The role of metformin and statins in the incidence of epithelial ovarian cancer in type 2 diabetes: a cohort and nested case-control study.

OBJECTIVE: To obtain evidence of the effects of metformin and statins on the incidence of ovarian cancer in women with type 2 diabetes (T2D). DESIGN: A retrospective cohort study and nested case-control study. SETTING: The data were obtained from a diabetes database (FinDM) combining information from several nationwide registers. POPULATION: A cohort of 137 643 women over 40 years old and diagnosed with T2D during 1996-2011 in Finland. METHODS: In full cohort analysis Poisson regression was used to estimate the hazard ratios (HR) in relation to ever use of metformin, insulin other oral anti-diabetic medication or statins. In the nested case-control analysis 20 controls were matched to each case of ovarian cancer. Conditional logistic regression was used to estimate HRs in relation to medication use and cumulative use of different medications. The estimates were adjusted for age and duration of T2D. MAIN OUTCOME MEASURE: Incidence of ovarian cancer. RESULTS: In all, 303 women were diagnosed with ovarian cancer during the follow up. Compared with other forms of oral anti-diabetic medication, metformin (HR 1.02, 95% CI: 0.72-1.45) was not found to be associated with the incidence of ovarian cancer. Neither was there evidence for statins to affect the incidence (HR 0.99, 95% CI: 0.78-1.25). In nested case-control analysis the results were essentially similar. CONCLUSIONS: No evidence of an association between the use of metformin or statins and the incidence of ovarian cancer in women with T2D was found. TWEETABLE ABSTRACT: No evidence found for metformin or statins reducing the incidence of ovarian cancer.

Cause-specific mortality in endometrioid endometrial cancer patients with type 2 diabetes using metformin or other types of antidiabetic medication.

AIM: To obtain further evidence of the association between metformin or other types of antidiabetic medication (ADM) and mortality from endometrial cancer (EC) and other causes of death in patients with endometrioid EC and type 2 diabetes (T2D). MATERIALS AND METHODS: A retrospective cohort of women with existing T2D and diagnosed with endometrioid EC from 1998 to 2011, obtained from a nationwide diabetes database (FinDM), were included in the study. Cumulative mortality from EC and that from other causes was described by using the Aalen-Johansen estimator. Cause-specific mortality rates were analyzed by using Cox models, and adjusted hazard ratios (HRs) with 95% confidence intervals (95% CIs) were estimated in relation to the use of different forms of ADM during the three-year period preceding EC diagnosis. RESULTS: From the FinDM cohort we identified 1215 women diagnosed with endometrioid EC, of whom 19% were metformin users, 12% were users of other types of oral antidiabetic medication, 25% used other types of oral antidiabetic medication plus metformin, 26% used insulin and 14% had no antidiabetic medication. Mortality from EC was not found to be different in women using metformin (HR 0.89, 95% Cl 0.52-1.54) but mortality from other causes was lower (HR 0.52, 95% Cl 0.31-0.88) compared with women using other types of oral ADM. CONCLUSIONS: Our findings are inconclusive as to the possible effect of metformin on the prognosis of endometrioid EC in women with T2D. However, use of metformin may reduce mortality from other causes.

The first host record of trichinosis in a red fox, Vulpes vulpes japonica, from Aomori Prefecture, northern Honshu, Japan.

A case of wildlife trichinosis was found in a red fox (Vulpes vulpes japonica) captured at Rokkasho, Aomori Prefecture on November 27, 1998. Trichinella larvae were obtained from almost all of the muscle tissues except for the masseter. The highest number of larvae per gram of tissue was found in the muscles of the gluteal region and throat. The lowest number was found in the diaphragm and tongue. Trichina cysts within the muscle fibers had groups of fatty cells at the poles, and minimal tissue reaction was observed around the cyst. No calcification was found in the cyst. These morphological findings suggested that the considerable time had elapsed since the invasion. This is the first case of trichinosis in a red fox in Japan.

Malignant struma ovarii with Graves' disease.

BACKGROUND: Malignant struma ovarii is a rare tumor, consisting of a struma ovarii with malignant change. Because of the rarity of the tumor, only a few reports with detailed data of thyroid function of the patient have been published. CASE: Medical and surgical treatments were performed in a case of malignant struma ovarii with Graves' disease and data from thyroid function tests were analyzed. After removal of the tumor, rapid improvement of thyroid function was observed and thyroglobulin level decreased. CONCLUSION: This case demonstrates the possible, if not dominant, contribution from the malignant struma ovarii to the hyperthyroidism of the patient.

Somatic mutations of multiple endocrine neoplasia type 1 gene in the sporadic endocrine tumors.

Endocrine tumors of the parathyroid and pancreas are encountered either as sporadic type or as part of multiple endocrine neoplasia type 1 (MEN 1). A high frequency of the loss of heterozygosity (LOH) has been observed in tumors of the sporadic type in the locus of the MEN 1 gene, which has recently been cloned and designated the menin gene. It would be of great interest to determine whether somatic mutations in the menin gene are responsible for the sporadic endocrine tumors. For this purpose, we have investigated the menin gene mutations in 21 sporadic parathyroid adenomas, 2 parathyroid carcinomas, 4 sporadic insulinomas, and 1 malignant VIP (vasoactive intestinal polypeptide)oma with WDHA (watery diarrhea, hypokalemia, and achlorhydria) syndrome, using PCR-single strand conformation polymorphism analysis and DNA sequencing. In none of these cases did the patient have a family history or other possible association with MEN 1. We have discovered somatic point mutations in two parathyroid adenomas (A340T and A541T), in one insulinoma (T429K), and in the malignant VIPoma (W198X). In addition, we have found two polymorphisms (D418D and V367V) in two parathyroid carcinomas and two parathyroid adenomas. Of these mutations and polymorphisms, three (A340T, T429K, and V367V) are first reported here, in the present article. Our results indicate that somatic mutations of the menin gene are responsible for a proportion of the sporadic parathyroid adenomas and pancreatic islet cell tumors.

Elevated serum lipoprotein (a) levels associated with ulcerative colitis in a young Japanese patient.

Thromboembolism has been shown to play a role in the pathogenesis of inflammatory bowel disease (IBD). A possibility exists that lipoprotein (a) [Lp(a)], a newly-discovered prothrombotic factor, also participates in the development of at least some cases of IBD. Marked elevation of serum Lp(a) levels was observed in a young patient with ulcerative colitis. A biopsy specimen of the rectal mucosa showed findings compatible with ulcerative colitis, as well as small vessel thrombus occurring within the muscularis mucosa in the rectum. Serum Lp(a) levels were markedly elevated on admission (71 mg/dl), with a gradual decrease to 46 mg/dl on discharge. Moreover, serum Lp(a) levels decreased in parallel with clinical improvement. In the quiescent clinical stage, no small vessel thrombus was observed in the mucosa on follow-up colonoscopy. The association between IBD and hyper-Lp(a)-emia would be presumable but it has been, to our knowledge, previously unreported. The case reported here would be the first young patient, suggesting the presence of hyper-Lp(a)-emia and small vessel thrombus formation occurring in association with the development of ulcerative colitis.

Structure and activity of Bombyx PBAN.

Two structurally related molecular species of pheromone biosynthesis activating neuropeptides (PBANs), PBAN-I and -II, were isolated from adult heads of the silkworm, Bombyx mori, and characterized. PBAN-I is a carboxyl-terminally amidated 33-residue peptide. Structure-activity relationship studies revealed that 1) its carboxyl-terminal pentapeptide is the smallest size showing activity, 2) the carboxyl-terminal amide is indispensable for activity, and 3) oxidation of three Met residues in PBAN-I to Met(O) (methionine sulfoxide) caused marked enhancement of activity, and the three Met(O) residues contribute equally to the enhancement of activity. Molecular design of PBAN analogs using a carboxyl-terminal hexapeptide showed that modification of the amino-terminal amino group brought about a dramatic increase in activity. This increase was presumed to be mainly due to the increased stability in hemolymph. PBANs share the common carboxyl-terminal sequence, -Phe-Xaa-Pro-Arg-Leu-NH2, with myotropic peptides isolated from locust and cockroach. Examination of cross-activity of these two groups of peptides revealed that PBAN and its analogs exhibited myotropic activity comparable to myotropic peptides, while myotropic peptides showed extremely high pheromonotropic activity. In B. mori, PBAN activates sex pheromone (bombykol) production presumably by promoting the reduction reaction from acyl to alcohol, which is the last step in the biosynthesis of bombykol.

A case of primary localized amyloidosis of urethra.

Amyloidosis of the urethra is a rare disease. The clinical appearance resembles carcinoma of the urethra, so that biopsy is required to make the appropriate diagnosis. Once primary localized amyloidosis of the urethra has been diagnosed, selection of the appropriate treatment for each case becomes important. We report a case of primary localized amyloidosis in the male anterior urethra. This case was treated successfully with urethral dilatation.

[A case of virilizing adrenocortical carcinoma in adult].

A case of virilizing adrenocortical carcinoma is reported. A 35-year-old woman was referred to our clinic because of left adrenal mass detected incidentally by ultrasonography. At the time of admission, facial acne, systemic hirsutism, hypertrophied clitoris and amenorrhea for two months were observed. Serum testosterone showed obviously high level and urinary 17-KS and 17-OHCS showed slightly high level. A computed tomography revealed a heterogeneous mass with calcification in the left adrenal region. Selective angiography revealed hypervascularity. Under the preoperative diagnosis of virilizing left adrenal tumor, left adrenalectomy was performed. The tumor measured 8 x 6 x 7 cm, and weighed 194 g. A diagnosis of adrenocortical carcinoma was made by pathological examination. Virilizing adrenocortical carcinoma is very rare in adults. We reviewed and discussed 10 cases of virilizing adrenocortical carcinoma in adults, including our case, in the Japanese literature.

[A case of retroperitoneal venous aneurysm].

A case of retroperitoneal venous aneurysm is reported. A 73-year-old woman was referred to us with the chief complaint of left abdominal mass. A giant abdominal mass was palpable and diagnostic imaging examination including ultrasound tomography, excretory pyelography, computed tomography, magnetic resonance imaging and angiography revealed a giant cystic mass encircled by calcification in the left retroperitoneal space. Operation for this cystic mass was performed under the preoperative diagnosis of a giant left renal cyst. During operation the mass was located between the left kidney and the left adrenal gland. Because it was difficult to separate the mass from the left kidney the mass was removed with the left kidney. The extirpated tumor measured 15.5 x 15.0 x 9.5 cm and contained old blood clots and red-yellow colored fluid. A histological examination revealed that the tumor wall was composed of smooth muscle and elastic fibers. Therefore, pathological diagnosis was retroperitoneal venous aneurysm. Retroperitoneal venous aneurysm is very rare. To our knowledge, this is the 8th case of retroperitoneal venous aneurysm reported in Japan.

[Transitional cell carcinoma of the ureter with inverted proliferation: a case report].

A case of transitional cell carcinoma of the ureter with inverted proliferation is presented. A 74-year-old man with the chief complaint of asymptomatic macrohematuria was referred for a suspicion of a ureteral tumor. Excretory urography demonstrated a filling defect with a round smooth contour in the right lower ureter. Urine cytology was negative for malignant cells. No bladder tumor was noted by cystoscopic examination. Under the clinical diagnosis of a right ureteral tumor, right total nephroureterectomy was performed. The gross specimen contained a 2.0 x 1.0 cm, polypoid, pedunculated and smooth-surfaced tumor. The pathological diagnosis was transitional cell carcinoma with inverted proliferation G2 much greater than G1. Malignant tumor with inverted proliferation in the ureter is very rare. In Japan, 8 cases of transitional cell carcinoma with inverted proliferation in the ureter, including our case, are reviewed.

[Primary carcinoma in situ of the upper urinary tract: a case report].

A case of primary carcinoma in situ of the upper urinary tract in a 72-year-old woman is reported. The patient who complained of left lower abdominal pain was referred for a suspicion of left ureteral stone. An excretory pyelogram showed mild left ureteral stricuture at the level of L3, but a stone was not detected in the ureter at the same level. Cytology of voided urine was positive for malignant cells several times. Cystoscopic examination revealed no abnormality in the bladder. Retrograde left pyelogram demonstrated the ureteral stricture and no lesions either of stone or tumor in the ureter. However malignant cells were detected cytologically in the left ureteral catheteral urine. Left total nephroureterectomy with the bladder cuff was carried out under the preoperative diagnosis of carcinoma in situ of the upper urinary tract. Macroscopically, the wall of the ureter at the stenotic level had induration without apparent tumor mass. The pathological diagnosis was transitional cell carcinoma in situ from the renal pelvis to the mid-ureter. The primary carcinoma in situ of the upper urinary tract is rare. To our knowledge, this case is the 26th case reported in the Japanese literature.

Radioprotective effect of exogenous glutathione on rat parotid glands.

The prophylactic effect of glutathione (GSH) on radiation injury in rat parotid glands was investigated. GSH was administered to male Wistar rats i.p. 15 min prior to irradiation. The necrosis index (NI) of the glands was determined histologically 24 h after a single dose of 15, 30, or 60 Gy. Total amylase activity, total protein content and wet weight of the glands were measured 30, 60 and 90 days after irradiation. Administration of GSH prior to radiation minimized acute and chronic radiation injuries as a function of the GSH dose: i.e. reduction of NI and prevention of the decrease in total amylase activity, total protein content and gland weight. The intraglandular level of non-protein-bound thiols (NPSH) and GSH increased significantly after i.p. administration of GSH, whether or not the glands were irradiated. An autoradiographic study revealed that i.p.-administered 35S-GSH was actively taken up by the glandular parenchyma, especially in the acini and ducts. It was shown that elevation of the intraglandular level of NPSH after exogenous administration of GSH protected the parotid glands from radiation injury in the rat.

[Combined preoperative treatment with bilateral intra-arterial chemotherapy (CBDCA + PEP) and radiotherapy of oral cancer on the midline].

Intra-arterial chemotherapy from bilateral superficial temporal arteries and radiotherapy were carried out preoperatively on two patients with oral cancer on the midline. Total doses of preoperative chemo- and radio-therapies were 160 mg/m2 of carboplatin, 50 mg of peplomycin and 20 Gy of 60Co-irradiation, respectively. Therapeutic effect of preoperative chemo- and radio-therapies was evaluated on the resected materials from histological point of view. In case 1, the effect was judged as Grade II A in Oboshi's classification, which indicated a mild destruction of architecture of tumor tissue and a few viable tumor cells, but an extreme reduction of the primary lesion was observed on clinical appearance. In case 2, the therapeutic effect was regarded as Grade II B, which indicated a severe destruction of architecture of tumor tissue and few viable tumor cells. Concerning toxicity, mucositis and slight thrombocytopenia (96,000/mm3) in case 1, and mucositis and leukopenia (2,300/mm3) in case 2 appeared. However, they soon recovered after termination of the preoperative therapies. From the above results, it was considered that a combination of bilateral intra-arterial chemotherapy and radiotherapy was quite effective as a preoperative treatment for oral cancers on the midline at the same doses of anti-neoplastic agents and irradiation as for the other unilateral oral cancers.

Familial bulbo-spinal muscular atrophy associated with testicular atrophy and sensory neuropathy (Kennedy-Alter-Sung syndrome). Autopsy case report of two brothers.

Autopsy cases of two brothers with bulbo-spinal muscular atrophy associated with gynecomastia, testicular atrophy and sensory neuropathy are reported. The disease started with finger tremor, proximal muscle weakness and facial muscle twitching at the second and fourth decades, accompanied by bulbar signs and glove-stocking type sensory disturbance. Systemic neurogenic patterns and diminished sensory nerve action potential amplitudes were recorded by electrophysiological studies. A marked loss of myelinated fibers was noticed upon sural nerve biopsy. Gonadal hormone values were normal, except for elevated urinary estrogen. Postmortem examinations revealed a remarkable degeneration of the facial and hypoglossal nuclei, and the spinal cord motoneurons. The skeletal muscles and the tongue showed neurogenic muscular atrophy with fatty replacement. Testicular atrophy was prominent showing hyalinized seminiferous tubuli with nodular and diffuse Leydig cell hyperplasia, containing estrogen immunoreactive substance. These clinical and histological features seemed to be highly compatible with those of Kennedy-Alter-Sung type bulbo-spinal muscular atrophy. The involvement of sensory peripheral nerves, however, was a distinct feature of this family.

Traumatic myositis ossificans in the masseter muscle.

Traumatic myositis ossificans in the left masseter muscle of a 25-year-old man is described. The lesion, which extended intramuscularly from the lateral surface of the zygomatic bone to the mandibular angle, was resected by an intraoral approach. The specimen was composed of mature cortical bone in the outer portion and spongy bone, including degenerated muscle fibers and marrow spaces, in the inner portion. At the lower end of the specimen was a sequence of bone formation involving fibrous connective tissue, cartilage, woven bone, and mature lamellar bone with many osteoblasts. Clinicopathologic features of 26 reported cases of traumatic myositis ossificans of the maxillofacial region are reviewed, and the pathogenesis of the disease is discussed.