Intraperitoneal injection of the SIRT1 activator SRT1720 attenuates the progression of experimental osteoarthritis in mice.

OBJECTIVES: This study aimed to examine the effects of SRT1720, a potent SIRT1 activator, on osteoarthritis (OA) progression using an experimental OA model. METHODS: Osteoarthritis was surgically induced by destabilization of the medial meniscus in eight-week-old C57BL/6 male mice. SRT1720 was administered intraperitoneally twice a week after surgery. Osteoarthritis progression was evaluated histologically using the Osteoarthritis Research Society International (OARSI) score at four, eight, 12 and 16 weeks. The expression of SIRT1, matrix metalloproteinase 13 (MMP-13), a disintegrin and metalloproteinase with thrombospondin motifs-5 (ADAMTS-5), cleaved caspase-3, PARP p85, and acetylated nuclear factor (NF)-κB p65 in cartilage was examined by immunohistochemistry. Synovitis was also evaluated histologically. Primary mouse epiphyseal chondrocytes were treated with SRT1720 in the presence or absence of interleukin 1 beta (IL-1ß), and gene expression changes were examined by real-time polymerase chain reaction (PCR). RESULTS: The OARSI score was significantly lower in mice treated with SRT1720 than in control mice at eight and 12 weeks associated with the decreased size of osteophytes at four and eight weeks. The delayed OA progression in the mice treated with SRT1720 was also associated with increased SIRT1-positive chondrocytes and decreased MMP-13-, ADAMTS-5-, cleaved caspase-3-, PARP p85-, and acetylated NF-κB p65-positive chondrocytes and decreased synovitis at four and eight weeks. SRT1720 treatment partially rescued the decreases in collagen type II alpha 1 (COL2A1) and aggrecan caused by IL-1ß, while also reducing the induction of MMP-13 by IL-1ß in vitro. CONCLUSION: The intraperitoneal injection of SRT1720 attenuated experimental OA progression in mice, indicating that SRT1720 could be a new therapeutic approach for OA.Cite this article: K. Nishida, T. Matsushita, K. Takayama, T. Tanaka, N. Miyaji, K. Ibaraki, D. Araki, N. Kanzaki, T. Matsumoto, R. Kuroda. Intraperitoneal injection of the SIRT1 activator SRT1720 attenuates the progression of experimental osteoarthritis in mice. Bone Joint Res 2018;7:252-262. DOI: 10.1302/2046-3758.73.BJR-2017-0227.R1.

Radiotherapy for adrenal gland metastasis from lung cancer: report of three cases.

Adrenal gland metastasis is often observed during the clinical course of patients with lung cancer. However, treatment of adrenal gland metastasis is seldom considered because of the systemic spread of the disease. Treatment with curative intent is very rare, but palliative treatment may sometimes be considered when symptoms such as flank pain are observed. Three cases of adrenal gland metastasis were reported. Two of them received surgery for lung cancer and developed a sole metastasis of the adrenal gland. Case 1 developed a sole left adrenal gland metastasis with left flank pain 14 months after surgery for large cell carcinoma of the lung. Curative radiotherapy after intra-arterial chemotherapy was given. A good response was obtained, and he has been alive for 2 years and 9 months. Case 2 developed a right adrenal gland metastasis after radiotherapy for brain metastasis, after having received right upper lobectomy because of SCLC. The increase in the size of the right adrenal gland led us to treat the lesion before symptoms developed. Radiotherapy was given on an outpatient basis. Case 3, who was previously treated with chemoradiotherapy for SCLC, developed brain, liver, and bilateral adrenal gland metastasis. Huge adrenal gland metastases displaced the pancreas and caused severe pain with the increase in serum amylase level. Concurrent radiotherapy with systemic chemotherapy was given and remarkable shrinkage of the adrenal gland metastases was obtained together with pain relief. Cases 2 and 3 died after 8 and 4 months, respectively. In some cases, radiotherapy for adrenal gland metastasis is a good palliative therapy even in the advanced stage patients. Radiotherapy can sometimes curatively treat adrenal metastasis from NSCLC, as in our Case 1, in which adrenalectomy appeared difficult at the time of recurrence.

Effectiveness of RF capacitive hyperthermia combined with radiotherapy for stages III and IV oro-hypopharyngeal cancers: a non-randomized comparison between thermoradiotherapy and radiotherapy.

Seventy-two patients with Stages III and IV (TNM, UICC, 1987) squamous-cell carcinoma of the oropharynx and hypopharynx (oro-hypopharyngeal cancer) were treated with external irradiation, or irradiation plus 13.56 MHz radiofrequency (RF) capacitive hyperthermia from 1989 to 1995. This study compared initial response, histological effect and 5-year survival rate of thermoradiotherapy (TRT) group with those of radiotherapy alone (RT) group. In the TRT group, 15 patients were treated definitively, and 18 patients preoperatively. In the RT group, 15 patients were treated definitively, and 24 patients preoperatively. With definitive irradiation, the complete response rate of the primary lesions was 73% in the TRT group and 27% in the RT group (p = 0.009) and the complete response rate of the metastatic lymph nodes was 80% in the TRT group and 27% in the RT group (p = 0.005). With preoperative irradiation, the pathological CR (No residual cancerous cells) rate of the primary lesions was 56% in the TRT group and 8% in the RT group (p = 0.01), and the pathological CR rate of the lymph nodes was 72% in the TRT group and 21% in the RT group (p = 0.001). The 5-year survival rates with definitive irradiation were 47.6% in the TRT group and 18.7% in the RT group (p = 0.025). Thus TRT was more effective than RT for advanced oro-hypopharyngeal cancer.

[A case of advanced esophageal cancer successfully treated by concurrent use of radiotherapy and low-dose CDDP and continuous infusion of 5-FU].

A 75-year-old male patient with advanced esophageal cancer was treated by radiotherapy and chemotherapy. External radiotherapy was performed by the field in field method. A total dose of 60 Gy was used in the small field (7 x 5 cm) (2.4 Gy/f and 25 f/5 wks) and a total dose of 45 Gy in the large field (14 x 6 cm) (1.8 Gy/f, 25 f/5 wks). Concurrent chemotherapy was performed at the 2nd and 5th weeks of the radiation therapy. In this chemotherapy of CDDP plus 5-FU, CDDP (25 mg/day) was given on days 1,3 and 5 of the week and 5-FU (500 mg/day) was given for 5 days by continuous infusion for the same week. By this treatment, a complete response (CR) was obtained, and no serious side effects were observed. After 1 year and 6 months, he is alive with no evidence of recurrence.

[Results of radiotherapy combined with CDDP (BAI) plus VP-16 in the treatment of inoperable non-small cell lung cancer].

Twenty-six patients with unresectable non-small cell lung cancer were treated by chemotherapy alone or chemotherapy followed by radiotherapy from June 1988 to May 1990. CDDP (80 mg/m2) was given by bronchial arterial infusion (BAI) on day 1 in each course, VP-16 (80 mg/body) was given by drip intravenous infusion on days 1 and 2, and VP-16 (150 mg/body) was given orally on days 3 and 5. The patients were irradiated after this regimen with a single dose of 1.8-2.0 Gy, five times each week, to a volume which encompassed only the primary tumor. A total dose of 60 Gy or more was delivered. There were 10 squamous cell carcinomas, nine adenocarcinomas, five large cell carcinomas, one adenosquamous cell carcinoma and one poorly differentiated carcinoma. Median survival time (MST) was 354 days in stage III B patients and 280 days in stage IV patients. MST was 155 days in adenocarcinoma and 310 days in squamous cell carcinoma. MST was 372 days in PS 0 to 1 patients and 140 days in PS 2 patients. With chemo-radiotherapy in 17 cases resulted in no complete remissions and 10 partial remissions. The overall response rate was 58.8%. It is concluded that CDDP via BAI combined with VP-16 administration and sequential irradiation is useful to acquire a high response rate in non-small cell lung cancer. However, further studies on this modality are required.

A case of pulmonary pseudolymphoma: five years' roentgenographic observation.

A patient with pulmonary pseudolymphoma whose chest X-ray shadows could be observed for over five years is reported. A 73-year-old man was admitted to our hospital in March 1993, because of abnormal shadows on a chest X-ray film. There was a solitary mass in the left upper lung field and infiltrate in the right middle and lower lung fields. These shadows had been observed on a chest X-ray film in 1988, and had been gradually growing for more than five years. Transbronchial lung biopsy (TBLB) of the left upper lobe mass resulted in a histological diagnosis of pulmonary pseudolymphoma. The shadows showed no change during the next nine months after his discharge. These findings are suggestive of the natural history of pulmonary pseudolymphoma. It seems that the process involved in this case was benign rather than malignant.

[A comparative study of psycho-social factors in peptic ulcer disease].

To evaluate the psycho-social factors of peptic ulcer, we carried out a comparative study. Seventy-six men and 19 women with peptic ulcers diagnosed at seven hospitals in Kyoto, Osaka and Hyogo Prefectures in Japan were surveyed during November 1990 about their daily hassles, depressive state, social support and life style using a self-administered questionnaire. The results were compared to those for two control groups. One control group was diagnosed with normal, atrophic gastritis, or superficial gastritis by the gastro-duodenal endoscopic examinations in the same hospitals. The other control group consisted of participants in a health-screening examination at one of the above hospitals. There were no significant differences between patients and controls in daily hassles, depressive state, and social support. However, being unmarried, smoking and eating irregular meals significantly increased the relative risk of peptic ulcer in men and family history of peptic ulcer significantly increased the risk in women.

[Depression, health status and lifestyles of residents of a rural community].

A survey was conducted to examine the prevalence of depressive symptomatology among residents of a rural community using the Center for Epidemiologic Studies Depression (CES-D) Scale. Subjects were 220 men and 319 women aged between 30 and 69 who participated in annual community health examinations. The relation of depressive symptomatology to the results of physical examination, self-rated health status, subjective symptoms and lifestyles were also examined. The results are as follows. 1) Of the subjects, 13.2% of the men and 16.3% of the women had depressive symptomatology (CES-D score > or = 16), with 4.5% of the men and 9.4% of the women having moderate or severe depressive symptomatology (CES-D score > or = 20). Prevalence was higher for younger men and for women in their forties, but these differences were not statistically significant. 2) There was a weak correlation between depressive symptomatology and the results of physical examination. Self-rated health status was more significantly correlated with depressive symptomatology. Self-rated health status and depressive symptomatology each correlated independently with the number of symptoms experienced by the subjects over the past year. The subjective symptoms that were correlated with depressive symptomatology were different from those correlated to self-rated health status. Men and women also had differences in links between depressive symptomatology, self-rated health status and symptoms experienced. 3) Lifestyles of those who had depressive symptomatology were worse than those who did not. But only duration of sleep and food intake had statistically significant relation to depressive symptomatology. Only weak correlations between lifestyles and self-rated health status were observed.(ABSTRACT TRUNCATED AT 250 WORDS)

Carpal tunnel syndrome: evaluation of median nerve circulation with dynamic contrast-enhanced MR imaging.

PURPOSE: To identify mechanism(s) responsible for carpal tunnel syndrome (CTS). MATERIALS AND METHODS: At dynamic gadolinium-enhanced magnetic resonance (MR) imaging, the enhancement pattern of the sagittal section of the median nerve in 10 wrists of nine patients with CTS (two men and seven women, aged 43-60 years [mean, 52 years 10 months]) was studied while each wrist was in a neutral, flexed, and/or extended position. Five asymptomatic volunteers (four men and one woman, aged 23-54 years [mean, 31 years 5 months]) also underwent MR imaging to establish the normal enhancement patterns. RESULTS: Two distinctly abnormal patterns of median-nerve enhancement were revealed: marked or no enhancement. Marked enhancement was attributed to nerve edema, and the lack of enhancement was attributed to ischemia. Marked enhancement changed to no enhancement changed to no enhancement when the wrists were in a flexed or extended position. This change was associated with an aggravation of the symptoms of CTS. CONCLUSIONS: CTS may result from a circulatory disturbance rather than from deformation or compression of the nerve.

[Treatment results of small cell lung cancer: referring to the clinical value of BAI combined with radiotherapy].

Results of 65 cases of small cell lung cancer (SCLC) treated from Jan. 1981 to May 1991 were reviewed. There were 58 male and 7 female patients and their age was ranging from 37 to 86 (mean 65). There were 41 limited disease (LD) and 24 extensive disease (ED) cases. According to TNM (UICC 1987) staging system, there were 2 cases of stage I, 4 of stage II, 9 of stage III A, 28 of stage III B and 22 of stage IV. Among 65 cases, 60 cases received radiotherapy and 55 cases of them received radiotherapy for primary site. There were 29 cases received radiotherapy combined with BAI (bronchial artery infusion) and 20 cases received systemic chemotherapy. On survival, the 2-year survival rate was 26% and MST was 13 months in LD patients (n = 41). No 2-year survivors were seen in ED patients and MST was 10 months. Tumor response of primary site was as follows. In systemic chemotherapy group, CR 35%, PR 59%, NC 6% and PD 0% before radiotherapy and CR 59% after radiotherapy were obtained. In BAI group (including BAI + systemic chemotherapy), CR 6% and PR 88% before radiotherapy in BAI group. BAI did not seem to improve response rate compared to systemic chemotherapy. On survival, BAI group did not show significant better survival compared to BAI (-) group in LD cases (n = 31). In responders (evaluable LD cases, n = 24), the MSTs were 25 months in CR cases and 13 months in PR cases. No 2-year survivors were seen in PR cases.(ABSTRACT TRUNCATED AT 250 WORDS)

The power of compassion: truth-telling among American doctors in the care of dying patients.

The perceptions of American doctors about their practice regarding truth-telling in the care of dying patients were examined based on semi-structured interviews with 32 physicians in a teaching hospital. The doctors inform patients of their disease using three basic styles; 'telling what patients want to know', 'telling what patients need to know' and 'translating information into terms that patients can take'. These styles are supported by five basic normative principles; 'respect the truth', 'patients rights', 'doctors' duty to inform', 'preserve hope' and 'individual contract between patients and doctors'. These styles and principles suggest that physicians adhere to the recent trends of American medical ethics based on informed consent doctrine, and give the impression that patients have control over obtaining information. But close analysis of their accounts shows that physicians still hold power to control information through their management of the information-giving process. The styles and principles are flexibly interpreted and selectively used in the process so that they facilitate a discourse which justifies, rather than eliminates, the information control. Clinical contexts of information control are analyzed by examining dissimilar manners of providing information about treatment as opposed to prognosis. Physicians give less, and vaguer information about prognosis, citing its uncertainty and lesser relevance to future actions as reasons. Information about treatment is more readily shared in order to counterbalance the negative impact of the news on patients. The analysis reveals that the way doctors control information is closely related to the way they handle aspects of the reality of clinical practice, such as physicians' own emotional coping, institutional and legal constraints, and power relationships among patients, doctors and other care-givers. Situating the findings in the historical context of normative discourse in American medicine, discussion focuses on the issues of trust and power of doctors. The humanistic role of the doctor, although suppressed in the currently dominant, contractual ethical framework, is still powerful in doctors' narratives. It expresses doctors' commitment to patients while preserving their authority. Implications of the individualistic approach to the doctor-patient relationship are also discussed.

[Percutaneous injection of cisplatin lipiodol suspension (CLS) in rabbit lung, aiming at intratumoral injection therapy for lung cancer].

Cisplatin lipiodol suspension (CLS: cisplatin 20 mg/ml) was percutaneously injected (cisplatin dose, 2, 4 or 6 mg/kg) in normal lungs of 10 rabbits (1.9-2.3 kg) to assess the safety and feasibility of intratumoral injection of CLS for lung cancer. Histological study revealed acute and chronic infiltrates with bronchiolitis and immature fibrosis at the injected lung tissue even at four weeks after injection. Intrathoracic leaks of CLS produced mild and focal fibrinous pleuritis. Intrabronchial leaks of CLS produced peripheral bronchiolitis with regenerative epithelia. However, no noxious parenchymal damage in the lung and surrounding tissues was noted. Neither oil embolism in brain nor renal toxicity was demonstrated. Seven of eight rabbits showed an increase in body weight. Concentration levels of plasma platinum were lower when compared with intravenous injection of cisplatin in the rabbit: highest at 30 minutes and unmeasurable one week after injection. Lipiodol accumulation in mediastinal lymph nodes was demonstrated in two of nine rabbits by X-ray examination, suggesting intralymphatic drainage of CLS. Intratumoral injection of CLS is safe even with CLS leaks in surrounding normal lung tissues and may be a potent therapy for controlling mediastinal lymph nodes metastasized from lung cancer as well as the primary tumor.

[Angiographic features of alveolar soft-part sarcoma].

The angiographic findings were analyzed in five patients with alveolar soft-part sarcoma. The angiographic appearance of the tumors was the same in all five cases: hypervascularity of the tumor including encasement, dilatation, tortuosity and displacement of feeding arteries, remarkable tumor stain and early venous filling. These angiographic findings are considered to be characteristic of alveolar soft-part sarcoma in the differential diagnosis of hypervascular soft tissue mass.

[Results of radiotherapy combined with BAI (bronchial artery infusion) for non-small cell lung cancer--analysis of 104 cases].

Results of 104 cases of non-small cell lung cancer (NSCLC) treated by radiotherapy combined with BAI (bronchial artery infusion) were analyzed retrospectively. In 104 cases (84 males and 20 females), 14 cases of stage I, 10 of stage II, 33 of stage IIIA, 29 of stage IIIB and 18 cases of stage IV were included. Overall cumulative survival rate was 11.4% and 50% survival time was 12 months. On PS (performance status), 50% survival time was 1 year and 3 months for both PS 0 and PS 1, 8 months for PS 2 and 2 year for PS 3 (n = 3), respectively. On stage, 50% survival time was 3 year and 4 months for stage I, 1 year and 2 months for stage II, 12 months for stage IIIA, 11 months for stage IIIB and 8 months for stage IV. There was no significant difference of survival rate between squamous cell carcinoma (n = 41) and adenocarcinoma (n = 43). On anticancer agents used for BAI, CDDP group (n = 68) showed better significant 2-year survival rate than that of MMC and/or ADR group (n = 36). Response rate (CR + PR) was 85% (75/88) by radiotherapy with BAI, and 10 cases of CR were obtained. Among 27 cases of 2-year survivors, 21 cases of responders (CR + PR) were included and 4 cases of them showed CR. On these results, radiotherapy combined with BAI seemed to contribute to improve long-term treatment results of NSCLC by higher response rate with the progress of anticancer agent used for BAI.

[Three cases of alveolar soft part sarcoma and MRI findings].

Three cases of alveolar soft part sarcoma were reported with characteristic MRI findings. On MRI findings, slightly higher signal intensity than muscles on T1 weighted image and remarkably high signal intensity on T2 weighted image were thought to be characteristic of alveolar soft part sarcoma.

[A case of a rare anomaly of the abdominal aorta--magnetic resonance image and angiographic finding].

A case of a rare anomaly of the abdominal aorta was reported. The abdominal aorta was divided into two abnormal vessels and one vessel was celiac artery, and the other was considered to be abdominal aorta. To review literature, this type of anomaly of abdominal aorta is rare. Anatomy of this case had been well demonstrated by MR imaging and angiography. Those findings and the embryological basis of this case were discussed.

Multiple primary malignant neoplasms of the head and neck.

This report analyzed the 7,763 cases treated at T.W.M.C., where radiotherapy has been mainly used, between 1968 and 1984. Of these, 258 cases (3.3%) had multiple primary malignant neoplasms, among which 88 cases involved head and neck cancer. The incidence averaged 1.6% during the first 5 years, but increased to an average of 5.7% during the last 5 years. Among head and neck cancer the incidence of multiple primary malignant neoplasms was 8.5% (88/1,033) and the incidence has been gradually increasing annually. Cancers of the head and neck were frequently combined with another primary lesion in the head and neck area or in the digestive tract, especially esophagus and stomach, followed by one in the both cases. The great majority of cancers in the head and neck occurred as the first cancer at age 60-70. The head and neck region is where the respiratory system and digestive system, including lymphatic organs originate and where the external carcinogenic factors enter into the body. These data suggested that multiple primary malignant neoplasms have been increasing in number and becoming an increasing problem. The possibility of multiple primary malignant neoplasms should not be forgotten in routine cancer related clinical work.