD44v9 mRNA and prognosis. RESULTS: In 60 out of 150 patients with colorectal cancer, expression of CD44v9 mRNA was positive in CTCs. In patients with stage III disease, the 5-year survival rate was 89% for patients with negative CD44v9 expression, whereas it was 52.4% in patients with positive expression (p<0.05). In patients with stage IV unresectable cancer, the 2-year survival rate was 70.1% in cases with CD44v9-negative expression and 33.3% in cases of positive expression (p<0.05). CONCLUSION: CD44v9 mRNA in the CTCs of colorectal cancer is useful as a factor predicting recurrence, prognosis, and treatment efficacy.

Protein-bound polysaccharide K reduced the invasive ability of colon cancer cell lines.

BACKGROUND/AIM: A protein-bound polysaccharide, polysaccharide K (PSK), is a non-specific immunological agent used in the treatment of colon cancer, however few studies have investigated the genetic changes in cancer cells treated with PSK. Therefore, we investigated the effect of PSK on cancer cell invasion, which is an indicator for the malignancy of colon cancer cell lines, and performed additional genetic analyses. MATERIALS AND METHODS: We performed Matrigel invasion assay to examine whether the invasive ability of colon cancer cell lines HT29, HCT116, and LoVo would be impacted upon stimulation with PSK. We used reverse transcription-polymerase chain reaction (RT-PCR) to evaluate for changes in the expression of matrix metalloproteinases (MMP)-2 and - 9 upon stimulation of colon cancer cell lines with PSK. RESULTS: The mean number of invasive cells in untreated HCT116, HT29, and LoVo cells was 146, 81, and 65, respectively, while that in PSK-treated cell lines was reduced to 24, 7, and 4, respectively. mRNA levels of MMP2 and MMP9 in PSK-stimulated cell lines were significantly lower than those in unstimulated cell lines. CONCLUSION: PSK reduced the expression of MMP2 and MMP9 mRNAs and cell invasion of this panel of colon cancer cell lines.