[Clinical pathways in oncology].

The diagnosis-related-group/prospective-payment system (DRG/PPS) was introduced into the health care system of the United States in 1983. This system triggered the development and implementation of clinical pathways aimed at reducing the length and cost of hospitalization. In Japan, trial use of a Japanese version of DRG/PPS was initiated in November 1998 in 10 hospitals under the control of the Ministry of Health and Welfare, and full-scale implementation of the system is expected in the near future. Clinical pathways, therefore, are a current focus of attention, mainly because of their success in enhancing management efficiency in the U.S. However, in actual clinical settings where clinical pathways are used, several Japanese health care providers have come to realize that they are also useful in improving staff coordination, patient satisfaction, and patient care, rather than simply reducing the length of hospital stay and cost of health care. The introduction of clinical pathways requires that treatment of the disease in question be defined and standardized. The implementation of pathways for the treatment of cancer, however, might prove difficult because of the high frequency of variation. In our experience, the main reason for the use of clinical pathways is not to reduce the number of variant cases but to provide high-quality care through the promotion of a team approach to treatment and enhanced patient care. Therefore, even if there were frequent variances following surgery for cancer, those occurring in accordance with the pathophysiological state of the patient would not interfere with management by clinical pathways. Clinical pathways are advantageous because they allow patients to know their treatment schedule; to prepare for hospitalization procedures; to have a better perspective on discharge; to reduce anxiety regarding hospital admission, even if it is the first time; to communicate better with doctors, nurses, and other medical care staff, leading to greater trust; and to improve their ability for self-management. These features are all important for the improvement of patient care. Furthermore, clinical pathways may lead to a situation in which the cost of hospitalization can be predicted prior to admission, enabling patients to compare differences between several hospitals. From our experience with gastric cancer, breast cancer, and esophageal cancer management, we consider clinical pathways to be of great benefit in helping to reform the current medical care system in regard to the management of cancer patients as well as patients with other diseases.

[Improving the anti-tumor activity of 5-fluorouracil by methotrexate].

The first clinical application of biochemical modulation (BCM) of 5-fluorouracil (5-FU) was the sequential MTX/5-FU regimen proposed in 1977 by Bertino for the treatment of colorectal cancer. In Japan, sequential MTX/5-FU therapy was mainly used as a new method of treating gastric cancer, and attracted a great deal of attention because it proved effective in many cases of advanced gastric cancer that had been unresponsive to the previous chemotherapy, particularly scirrhous gastric cancer with poor prognosis. Its therapeutic efficacy varied according to histologic type, it was effective in cases of peritoneal dissemination and disseminated intravascular coagulopathy (DIC), it was associated with fewer adverse effects, and it was a multidrug chemotherapy based on a clear rationale. With sequential MTX/5-FU therapy as a starting point, fundamental studies of BCM and its clinical applications have expanded rapidly in Japan. This paper provides an outline of sequential MTX/5-FU therapy from the aspects of its mechanism of action, indications, therapeutic efficacy, relevance to adjuvant therapy, counter-measures to adverse effects, and emergence of resistance to the drugs involved. The high therapeutic efficacy of this therapy in certain histologic types is also discussed, and its combined use with other forms of BCM, as in triple BCM (LV/5-FU + CDDP/5-FU + MTX/5-FU), is introduced.

Nerve fibres containing neuropeptide Y in the atrioventricular valves of Japanese monkey and rat; a light and electron microscopic study.

Dense distribution of varicose fibres containing neuropeptide Y-like immunoreactivity (NPY-LI) was found in the atrioventricular valves of the Japanese monkey, and moderately in the rat. The immunoelectron microscopy using immunogolds resulted in the localization of NPY-LI within the dense-cored vesicles which existed with the small clear vesicles in the unmyelinated axons near the endocardium. These NPY-LI-containing fibres may participate in regulation of vasomotor role or other functions of the atrioventricular valves.

[Dysplasia in ulcerative colitis detected by surveillance colonoscopy].

A total of 222 surveillance colonoscopies were performed in 84 patients with ulcerative colitis between 1979-1989. In 60 patients with total colitis, 3 carcinomas, 2 high-grade, 4 low-grade and 8 indefinite for dysplasia were found. In 24 with left-sided colitis, 1 low-grade and 1 indefinite for dysplasia were found. The overall incidence of dysplasia in patients with total colitis was 28%, similar to the reported incidence from the Western countries. A sequence of dysplasia development was recorded in 14 cases. Progression of dysplasia was found in some of the low-grade or indefinite cases, however regression was also recorded in another cases. These results suggest the usefulness of surveillance colonoscopy for early detection of carcinoma in long-standing ulcerative colitis.

Sialic acid histochemistry and the adenoma-carcinoma sequence in colorectum.

A change in sialic acid, notably loss of O acetyl substitution, was studied histochemically in a series of 93 colorectal adenomas that included 14 malignant polyps. Changes in sialic acid were uncommon in adenomas showing mild dysplasia but became increasingly common in moderately and severely dysplastic adenomas and were always present in carcinomatous areas. There was no correlation between a change in sialic acid and either size or villous architecture of benign adenomas. As mucin change often preceded the development of invasive cancer, it could not be used on its own to distinguish between epithelial displacement (pseudoinvasion) and malignant invasion. An abundant luminal accumulation of altered sialic acid in association with an epithelial lining that was non-mucin secreting, however, was specific for cancer. Conversely, the presence of unchanged intracellular or intraluminal O-acetyl sialic acid may help to exclude a diagnosis of malignancy in equivocal cases. The change is not specific for colorectal neoplasms and probably represents a metaplasia to a small intestinal phenotype.

Mucin abnormality of colonic mucosa in ulcerative colitis associated with carcinoma and/or dysplasia.

Twenty cases of resected specimens of carcinoma and/or dysplasia complicating ulcerative colitis were histochemically investigated by the periodic acid-thionein Schiff/potassium hydroxide/periodic acid-Schiff (PAT/KOH/PAS) staining method to see mucin characteristics of carcinoma, dysplasia, and the background mucosa of these lesions. As a control, 11 resected specimens of ulcerative colitis without dysplastic changes and 26 specimens of colonic carcinoma were examined also. All dysplasia and carcinoma in ulcerative colitis stained blue, whereas normal colonic mucin stained red in 65 percent. In 14 of 20 specimens with carcinoma and/or dysplasia, the background mucosa appeared normal with hematoxylin and eosin staining, but showed a mosaic staining pattern with PAT/KOH/PAS. However, only two of 11 specimens of ulcerative colitis without dysplasia and none of 26 specimens of flat mucosa with colorectal carcinoma showed a mosaic staining pattern. From these observations it was concluded that the PAT/KOH/PAS staining method could be useful as a histochemical marker of premalignant change in longstanding ulcerative colitis.

Multiple cavernous hemangiomas of the orbits.

Intraocular tumors were detected in both orbits simultaneously by computed tomography scanning in a 45-year-old woman complaining of proptosis of the right eye, decreased visual acuity, and diplopia. The tumor in the right orbit was resected by the subfrontal extradural approach, and that in the left orbit by the Krönlein-Berke method. The right tumor was found on the side of the external ear of the muscle cone and the left tumor was located inferiorly on the side of the external ear of the muscle cone. Both tumors were cavernous hemangiomas with identical macroscopic and histologic features.

Mucin abnormality in colonic mucosa in patients with familial polyposis coli.

Colonic mucosa of the left colon in 41 patients with familial polyposis coli (FPC) was stained by a periodic acid-thionin Schiff/potassium hydroxide/periodic acid-Schiff method in which the normal colonic mucosa usually stained red and carcinoma stained blue or purple. In FPC 82.9% stained blue or purple whereas 35.5% stained blue or purple in normal controls. The data suggest that sialomucin properties of the flat mucosa surrounding polyps in FPC are different from those of the normal colon and that this simple technique may be useful for the early detection of high-risk family members in the FPC family.

[Endoscopic diagnosis and management of colonic polyps].

Colonoscopic diagnosis of colonic polyps is a rather easy task, although some small polyps might be missed when they are situated around the steep angulation or behind the fold. A correct diagnosis of mucosal carcinoma is difficult not only by colonoscopy but also by biopsy because the cancer focus may be small or not exposed on the polyp surface. Therefore, colonoscopic polypectomy is the best procedure of choice for correct histologic diagnosis of mucosal and invasive carcinoma. Only by polypectomy can correct diagnosis of invasive carcinoma be made, although there are various endoscopic signs such as irregularity of the surface configuration and white spots on the surrounding mucosa suggesting invasive carcinoma. Over the course of several years experience of colonoscopy we have encountered small flat elevations under 1 cm in diameter of which 58% were benign adenomas and 42% contained minute foci of carcinoma. These small flat lesions might have been missed quite easily during routine examination in the past and they might play an important role in the pathogenesis of colonic carcinoma. Benign polyp and mucosal carcinoma can be adequately treated by polypectomy only, whereas invasive carcinoma needs further treatment as it has a risk of node metastasis. Risk factors influencing metastasis are lymphatic permeation, poorly differentiated carcinoma, massive invasion close to the cut end. Only when one of these findings is seen in the removed polyp, further surgical treatment must be considered. However, the patient's general condition, age and site of the polyp should be carefully taken into account in order to choose the appropriate treatment in each individual case as the risk of metastasis under such situations mentioned above is not so high. Management of invasive carcinoma is still a controversial issue and a long-term, clinicopathologic study will be needed to solve this question.

Small "flat adenoma" of the large bowel with special reference to its clinicopathologic features.

Thirty-three small "flat adenomas," not more than 1 cm in diameter, were collected from surgically and colonoscopically removed specimens, and their colonoscopic and histologic characteristics were described. There were 14 adenomas with mild atypia, five with moderate atypia, 14 with severe atypia (or focal carcinoma limited to the mucosa). The grade of atypia seems to increase with the size of lesions, and these lesions were assumed to play an important role in the adenoma-carcinoma sequence. The importance of recognizing the presence of these small "flat adenomas" in everyday practice is stressed.

Mucin abnormality of colonic mucosa in patients with familial polyposis coli. A new tool for early detection of the carrier?

Colonic mucosa in 62 patients with familial polyposis coli (FPC) was stained by a Periodic Acid-Thionin Schiff/Potassium Hydroxide/Periodic Acid-Schiff method in which the normal colonic mucosa usually stained red and carcinoma stained blue or purple. In FPC, 82.2 percent stained blue or purple, whereas 38.8 percent stained blue or purple in normal controls. The data suggest that sialomucin properties of the normal-appearing flat mucosa in FPC are different from those of the normal colon, and that this simple technique may be useful for the early detection of high-risk individuals in the FPC family.