Kiyoshi Tsukamoto

Successful Chemotherapeutic Modality of Doxorubicin Plus Dacarbazine for the Treatment of Desmoid Tumors in Association With Familial Adenomatous Polyposis

PURPOSE Desmoid tumors are locally aggressive and can be fatal in familial adenomatous polyposis (FAP) patients if they are not suitable for surgery or radiation therapy. Here, we prospectively investigated the efficacy of a chemotherapeutic regimen involving doxorubicin (DOX) and dacarbazine (DTIC) for inoperable FAP-associated desmoid tumors. PATIENTS AND METHODS From an initial group of 120 FAP patients, seven of the 11 individuals with symptomatic unresectable desmoid tumors that were unresponsive to conventional hormone therapy were enrolled onto this study. The general chemotherapy regimen comprised four or five cycles of DOX (20 mg/m2 daily) plus DTIC (150 mg/m2 daily) throughout 4 days of drip intravenous infusion (day 1 through 4) every 28 days, followed by the cyclooxygenase-2 inhibitor meloxicam (10 mg/m2). The primary end point was relapse-free survival. The secondary end points included toxicity, clinical improvement, and tumor regression according to computed tomography. RESULTS Significant tumor regression was observed clinically and radiologically in all seven patients. Three patients showed a complete response. The average progression-free survival period was 74.0 months (range, 32.5 to 107.5 months). Three patients showed grade 3 adverse events with no treatment-related mortality. All seven patients survived and remained without tumor progression. An adenomatous polyposis coli germline-mutation analysis revealed no mutations in the specified regions. CONCLUSION A chemotherapeutic regimen of DOX plus DTIC followed by meloxicam is an effective and safe treatment for FAP-associated desmoid tumors. This modality should be considered for use as first-line chemotherapy in symptomatic desmoid tumors that are unresponsive to conventional medical therapy, due to the absence of useful presymptomatic markers.

Endogenous acyl ghrelin is involved in mediating spontaneous phase III-like contractions of the rat stomach.

Abstract  In humans and dogs, it is known that motilin regulates phase III contractions of migrating motor complex (MMC) in the fasted state. In rats, however, motilin and its receptor have not been found, and administration of motilin failed to induce any phase III‐like contractions. Ghrelin was discovered as the endogenous ligand for the growth hormone secretagogue receptor (GHS‐R) from the rat stomach. Ghrelin promotes gastric premature phase III (phase III‐like contractions) in the fasted state in rats. We hypothesized that endogenous ghrelin regulates spontaneous phase III‐like contractions in rats. Strain gauge transducer was sutured on the antrum and a catheter was inserted into the jugular vein. We studied the effects of i.v. administration of ghrelin and a GHS‐R antagonist on gastric phase III‐like contractions in conscious rats. Plasma level of ghrelin was measured by a radioimmunoassay. Ghrelin augmented spontaneous phase III‐like contractions and a GHS‐R antagonist significantly attenuated the occurrence of spontaneous phase III‐like contractions. During the phase I period, plasma ghrelin level increased to its peak then returned to basal level, subsequently phase III‐like contractions were observed. These results suggest that endogenous ghrelin regulates gastric phase III‐like contractions in rats.

Ghrelin accelerates gastric emptying via early manifestation of antro-pyloric coordination in conscious rats

Ghrelin is known to enhance gastric motility and accelerate gastric emptying of liquid and solid food in rats. As solid gastric emptying is regulated by the coordinated motor pattern between the antrum and pylorus (antro-pyloric coordination), we studied the correlation between solid gastric emptying and antro-pyloric coordination in response to ghrelin. Rats were given 1.5 g of solid food after a 24-h fasting. Immediately after the ingestion, ghrelin (0.4-8.0 microg/kg) or saline was administered by intraperitoneal (i.p.) injection. Ninety minutes after the feeding, rats were euthanized and gastric content was removed to calculate gastric emptying. To evaluate the antro-pyloric coordination, strain gauge transducers were sutured on the antrum and pylorus. The incidence of postprandial antro-pyloric coordination was compared between ghrelin-and saline-injected rats. In saline-injected rats, gastric emptying was 58.3+/-3.7% (n=6). Ghrelin (4.0-8.0 microg/kg), accelerated gastric emptying. Maximum effect was obtained by ghrelin (4.0 microg/kg), which significantly accelerated gastric emptying to 77.4+/-3.7% (n=6, p<0.05). The number of antro-pyloric coordination 20-40 min after feeding was significantly increased in ghrelin-injected rats, compared to that of saline-injected rats (n=4, p<0.05). It is suggested that enhanced antro-pyloric coordination play an important role in accelerated solid gastric emptying induced by ghrelin.

Central glucagon like peptide-1 delays solid gastric emptying via central CRF and peripheral sympathetic pathway in rats.

It has been shown that glucagon like peptide-1 (GLP-1) acts on the central nervous system (CNS), in addition to its peripheral actions. Central administration of glucagon like peptide-1 (GLP-1) delays liquid gastric emptying via non-adrenergic, non-cholinergic neurons in rats. However, it remains unclear how central GLP-1 delays solid gastric emptying in rats. GLP-1 receptors at the CNS mediates the endocrine and anxiety responses to psychogenic and interoceptive stress. Corticotropin-releasing factor (CRF) is also known as a stress-related peptide, which delays gastric emptying of liquid and solid food via the autonomic nervous system. We have recently showed that central CRF delays solid gastric emptying via sympathetic pathways in rats. However, it remains unknown how central GLP-1 and CRF interact in mediating the inhibitory effect on solid gastric emptying. After a 24 h-fasting, GLP-1 was administered by intracisternal (ic)-injection immediately after the solid meal ingestion. Ninety minutes after the peptide injection, gastric contents were measured. Ic-injection of GLP-1 (30-3000 pmol) dose-dependently inhibited solid gastric emptying. Ic-injection of GLP-1 (3000 pmol)-induced delay of gastric emptying was partially antagonized by celiac ganglionectomy but not by atropine or N(G)-nitro-l-arginine methyl ester (L-NAME). Ic-injection of a CRF antagonist, astressin (2.8 nmol), partially antagonized GLP-1-induced delay of solid gastric emptying. These results indicate that central CRF and peripheral sympathetic pathway are, at least in part, involved in mediating central GLP-1-induced delay of solid gastric emptying in rats.

Glucagon like peptide-1 accelerates colonic transit via central CRF and peripheral vagal pathways in conscious rats

Glucagon like peptide-1 (7-36) (GLP-1), one of the gastrointestinal (GI) regulatory peptide, is known to act as a stress related brain neurotransmitter mediating GI function. Central administration of GLP-1 inhibits gastric emptying. However, little is known about the effect of central GLP-1 on colonic transit. Effects and mechanism of GLP-1 on colonic transit were investigated in conscious rats. Immediately after intracerebroventricular (icv)-injection of GLP-1, 51Cr was applied via the catheter positioned to the proximal colon. 90 min after 51Cr injection, rats were euthanized and the colon was removed and divided into 10 equal segments. The radioactivity of each segment was counted and the geometric center (GC) was calculated. Icv-injection of GLP-1 (0.3-3 nmol) dose-dependently accelerated colonic transit [(GC: 4.4+/-0.2 in controls, 7.8+/-0.5 in GLP-1 (3 nmol)]. In contrast, intraperitoneal (ip)-injection of GLP-1 (3 nmol) did not modify colonic transit. Icv-injection of GLP-1 (3 nmol)-induced acceleration of colonic transit was attenuated by vagotomy, atropine and hexamethonium, but not by guanethidine. Icv-injection of GLP-1 (3 nmol)-induced acceleration of colonic transit was abolished by corticotropin releasing factor (CRF) antagonist, astressin. Restraint stress-induced acceleration of colonic transit was abolished by a selective GLP-1 receptor antagonist, exendin. These results indicate that the endogenous GLP-1 is involved in mediating stress-induced alteration of colonic transit via a central CRF and peripheral cholinergic pathways in rats.

Projections to the alimentary canal from the dopaminergic neurons in the dorsal motor nucleus of the vagus of the rat

The motility of the alimentary canal is regulated not only by neurons that contain acetylcholine or adrenaline, but also by nonadrenergic noncholinergic neurons. There are many neurons containing dopamine in the dorsal motor nucleus of the vagus (DMV). We examined the projections of these dopaminergic neurons to the alimentary canal with double-labeling immunohistochemistry for tyrosine hydroxylase (TH) and the retrograde tracer cholera toxin subunit b following its injection into the subdiaphragmatic esophagus, the cardia, the pylorus, the duodenum, the jejunum, and the ascending colon. Almost all double-labeled neurons were found in the half of the DMV caudal to the area postrema. In the caudal half of the DMV, about 58% of the TH-immunoreactive neurons projected to the cardia, about 36% projected to the pylorus, and about 28% projected to the subdiaphragmatic esophagus. Only a few TH-immunoreactive neurons projected to the duodenum, the jejunum, or the ascending colon. As a whole, less than 10% of the neurons in the DMV that projected to the alimentary canal showed TH-like immunoreactivity. These results suggest that some of the dopaminergic neurons in the DMV might regulate the activities of the stomach and the subdiaphragmatic esophagus.

Metastatic lobular carcinoma of the breast masquerading as a primary rectal cancer

BackgroundColorectal metastasis of lobular carcinoma of the breast is a diagnostic challenge. It may macroscopically simulate primary colon cancer or inflammatory bowel disease. In some cases, the interval between the primary breast cancer and metastatic colorectal lesions is so long that the critical records for diagnosis including history might be lost or missed.Case presentationReported herein is a case of metastatic lobular carcinoma of the breast masquerading as a primary rectal cancer developed in a 62-year-old Japanese woman. The case initially presented as a circumferential rectal lesion, and information on the patient’s history of breast cancer was not noted. As the result of endoscopic biopsy, diagnosis of poorly differentiated rectal adenocarcinoma was made. The lesion was surgically resected after chemo-radiotherapy. Histopathological examination of the resected specimen with hematoxylin and eosin (HE) stain revealed a single-file arrangement of the tumor cells, reminiscent of lobular carcinoma of the breast. Immunohistochemical analysis revealed an immunophenotype consistent with lobular carcinoma of the breast. Because further review of the patient’s history revealed an occurrence of ‘poorly differentiated adenocarcinoma of the breast’, which she had experienced 24 years earlier, the final diagnosis of the lesion was made as rectal metastasis from lobular breast carcinoma.ConclusionsPoorly differentiated adenocarcinoma of the colorectum is rarer than that of the stomach. Linitis plastica-type cancer of the colorectum is also rarer than that of the stomach. A lesson from the present case is that before we conclude a linitis plastica-type cancer of poorly differentiated type as a primary colorectal cancer, it is critical to exclude a possibility of metastatic colorectal cancer.

Postoperative enteroenteric intussusception in patients with Crohn’s disease: Report of two cases

Postoperative enteroenteric intussusception is a rare complication in adult patients with Crohn’s disease. We treated two patients with Crohn’s disease accompanied by an ileal obstruction, each of whom underwent an elective resection. In both, the upper left quadrant of the abdoment became progressively distended following ileocecal resection and each required surgical treatment after diagnosis of postoperative enteroenteric intussusception by abdominal computed tomography scanning, as the intussusception could not be reduced by conservative treatment. There were no Crohn’s lesions found in the intussuscepted specimens, and the condition was thought to have been caused by a segment of thickened and fibrotic intestine that had developed because of long-standing bowel dilatation from obstructive Crohn’s lesions. In one of the patients, the intussusceptum was irreducibly incarcerated and required a resection, whereas it was able to be manually reduced in the other.

Management strategies in Lynch syndrome and familial adenomatous polyposis: a national healthcare survey in Japan.

Lynch syndrome (LS) and familial adenomatous polyposis (FAP) are major sources of hereditary colorectal cancer (CRC) and are associated with other malignancies. There is some heterogeneity in management strategies in Japan. We undertook a survey of management of hereditary CRC in hospitals that are members of the Japan Society of Colorectal Cancer Research. One hundred and ninety departments responded, of which 127 were from designated cancer care hospitals (DCCHs) according to the Japanese government. There were 25 488 operations for CRC in these departments in 2015. The DCCHs performed better with regard to usage of Japan Society of Colorectal Cancer Research guidelines, referring new CRC patients for LS screening, and having in‐house genetic counselors and knowledge of treatment for LS. There were 174 patients diagnosed with LS and 602 undergoing follow‐up in 2011–2015, which is fewer than the number expected from CRC operations in 2015. These numbers were not affected by whether the institution was a DCCH. Universal screening for LS was carried out in 8% of the departments. In contrast, 541 patients were diagnosed with FAP and 273 received preventive proctocolectomy/colectomy in 2011–2015. The DCCH departments undertook more surgery than non‐DCCH departments, although most of the management, including surgical procedures and use of non‐steroidal anti‐inflammatory drugs, was similar. Management of desmoid tumor in the abdominal cavity differed according to the number of patients treated. In conclusion, there was heterogeneity in management of LS but not FAP. Most patients with LS may be overlooked and universal screening for LS is not common in Japan.

Evaluation of appropriate follow-up after curative surgery for patients with colorectal cancer using time to recurrence and survival after recurrence: a retrospective multicenter study

Introduction The follow-up schedule for colorectal cancer patients after curative surgery is inconsistent among the guidelines. Evaluation of time to recurrence (TTR) and survival after recurrence (SAR) may provide evidence for appropriate follow-up. Methods We assessed 3039 colon cancer (CC) and 1953 rectal cancer (RC) patients who underwent curative surgery between 2007 and 2008. We evaluated the pre- and post-recurrent clinicopathological factors associated with TTR and SAR in each stage of CC and RC. Results The recurrence rates of stages I, II, and III were 1.2%, 13.1%, and 26.3%, respectively, for CC, and 8.4%, 20.0%, and 30.4%, respectively, for RC. In CC patients, high carcinoembryonic antigen (CEA) level and lymphovascular invasion were independent predictors of short TTR. In RC patients, metastatic factors (liver metastasis in stage III) and venous invasion (stage III) were independent predictors of short TTR. The prognostic factors of SAR were age (stage II CC and stage III RC), female gender (stage III RC), high CEA level (stage II RC), histological type (stage III CRC), nodal status (stage III CC), recurrence within 1 year (stage III RC), M1b recurrence (stage II CRC), local recurrence (stage II CC), and no surgical resection after recurrence (stage II and III CRC). Conclusions The follow-up schedule for stage I should be different from that for the other stages. We recommend that intensive follow-up is appropriate in stage III CC patients with undifferentiated adenocarcinoma or N2 nodal status, stage II RC patients with high preoperative CEA level, and stage III RC patients.