[Analysis of KRAS status in cancer tissue with submucosal or deeper invasion in patients with familial adenomatous polyposis].

The KRAS status in cancer tissue with submucosal or deeper invasion was investigated in patients with familial adenomatous polyposis (FAP). Fifteen cancerous lesions in 10 FAP patients were subjected to analysis for KRAS status. The clinical features of FAP were the dense type in 2 patients and the sparse type in 8 patients. Of the 15 cancerous lesions, 6 (40%) were identified as having wild-type KRAS and the remaining 9 (60%), as having mutated KRAS. Of the 9 mutated lesions, the G13D mutation was recognized in 4 patients and was the most frequent pattern. With regard to the KRAS status in patients with multiple cancerous lesions, 1 patient had 3 cancerous lesions of which 2 were of the mutated type and 1 was of the wild type and another patient had 4 cancerous lesions of which 3 were of the mutated type and 1 was of the wild type. These results suggest that the frequency of wild-type KRAS in cancer associated with FAP was approximately 40%, although it was lower than that in sporadic cancer. Moreover, we need to analyze the KRAS status in all cancerous lesions in clinical practice when chemotherapy with anti-epidermal growth factor receptor (EGFR) antibody is required for the treatment of FAP patients with unresectable advanced multiple cancers.

[Strategy for surgery in familial adenomatous polyposis patients with invasive colorectal cancer].

PURPOSE: Total proctocolectomy with ileal pouch-anal anastomosis (IPAA) has been established as the standard operative procedure for classic familial adenomatous polyposis( FAP). However, it is unclear which type of surgery should be undertaken for FAP patients with invasive colorectal cancer in clinical practice. This study evaluated the outcome of different surgeries performed in FAP patients with invasive colorectal cancer. PATIENTS AND METHODS: The study included 21 classic FAP patients with or without invasive colorectal cancer, who underwent proctocolectomy at our institute between 2000 and 2013. Patient background, type of operation, and prognosis were retrospectively examined. RESULTS: In the non-invasive cancer group, total proctocolectomy with IPAA was performed in 7 patients, and colectomy with ileorectal anastomosis (IRA) was performed in 5 patients. Conversely, in the invasive cancer group, IPAA, proctocolectomy with end ileostomy (TPC), and IRA were performed in 2, 2, and 5 patients, respectively. Overall survival did not differ significantly between the 2 groups( 5 year survival, 88.9% vs 75.0%, p=0.48). CONCLUSION: These results suggest that IPAA, IRA, or TPC might contribute to survival time prolongation in patients with invasive colorectal cancer, as is the case for those without invasive colorectal cancer.

[Effect of chemotherapy in primary tumor of MSI-H colon cancer aged 50 years or younger].

Microsatellite instability( MSI) in colorectal carcinoma is reportedly associated with resistance to 5-fluorouracil-based chemotherapy. Moreover, colorectal cancer patients aged ≤ 50 years could potentially have Lynch syndrome. In the present study, we examined 11 colorectal cancer patients with unresectable Stage IV disease who underwent resection of the primary tumor between January 2006 and December 2012. The relationship between the MSI status and the efficacy of first- line oxaliplatin-based chemotherapy was retrospectively examined. The MSI status included MSI-H in 1 patient, MSS-L in 2 patients, and MSS in 8 patients. The MSI-H in 1 patient was associated with familial adenomatous polyposis. Following chemotherapy, among 8 MSS patients, 3 showed stable disease (SD) and 1 showed partial response (PR). Moreover 2 MSH-L patients and 1 MSI-H patient showed progressive disease (PD) after chemotherapy. However, additional data collection is required to determine the effect of oxaliplatin-based chemotherapy for MSS-H or MSS-L colorectal patients aged ≤ 59 years.

[Intra-arterial infusion chemotherapy for advanced breast cancer--5 cases of marked response].

In order to obtain less severe toxic reactions, while attaining maximal therapeutic effects, CPA, 5-FU and ADM or EPI have been administered through the catheter inserted into the internal thoracic artery with the IVR technique and the implantable infusion port system. Of the 181 patients with the unresectable or recurrent breast cancers attempted with intra- arterial infusion chemotherapy for the past 19 years, more than half of the patients showed a good response to this modality of the chemotherapy. In 4 out of the 5 patients with unresectable breast cancer, radical mastectomy became feasible following the marked response with the intra-arterial infusion chemotherapy. However, a distant metastasis proved to be a limiting factor for improvement of survival.

[Switching to direct intrahepatic arterial infusion of 5-FU after a progression of liver metastases from colorectal carcinoma treated with systemic infusion of FOLFOX].

Direct intrahepatic arterial infusion of 5-FU produced a significantly higher response rate than systemic infusion of FOLFOX in the treatment of hepatic metastases from colorectal carcinoma. Fourteen patients switched over from systemic FOLFOX therapy to intrahepatic protracted 5-FU infusion after a progression of liver metastases treated with systemic therapy. Of the 14 patients whose tumors had initially failed to respond to systemic FOLFOX therapy, 12 (85%) had a partial response, and 13 (93%) had a reduction in their tumor marker (CEA, CA19-9, TPA) when the treatment was switched to intrahepatic 5-FU therapy. Traditional chemotherapy toxicity, such as myelosuppression, nausea, vomiting and neurotoxicity did not occur in the intrahepatic group. Three out of 14 patients survived more than a year, and the longest was 18 months. A better survival rate can be achieved with the use of hepatic artery infusion therapy.

Primary diffuse large B-cell lymphoma of the breast.

Diffuse large B cell lymphoma (DLBL) of the breast is a rare subtype of breast tumor, the diagnosis of which is based on the cytological and histopathological features of this unique neoplasm. A 28-year-old woman noticed a mass in her right breast. It could not be definitely diagnosed clinically by diagnostic imaging (mammography, ultrasonography), so malignant tumor not otherwise specified was diagnosed. Fine-needle aspiration cytology (FNAC) suggested that it was malignant lymphoma; however it was difficult to distinguish from reactive lymphocytes. Excisional biopsy of the breast mass suggested malignant lymphoma. Based on the diagnosis of malignant lymphoma by FNAC and excisional biopsy, lumpectomy was performed and DLBL was diagnosed histologically according to the World Health Organization classification. DLBL is difficult to distinguish from other types of malignant lymphoma by routine immunohistochemical evaluation. Some previous studies have showed that the octamer-binding transcription factor 2 (Oct2) and coactivator B-cell Oct-binding protein 1 (BOB.1) and the pan-B-cell markers CD20 and CD79a may aid in the diagnosis of malignant lymphoma. In our case, the staining of large atypical lymphocytes for CD20, CD79a, BOB.1 and Oct2 was strongly positive and supports the notion that BOB.1 and Oct2 are also useful immunohistochemical markers for DLBL of the breast.

Expression of E-cadherin, alpha-catenin, and beta-catenin in tubulolobular carcinoma of the breast.

Tubulolobular carcinoma (TLC) of the breast is a rare subtype of breast carcinoma categorized by Fisher et al. (Hum Pathol 8:679-683, 1977) as a tubular variant of lobular carcinoma. E-cadherin is a transmembrane glycoprotein, and complete loss of E-cadherin expression has been observed in invasive lobular carcinoma. Ductal carcinoma retains at least some expression of E-cadherin. Moreover, the adhesive function of E-cadherin is dependent on the integrity of the catenin components, which link E-cadherin to the actin filaments. In order to achieve improved categorization of TLC, we decided to investigate both E-cadherin and the catenins in TLCs and invasive lobular carcinomas. We reviewed all 1,430 cases of primary breast carcinoma that were surgically resected at Saitama Medical Center, Saitama Medical School, and at Saitama Red Cross Hospital between 1990 and 2005. Among these, 16 cases of TLC were reported retrospectively. The results were compared with those of 20 cases of invasive lobular carcinomas that were included as controls. Tumor tissue was immunostained for E-cadherin, alpha-catenin, and beta-catenin. The presence of immunoreactivity in the TLC was seen in 12 (75%) cases for E-cadherin, in 8 (50%) cases for alpha-catenin, and in 10 (62.5%) cases for beta-catenin. However, plasma-membrane-associated staining for E-cadherin, alpha-catenin, and beta-catenin was completely absent in invasive lobular carcinomas. These results suggest the possibility that TLCs are not a variant of lobular carcinoma, but rather ductal carcinomas with a lobular growth pattern.

APC gene mutations in a jejunal adenoma causing intussusception in a patient with familial adenomatous polyposis.

Adenomatous polyps of the jejunum/ileum in patients with familial adenomatous polyposis (FAP) are usually small (<5 mm) and are considered to be of little clinical importance. Genetic alterations in these polyps have not previously been analyzed. We herein report an extremely rare case of FAP presenting with intussusception caused by jejunal adenomas. Both somatic and germline mutations of the APC gene were detected in one of the polyps. A 40-year-old man with FAP was admitted for closure of an ileostomy that had been created because of an anastomotic leak after subtotal proctocolectomy with ileo-anal-canal anastomosis. During the follow-up after that surgery, he had occasionally complained of colicky abdominal pain, but it had quickly subsided. At the second laparotomy, for closure of the ileostomy, jejuno-jejunal intussusception was incidentally found, and segmental resection of the jejunum, including the leading point of the intussusception, was performed. There were five polyps clustered in the resected jejunum. Histologically, the polyps, ranging from 5 to 26 mm in diameter, were adenomas with moderate to severe atypia. Genetic examinations of one of the largest polyps, using polymerase chain reaction single-strand conformation polymorphism (PCR-SSCP) and direct sequencing methods, revealed somatic (T insertion at codon 1557) and germline mutations (4 base-pair deletion at codons 181-182) of the APC gene. This is the first evidence that the coexistence of somatic and germline alterations in the APC gene is involved in the development of a jejunal adenoma causing small-bowel intussusception.

[Evaluation of liver metastasis of colorectal cancer following hepatic arterial infusion with degradable starch microspheres and adriamycin, mitomycin C as seen in changes in CEA at early stage of therapy].

OBJECTIVE: Recently, for the treatment of unresectable colorectal cancer with liver metastasis, hepatic artery injection of anticancer drugs suspended in degradable starch microspheres (DSM) is being performed. To predict its effectiveness, we did a retrospective study to see whether or not changes in CEA at early stages of therapy are significant. SUBJECTS AND METHOD: The subjects were 16 patients with unresectable colorectal cancer with liver metastasis (H3) who had undergone DSM therapy at least three times (mean age 65, male to female ratio of 10:6, 6 cases of synchronous metastasis and 10 cases of metachronous metastasis). Adriamycin (ADM) 30 mg and mitomycin C (MMC) 10 mg were suspended in 600 mg of DSM and injected into the common hepatic artery until embolization of the vessel was recognized (once/3-4 weeks). We examined the changes in CEA level (doubling time or half time) and the time to progression (TTP) of CEA after the third DSM treatment. RESULTS: Of the 16 patients, 4 (25%) showed rise in CEA, of which 3 died within a year. In the 12 cases with decreased CEA, the half time was 20-526 days (mean of 80 days). When the TTP of CEA was compared for the group with CEA half time less than 80 days (n = 6) to those with more then 80 days (n = 6), the TTP was significantly longer in the group with half time less than 80 days (p = 0.02 logrank test). CONCLUSION: To evaluate the effectiveness of DSM therapy, it is important to examine the changes in CEA at the early stages of treatment.

[Audit of the safety of hepatic arterial infusion of degradable starch microspheres (DSM). Adriamycin (ADM).mitomycin C (MMC) on aged patients with liver metastases of colorectal cancer].

The purpose of this study was to clarify the safety of hepatic arterial infusion of degradable starch microspheres (DSM).adriamycin (ADM).mitomycin C (MMC) on aged patients with liver metastases of colorectal cancer. A total of 19 patients who received this therapy (DSM: 600 mg or less, ADM: 30 mg, and MMC: 10 mg) three times or more every three weeks were included. Changes in laboratory data and frequency of the occurrence of the adverse effects were compared between patients aged 75 (n = 5) or more and those aged 74 or less (n = 14). There were no significant differences in changes in the leukocyte counts, AST, ALT, and c-reactive protein levels between the groups. The frequency of adverse effects also was not different between the groups. These results suggests that this therapy is feasible with acceptable safety even in patients aged 75 years or more.

[Relationship between effectiveness of hepatic artery injection chemotherapy and serum VEGF].

Elevated plasma VEGF levels were reported in patients with colorectal cancer. This report presents regarding VEGF in patients who underwent hepatic artery injection chemotherapy (TAI) for liver metastasis of colorectal cancers. Thirty patients who underwent TAI for liver metastases of colorectal cancer during January 2002 to March 2003 were studied. Their serum CEA, CA19-9, and plasma VEGF were measured, and the relationships between these, their doubling times (DT) and therapeutic efficacy were examined. While the detected values and DTs were not considered significant, the tendency for DT to be the same was observed. One case with negative CEA and CA19-9 had high VEGF but negative VEGF-DT, which is compatible with therapeutic effects (PR). It appears that VEGF is a parameter that changes without direct correlation to CEA or CA19-9, and that VEGF may possibly be used as a therapeutic marker for cases with negative CEA or CA19-9.

[A case of liver metastasis of rectal cancer demonstrating complete response to 5-FU + Leucovorin + UFT].

Dihydropyrimidine dehydrogenase (DPD) is a rate-limiting enzyme that metabolizes 5-fluorouracil (5-FU). We report a patient with metachronous liver metastasis from rectal cancer with low expression of DPD, who demonstrated complete response to chemotherapy comprising 5-FU, Leucovorin, and UFT. A 53-year-old man underwent macroscopically curative proctectomy with coloanal anastomosis for lower rectal cancer (Curability B). The DPD level in the primary tumor determined by an enzyme-linked immunosorbent assay was extremely low (10.3 U/mg.protein). Three months postoperatively, 5-FU (333 mg/m2) + Leucovorin (200 mg/m2) therapy (once a week for 3 weeks with a one-week rest interval, repeatedly) was started as an adjuvant therapy. However, computed tomography demonstrated a solitary liver metastasis 3 cm in size 1 month later. Chemotherapy was continued with dose escalation of 5-FU (500 mg/m2) and with oral administration of UFT-E (400 mg/body, daily). Five months later, computed tomography did not detect the liver metastasis, and this finding was maintained for two months (complete response). This case provides evidence that a low expression of DPD in the primary lesion is related to a favorable response of liver metastasis to 5-FU-based systemic chemotherapy.

[Usefulness of F-18-fluorodeoxyglucose positron emission tomography for evaluating the efficacy of transient hepatic arterial chemoembolization for liver metastases of rectal cancer--a case report].

It is pointed out that there can be a discrepancy between the effect diagnosed by radiographic imaging and that by histological examination, when we treat patients with liver metastases of colorectal cancer by a transient hepatic arterial chemoembolization. We report a case of liver metastases of rectal cancer in which F-18-fluorodeoxyglucose positron emission tomography (FDG-PET) was useful for evaluating the therapeutic efficacy for transient hepatic arterial chemoembolization. A 58-year-old man with synchronous liver metastases (H2) of rectal cancer underwent a low anterior resection, a partial hepatectomy, cholecystectomy, and ligation of the gastroduodenal artery. After these operations, the patient received 6 hepatic arterial injections with degradable starch microspheres (300-600 mg), adriamycin (30 mg), and mitomycin C (10 mg) for the remaining metastatic lesion (S7). Although abdominal CT scan revealed a partial response, FDG-PET did not show any abnormal deposits. Hepatic posterior segmentectomy was performed 7 months after the first operation. Histological examination did not show any viable tumor cells in the resected specimen.

[Histological examination of the effect of hepatic arterial infusion of degradable starch microspheres mixed with adriamycin and mitomycin C for liver metastases of colorectal cancer--second report].

We histologically examined the effect of hepatic arterial infusion of degradable starch microspheres mixed with adriamycin and mitomycin C (DSM therapy) for liver metastases of colorectal cancer. The subjects were 15 liver metastatic lesions from 9 patients with colorectal cancer who underwent potentially curative hepatectomy after DSM therapy. Ages were ranged from 36 to 71 years old (mean, 57). The ratio of male to female was 4 to 5. Six patients had synchronous lesion(s). A single injection dosage of the DSM therapy was comprised of 300-600 mg degradable starch microspheres, 30 mg ADM, and 10 mg MMC. Three lesions from the two patients who were given a single DSM therapy did not show any radiographical changes. In addition, histological examination of these lesions demonstrated a grade 1 effect. The radiographical effect of the 12 lesions from the 7 patients, who were given the DSM therapy at least three times, showed SD in 4 lesions, PR in 6 lesions, and PD in two lesions. Histological examination of these lesions demonstrated Grade 2 in 4 lesions and Grade 3 in 5 lesions. In conclusion, it was histologically confirmed that a repeated DSM therapy could cause satisfactory effects beyond expectations by radiographic imaging in patients with liver metastases of colorectal cancer.

[Hepatic recurrence after prophylactic hepatic arterial infusion of 5-fluorouracil for Dukes' C colorectal cancer--correlation with the expression of dihydropyrimidine dehydrogenase in the primary tumor].

PURPOSE: The purpose of this study was twofold: (1) to disclose the intermediate outcome of a non-randomized trial of prophylactic hepatic arterial infusion chemotherapy (PHAI) for curatively resected Dukes' C colorectal cancer performed between November 1996 and April 2000, and (2) to examine the relationship between the expression of dihydropyrimidine dehydrogenase (DPD) in tumor tissue and the efficacy of this chemotherapy. PATIENTS AND METHODS: The oncological outcomes were compared between patients (n = 28) receiving PHAI (5-FU: 500 mg/body/w x 50 cycles) plus oral administration of UFT-E (400 mg/body/day, for 24 months) and those (n = 21) receiving UFT-E alone. The levels of tumoral DPD were determined in a total of 43 patients (n = 25, PHAI group; n = 18, control group) by an enzyme-linked immunosorbent assay. RESULTS: Seven (25%) in the PHAI group and four (19%) in the control group developed liver metastasis postoperatively. The liver metastasis-free survival was not different between the groups (p = 0.94). When the analysis was restricted to patients who developed liver metastasis, the duration from surgery to detecting liver metastasis tended to be longer in the PHAI group (p = 0.09). In addition, the overall survival tended to be better in the PHAI group (p = 0.12). In the control group, the level of DPD was higher in patients who developed liver metastases (n = 4) than in those who did not (n = 14, p = 0.04). However, in the PHAI group, the level of DPD was not different regardless of the occurrence of liver metastases (p = 0.30). CONCLUSIONS: These results suggest that (1) PHAI is unlikely to improve the prognosis of Dukes' C patients remarkably, and (2) the efficacy of this regimen cannot be predicted by determining the levels of tumoral DPD.

[Efficacy of hepatic arterial infusion of adriamycin and mitomycin C mixed with degradable starch microspheres for liver metastasis of colorectal cancer--correlation with the mRNA expression of DNA topoisomerase-IIalpha and glutathione-S transferase-pi in primary lesions].

DNA topoisomerase-IIalpha (topo-IIalpha) is a target enzyme of adriamycin (ADM). Glutathione-S-transferase-pi is known to be correlated with the resistance of various anticancer drugs including mitomycin C (MMC) and ADM. Expression levels of topo-IIalpha and GST-pi mRNA of primary colorectal lesions were semi-quantitatively determined by the RT-PCR method in 22 patients with colorectal cancer, who underwent hepatic arterial infusion of ADM and MMC mixed with degradable starch microspheres for synchronous (n=17) or metachronous (n=5) liver metastasis. Expression of topo-IIalpha mRNA/beta-actin mRNA was 0.872+/-0.564 (mean+/-SD) in responders (PR, n=10) and 0.369+/-0.133 in non-responders (SD+PD, n=12) (p=0.047). The relative expression of GST-pi was 0.638+/-0.593 in responders and 1.014+/-0.682 in non-responders (p=0.22). These results suggest that determining the mRNA expression of topo-IIalpha is useful for predicting the efficacy for this regimen, whereas determining the mRNA expression of GST-pi is not.

[Results of prophylactic hepatic arterial chemotherapy for liver metastases of Dukes C colorectal cancer--correlation with tumoral expression of dihydropyrimidine dehydrogenase, thymidylate synthase, p53, or orotate phosphoribosyl transferase].

The purpose of this study was (1) to disclose data from a non-randomized trial of prophylactic hepatic arterial chemotherapy for liver metastases from Dukes'C colorectal cancer, (2) to examine the influence of the expression of dihydropyrimidine dehydrogenase (DPD), thymidylate synthase (TS), and p53 in the primary lesion on this chemotherapy, and (3) to examine the expression of orotate phosphoribosyl transferase (OPRT) mRNA levels in the cases of recurrence included in this study. Patients who underwent curative resection of Dukes'C colorectal cancer between November 1996 and April 2000 were examined. After curative resection, patients were non-randomly divided into two groups after obtaining their informed consent: Hepatic arterial infusion (HAI) group patients (n = 28) were given 5-FU (500 mg/body for 1 h per week, repeated 50 times) via the hepatic artery and peroral UFT-E after resection of Dukes'C colorectal cancer. Control group patients (n = 21) received UFT-E alone. Liver metastasis-free survival did not differ between the groups. Immunohistochemical examinations revealed that the expression of tumoral DPD or p53 was unlikely to affect the hepatic recurrence, although patients with a low expression of TS tended to have better survival in both groups. However, multivariate analysis by the Cox proportional hazard model revealed that a significant prognostic factor influencing the hepatic recurrence is extensive venous invasion. Expression levels of OPRT mRNA, measured in tumors of patients with recurrence (n = 6 for the HAI group; and n = 4 for the control group) were not significantly different between the groups. These results suggest that (1) intermittent hepatic arterial infusion of 5-FU in addition to oral UFT-E was not more useful than administration of UFT alone, and (2) the expression of DPD, TS, p53, and OPRT in the primary lesion was unlikely to affect the prognosis of patients included in this study.

Clinical and pathologic features of fibroadenoma of the mastopathic type.

PURPOSE: Fibroadenoma with mastopathic change (FAM) is a relatively uncommon subtype of fibroadenoma of the breast, with a high incidence of pathological misdiagnosis. This histological subtype remains poorly understood because of its rarity. Many questions remain unanswered about its clinicopathological importance, especially in the differential diagnosis of breast cancers. METHODS: Among 218 breast fibroadenomas surgically resected as excisional biopsies at our institute between 1990 and 2004, 19 were pathologically diagnosed as FAM. We reviewed these 19 patients. RESULTS: The ages of the patients ranged from 20 to 51 years (mean 36.8 years). The tumor sizes ranged from 0.8 to 7 cm (mean 2.1 cm). Six of the 19 patients underwent core needle biopsy, resulting in a diagnosis of fibroadenoma in four patients and atypical ductal hyperplasia in two patients. Ultrasonography showed findings suggestive of solid tubular carcinoma in seven patients, fibroadenoma in ten patients, and unspecific malignant tumors in two. They were not specified clinically. CONCLUSION: Recognition of this distinctive variant of fibroadenoma is important because it resembles intraductal carcinoma and is increasing in incidence. It is crucial to distinguish FAM from intraductal carcinoma in biopsy specimens. Thus, not only pathologists but also clinicians must be able to recognize this type of fibroadenoma, and cooperate closely to establish an accurate diagnosis.