Takahiro Tsujimura

A non-peptide CCR5 antagonist inhibits collagen-induced arthritis by modulating T cell migration without affecting anti-collagen T cell responses

The chemokine receptors CCR5 and CXCR3 have been implicated as playing a central role in directing a Th1 inflammatory response. Here, we investigated whether a synthetic CCR5 antagonist affects the process of T cell migration to sites of inflammation. Immunization of DBA/1 mice with type II collagen resulted in typical arthritis, which is associated with cellular infiltration. Treatment with a CCR5 antagonist strikingly affected the development of arthritis by reducing both incidence and severity of disease. There was no substantial difference between collagen‐immunized mice with and without antagonist treatment in the induction of anti‐collagen T cell responses and the capacity to produce IL‐12. This endogenous IL‐12 functioned to induce comparable levels of CCR5 in these two immunized groups of T cells. Whereas a massive infiltration of inflammatory cells including CCR5+ T cells occurred in the joints of mice immunized without antagonist, cellular infiltration in the antagonist‐treated group was only marginal. These results indicate that administration of a CCR5 antagonist inhibits the development of arthritis not by affecting the generation of collagen‐sensitized T cells but by interfering with their migration to joint lesions.

IL-12-induced tumor regression correlates with in situ activity of IFN-gamma produced by tumor-infiltrating cells and its secondary induction of anti-tumor pathways.

Administration of recombinant interleukin‐12 (rIL‐12) into CSA1M fibrosarcoma‐bearing mice results in complete regression of growing tumors. This tumor regression is associated with massive lymphoid cell infiltration to tumor sites and is completely blocked by injection of anti‐interferon‐γ (IFN‐γ) monoclonal antibody (mAb). We investigated whether anti‐IFN‐γ mAb exerts its suppressive effect on tumor regression by blocking the IL‐12‐induced lymphoid cell migration to tumor sites or by inhibiting the secondary effects of IFN‐γ produced by infiltrating cells. Injection of anti‐IFN‐γ mAb to CSA1M‐bearing mice before IL‐12 treatment prevented the induction of tumor regression, whereas this treatment affected only marginally the infiltration of lymphoid cells to tumor masses. In accordance with this, IFN‐γ mRNA was expressed inside tumor masses by infiltrating cells after IL‐12 therapy irrespective of whether anti‐IFN‐γ mAb was injected. However, anti‐IFN‐γ mAb treatment almost completely abrogated the in situ expression of inducible nitric oxide synthase (iNOS) as well as IFN‐inducible protein‐10 (IP‐10) genes as examples of IFN‐γ‐inducible genes. Immunohistochemical analyses also revealed that the expression of iNOS protein was completely inhibited by anti‐IFN‐γ injection. These results suggest that the implementation of in situ IFN‐γ activity and its secondary induction of antitumor pathways such as iNOS and IP‐10 expression are important processes in the IL‐12‐induced tumor regression. J. Leukoc. Biol. 62: 450–457; 1997.

Tumor vaccination that enhances antitumor T-cell responses does not inhibit the growth of established tumors even in combination with interleukin-12 treatment: the importance of inducing intratumoral T-cell migration.

Interleukin-12 (IL-12) treatment is effective in the CSA1M but not in the Meth A and CSA1M-variant tumor models. The authors investigated the cause by which IL-12 treatment fails to induce tumor regression in these two tumor models. T cells from CSA1M-bearing mice have high levels of IL-12 responsiveness, whereas cells from Meth A–bearing mice display marginal levels of responsiveness. Because IL-12 responsiveness in T cells is induced after T-cell receptor stimulation, the lack of IL-12 responsiveness suggests that T cells in Meth A–bearing mice are not sensitized to Meth A tumor antigen. Immunization of normal mice with attenuated Meth A tumor cells resulted in a protective immunity, as shown by the rejection of challenged viable Meth A cells. Such an immunization, when performed in Meth A–bearing mice, induced potent IL-12 responsiveness in T cells. Nevertheless, IL-12 treatment in these mice did not inhibit tumor growth. In another IL-12–incurable (CSA1M-variant) model, IL-12 responsiveness was observed before tumor cell immunization. However, IL-12 treatment was ineffective regardless of whether tumor cell immunization was performed. In these two models, the failure of IL-12 treatment to induce tumor regression was associated with the lack of T-cell migration to tumor sites. These results indicate that the sensitization of T cells to tumor antigens and generation of IL-12 responsiveness are insufficient to induce tumor regression when these sensitized T cells are not allowed to migrate to tumor sites.

INCIDENCE OF PROSTATIC INTRA-EPITHELIAL NEOPLASIA IN OSAKA, JAPAN

High‐grade prostatic intra‐epithelial neoplasia (HGPIN) is the most likely precancerous lesion for prostatic carcinoma. A high incidence of its association with cancer has been reported in Western countries. On the other hand, information regarding its incidence is limited in Japan, where the mortality due to prostate cancer is much lower. We reviewed 53 clinical stage T2 or T3 prostatic cancers of Japanese patients living in Osaka, Japan (mean age, 67.2 years). These cases were subdivided into a pre‐operatively non‐castrated group (34 cases) and a medically or surgically castrated group (19 cases). HGPIN was found in 27 cases. The incidence of HGPIN was significantly lower in the castrated group (21.0%) compared with the non‐castrated group (67.6%). In the non‐castrated group, patient age, pathological stage, Gleason score, tumor size and serum prostate‐specific antigen showed no significant correlation with HGPIN. Advanced pathological stage and tumor size tended to decrease the incidence of HGPIN, although this was not statistically significant. When the study group was limited to stage T2 tumors of the non‐castrated group, the incidence of HGPIN was 81.0%. HGPIN in Japan may also be clinically and etiologically significant as a precursor of clinical cancer. Int. J. Cancer 73:808–811, 1997.

Anti-HER-2/neu immune responses are induced before the development of clinical tumors but declined following tumorigenesis in HER-2/neu transgenic mice.

HER-2/neu oncogene products have been implicated as a potential target of T cell–mediated immune responses to HER-2/neu–induced tumors. Using HER-2/neu transgenic mice (oncomice), we investigated whether, and if so how, anti–HER-2/neu immune responses are induced and modulated in these oncomice from birth to tumor initiation. Female oncomice carrying the activated HER-2/neu oncogene displayed apparent hyperplasia in mammary glands at 10 weeks of age and developed mammary carcinomas around an average age of 26 weeks. Unfractionated spleen cells from 10- to 15-week-old oncomice that were cultured without any exogenous stimuli exhibited cytotoxicity against the F31 tumor cell line established from an HER-2/neu–induced mammary carcinoma mass. The final antitumor effectors were a macrophage lineage of cells. However, this effector population was activated, depending on the stimulation of oncomouse CD4+ T cells with oncomouse-derived antigen-presenting cell (APC) alone or with wild-type mouse APC in the presence of F31 membrane fractions, suggesting the presence of HER-2/neu–primed CD4+ T cells and HER-2/neu–presenting APC in 10- to 15-week-old oncomice. These antitumor cytotoxic responses were detected at ∼5 weeks of age and peaked at age 10 to 15 weeks. However, the responses then declined at tumor-bearing stages in which the expression of target proteins could progressively increase. This resulted from the dysfunction of CD4+ T cells but not of APC or effector macrophages. These results indicate that an anti–HER-2/neu CD4+ T cell–mediated immune response was generated at the pretumorigenic stage but did not prevent tumorigenesis and declined after the development of clinical tumors.

Curative resection of a small cell carcinoma of the pancreas: report of a case of long survival without chemotherapy.

Abstract  A 41‐year‐old asymptomatic man was, by chance, diagnosed as having a mass in the left upper quadrant of the abdomen by ultrasound. Computed tomography and magnetic resonance imaging showed a slightly enhanced heterogeneous mass, measuring about 5 cm in diameter, adjacent to the pancreas tail and spleen. On abdominal angiography the tumor was found to be fed by the splenic artery, and no encasement was observed. At operation the tumor was connected to the pancreas tail and attached to the spleen, and no metastasis was evident. As a result of these observations, a curative resection was performed. On histological examination the tumor cells had no ductal or architectural organization and were continuous to the normal pancreatic tissues. The cells were negative for Grimelius argylphile and the periodic acid schiff stain. Immunohistochemistry indicated that the tumor cells were positive for keratin and epithelial membrane antigen, but negative for chromogranin A, vimentin, α1‐antitrypsin and α1‐antichymotrypsin. The tumor was diagnosed as a small cell carcinoma of the pancreas, which is a rare disease. In previously reported cases curative resection of the tumor had not been possible because of its rapid progression and metastasis, and the prognosis is generally very poor. In our case, however, curative resection of the tumor was done, and the patient is healthy with no signs of recurrence for 56 months after the operation and with no additional therapy.

下垂体への小転移を伴う胃癌原発の髄膜癌腫症に cerebral salt wasting syndrome が続発した1例

A 68-year-old man with disturbed consciousness had repeatedly developed light-headedness and dizziness since the summer of 1996 and was admitted to a hospital for detailed examinations on October 8, 1996. On admission, he weighed 49 kg and showed subclinical hypothyroidism with low T3 syndrome. The adrenal function and serum electrolytes were normal. Since the stool samples were positive for occult blood, gastroscopy was performed. Examination of the biopsy specimens demonstrated gastric cancer. On October 21, blood examination showed hyponatremia (127 mEq/l). On October 22, marked disturbance of consciousness developed. On October 24, the serum Na level further decreased to 116 mEq/l. On November 8, he was referred to our hospital. On admission, his skin and tongue showed marked dehydration, and severe disturbance of consciousness and neck stiffness were observed. The central venous pressure was 4 cmH2O. In the cerebrospinal fluid, atypical cells were observed, and a diagnosis of meningeal carcinomatosis was made. Syndrome of inappropriate secretion of antidiuretic hormone (SIADH) was excluded because of marked dehydration, a normal blood ADH level, and because plasma osmotic pressure was greater than urinary osmotic pressure. Considering the possibility of cerebral salt wasting syndrome (CSWS) or hypoadrenocorticism, Na supplementation and drip infusion of prednisolone (20 mg/day) were performed. The serum Na has normalized (140.1 mEq/l), and his consciousness improved. He died of aggravation of the general condition on December 16. Pathological examination demonstrated a small metastatic lesion in the infundibular part of the pituitary gland and a small metastatic lesion in the parenchyma of the bilateral adrenal glands. However, since neither hypotension nor hypoglycemia was observed before treatment, and the blood cortisol level and the serum K level were normal, hypoadrenocorticism was excluded. Hypoaldosteronism was also excluded because of a normal serum K level. CSWS has been reported to be caused by head trauma, subarachnoid hemorrhage, or trans-sphenoidal pituitary operation. This patient is a rare case of CSWS developed in the presence of meningeal carcinomatosis accompanied by a small pituitary metastatic lesion from gastric cancer. The aged with decreased ability to retain water and sodium in the body are more susceptible to CSWS than the young. In the aged with central hyponatremia, the possibility of CSWS should be considered, and early diagnosis and treatment are necessary.

Why couldn’t an accurate diagnosis be made? An analysis of 1044 consecutive autopsy cases

The protocols of 1044 consecutive patients autopsied between 1983 and 1997 at Sumitomo Hospital (Osaka, Japan) were retrospectively analyzed and the findings were compared with clinical diagnoses. In 73 cases, the clinical diagnosis apparently differed from the autopsy findings, and in six cases the origin of a malignant neoplasm remained unsolved even at autopsy. Of the 73 discrepant cases, 24 were a result of clinician misjudgment and a neglect to conduct further examinations. Missed diagnosis due to an erroneous pathological report, technical error of endoscopy, and misleading results obtained by new non‐invasive technologies accounted for seven, nine, and 11 cases, respectively. Twenty‐two cases were missed because the clinician could not carry out precise examination. It is concluded that advances in diagnostic technology and medical knowledge have not reduced the value of an autopsy.

Phosphaturic mesenchymal tumor, mixed connective tissue variant (oncogenic osteomaiacia)

A case of tumor‐induced phosphaturic osteomaiacia in a 54 year old man is reported. The patient was admitted because of progressive muscle spasms with pain and weakness in the bilateral thighs. Laboratory data showed hypophospha‐temia, decreased tubular resorpnon of phosphate (TRP), a low 1, 25‐dlhydroxyvitamin D level, and a high serum alkaline phosphatase level. Radiologic examinations revealed multiple lesions of osteomaiacia in the ribs, and a small mass in the lower posterior mediastinum. After removal of the tumor, clinical symptoms disappeared and hypopnosphatemia, decreased TRP, and the 1,25‐dihydroxyvitamin D level were corrected. Microscopical examination revealed that the tumor was composed of mature adipose tissues, osseous tissues, and primitive stromai zones including osteoclast‐like giant cells, non‐mineralized woven bone, and various sized blood vessels. Patho‐physiologic observations suggested that the tumor secreted some humoral substances Inhibiting 25‐hydroxyvitamin D‐1α‐hydroxylase activity, renal phosphate resorption, and parathyroid hormone production.

Two cases of peritoneal serous papillary adenocarcinoma.

Two cases of peritoneal papillary carcinoma are reported. The patient in the first case was a 71‐year‐old woman with symptoms of obstructive ileus. Laparotomy revealed a tumor in the omentum involving the transverse colon, and several small tumors in the peritoneum and pelvic wall. However, no primary site of the tumor was seen in the ovary, pancreas, or gastrointestinal tract. The patient in the second case was a 44‐year‐old woman with carcinomatous peritonitis. Postmortem examination revealed multiple tumors in the peritoneum, omentum, and pelvic wall. Tumors were also found in the cortex with mild invasion of the underlying parenchyma of the bilateral ovaries, although these lesions were thought to be metastatic. The histologic features of the tumor in both cases were those of tubulopapillary adenocarcinoma containing scattered psammoma bodies. The cells were positive with the PAS D technique, but negative with alcian blue staining. In both cases, the serum levels of CA‐125 were considerably elevated, and the tumor cells showed positivity for CA‐125, S 100 protein, cytokeratin and EMA by im‐munohistochemistry. The present cases were most likely peritoneal serous papillary adenocarcinoma derived from extraovarian peritoneal mesothelium with miillerian potential, being different from the usual type of diffuse malignant mesothelioma. Acta Pathol Jpn 41: 642‐646, 1991.