Association between Inflammation and Functional Outcome in Patients with Sarcopenic Dysphagia.

OBJECTIVES: This study aimed to investigate whether inflammation affects the outcome of swallowing ability to improve treatment for sarcopenic dysphagia. DESIGN: A retrospective observational cohort study was performed using data from the Japanese sarcopenic dysphagia database. SETTING: The database was constructed using data from 19 hospitals and one home visiting rehabilitation team. PARTICIPANTS: Patients with sarcopenic dysphagia with measurements of C-reactive protein (CRP) and serum albumin (Alb) were included. MEASUREMENTS: Patients were assigned to two groups using CRP, Alb, and the Japanese modified Glasgow Prognostic Score (mGPS). The Food Intake LEVEL Scale (FILS) was measured at the times of admission and follow-up (FILS follow-up) to assess swallowing function. RESULTS: A total of 197 patients were included. Mean or median values of each parameter were as follows: age: 83.8±8.7, Alb: 3.2 ± 0.6 g/dL, CRP: 8.0 [3.0, 29.0] mg/L, mGPS: 1 [1-2], FILS: 7 [6-8], FILS follow-up: 8 [7-8], and duration of follow-up: 57.0 [27.0, 85.0] days. The FILS score at follow-up was significantly lower in the high CRP group (≥ 5.0 mg/L) than in the low CRP group (< 5.0 mg/L) (p = 0.01). Further, the FILS score at follow-up was significantly lower in the high mGPS group (class; 2) than in the low mGPS group (class; 0 and 1) (p = 0.03). In the multiple linear regression analyses without FILS at baseline, CRP and mGPS were independent risk factors for FILS follow-up. When FILS at baseline was entered, CRP and mGPS were not an independent risk factors for FILS follow-up. CONCLUSIONS: Inflammation could modify the outcome of the patients with sarcopenic dysphagia. Inflammation may be an important risk factor in evaluating patients with sarcopenic dysphagia.

Prevalence of Hoarseness and Its Association with Severity of Dysphagia in Patients with Sarcopenic Dysphagia.

OBJECTIVES: To investigate the prevalence of hoarseness and its association with the severity of dysphagia in patients with sarcopenic dysphagia. DESIGN: Cross-sectional study using the Japanese sarcopenic dysphagia database. SETTING: 19 hospitals including 9 acute care hospitals, 8 rehabilitation hospitals, 2 long-term care hospitals, and 1 home visit rehabilitation team. PARTICIPANTS: 287 patients with sarcopenic dysphagia, aged 20 years and older. MEASUREMENTS: Sarcopenic dysphagia was diagnosed using a reliable and validated diagnostic algorithm for the condition. The presence and characteristics of hoarseness classified as breathy, rough, asthenic, and strained were assessed. The prevalence of hoarseness and the relationship between hoarseness and Food Intake LEVEL Scale (FILS) were examined. Order logistic regression analysis adjusted for age, sex, naso-gastric tube, and handgrip strength was used to examine the relationship between hoarseness and FILS at baseline and at follow-up. RESULTS: The mean age was 83 ± 10 years. Seventy-four (26%) patients had hoarseness, while 32 (11%), 20 (7%), 22 (8%), and 0 (0%) patients had breathy, rough, asthenic, and strained hoarseness, respectively. Median FILS at the initial evaluation was 7 (interquartile range, 5-8). Hoarseness (ß=0.747, 95% confidence intervals= 0.229, 1.265, p=0.005), age, sex, naso-gastric tube, and handgrip strength were associated independently with baseline FILS, while hoarseness (ß=0.213, 95% confidence intervals= -0.324, 0.750, p=0.438) was not associated independently with the FILS at follow-up. CONCLUSIONS: Hoarseness was associated with the severity of dysphagia at baseline, however not a prognostic factor for sarcopenic dysphagia. Resistance training of swallowing and respiratory muscles and voice training as part of rehabilitation nutrition might be useful for treating sarcopenic dysphagia.

The Mass of Geniohyoid Muscle Is Associated with Maximum Tongue Pressure and Tongue Area in Patients with Sarcopenic Dysphagia.

OBJECTIVES: We investigated the associations about the mass of geniohyoid and tongue muscle and the maximum tongue pressure in patients with sarcopenic dysphagia using ultrasonography. DESIGN: Cross sectional study. SETTING: 5 hospitals including 3 acute and 2 rehabilitation hospitals and 1 older facility. PARTICIPANTS: 36 inpatients with sarcopenic dysphagia. MEASUREMENTS: Ultrasonography was performed for geniohyoid muscle and tongue. The area for geniohyoid and tongue muscles in sagittal plane and the mean brightness level (0-255) in the muscle area were calculated. Maximum tongue pressure as strength of swallowing muscle were investigated. Partial correlation coefficient and multiple regression analysis adjusting for age and sex were performed. RESULTS: The mean age was 81.1 ± 7.9. Men were 23. The mean BMI was 19.0 ± 4.1. The mean maximum tongue pressure was 21.3 ± 9.3 kPa. The mean cross sectional area for geniohyoid muscles was 140 ± 47 mm2. The mean brightness for geniohyoid muscle was 18.6 ± 9.0. The mean cross sectional area for tongue muscles was 1664.1 ± 386.0 mm2. The mean brightness for tongue muscles was 34.1 ± 10.6. There was a significant positive correlation between area of geniohyoid muscle and maximum tongue pressure (r = 0.38, p = 0.04). Geniohyoid muscle area was an explanatory factor for maximum tongue pressure (p = 0.012) and tongue muscle area (p = 0.031) in multivariate analysis. CONCLUSIONS: Geniohyoid muscle mass was an independent explanatory factor for maximum tongue pressure and tongue muscle mass.

FOLFIRI plus bevacizumab as second-line therapy in patients with metastatic colorectal cancer after first-line bevacizumab plus oxaliplatin-based therapy: the randomized phase III EAGLE study.

BACKGROUND: A targeted agent combined with chemotherapy is the standard treatment in patients with metastatic colorectal cancer (mCRC). The present phase III study was conducted to compare two doses of bevacizumab combined with irinotecan, 5-fluorouracil/leucovorin (FOLFIRI) in the second-line setting after first-line therapy with bevacizumab plus oxaliplatin-based therapy. PATIENTS AND METHODS: Patients were randomly assigned to receive FOLFIRI plus bevacizumab 5 or 10 mg/kg in 2-week cycles until disease progression. The primary end point was progression-free survival (PFS), and secondary end points included overall survival (OS), time to treatment failure (TTF), and safety. RESULTS: Three hundred and eighty-seven patients were randomized between September 2009 and January 2012 from 100 institutions in Japan. Baseline patient characteristics were well balanced between the two groups. Efficacy was evaluated in 369 patients (5 mg/kg, n = 181 and 10 mg/kg, n = 188). Safety was evaluated in 365 patients (5 mg/kg, n = 180 and 10 mg/kg, n = 185). The median PFS was 6.1 versus 6.4 months (hazard ratio, 0.95; 95% confidence interval [CI] 0.75-1.21; P = 0.676), and median TTF was 5.2 versus 5.2 months (hazard ratio, 1.01; 95% CI 0.81-1.25; P = 0.967), respectively, for the bevacizumab 5 and 10 mg/kg groups. Follow-up of OS is currently ongoing. Adverse events, including hypertension and hemorrhage, occurred at similar rates in both groups. CONCLUSION: Bevacizumab 10 mg/kg plus FOLFIRI as the second-line treatment did not prolong PFS compared with bevacizumab 5 mg/kg plus FOLFIRI in patients with mCRC. If bevacizumab is continued after first-line therapy in mCRC, a dose of 5 mg/kg is appropriate for use as second-line treatment. CLINICAL TRIAL IDENTIFIER: UMIN000002557.

Activation of p38 mitogen-activated protein kinase mediates thyroid hormone-stimulated osteocalcin synthesis in osteoblasts.

It is well known that thyroid hormone modulates osteoblast cell function. We have previously shown that triiodothyronine (T(3)) activates p44/p42 mitogen-activated protein (MAP) kinase, which limits T(3)-induced alkaline phosphatase activity in osteoblast-like MC3T3-E1 cells. In the present study, we investigated whether p44/p42 MAP kinase or p38 MAP kinase is involved in the thyroid hormone-stimulated osteocalcin synthesis in these cells. T(3) markedly induced the phosphorylation of p38 MAP kinase in addition to p44/p42 MAP kinase. PD98059 and U0126, inhibitors of the upstream kinase that activates p44/p42 MAP kinase, had little effect on the T(3)-induced synthesis of osteocalcin. On the contrary, the T(3)-induced osteocalcin synthesis was significantly reduced by SB203580 and PD169316, inhibitors of p38 MAP kinase. SB203580, PD169316 or PD98059 suppressed the T(3)-phosphorylation of myelin basic protein. T(3)-induced osteocalcin synthesis was significantly reduced by SB203580 or PD169316 also in primary cultured mouse osteoblasts. These results strongly suggest that p38 MAP kinase but not p44/p42 MAP kinase takes part in the thyroid hormone-stimulated osteocalcin synthesis in osteoblasts.

Detection of peritoneal micrometastases by reverse transcriptase-polymerase chain reaction targeting carcinoembryonic antigen and cytokeratin 20 in colon cancer patients.

Peritoneal recurrence after curative resection of malignant tumor with negative cytology is considered to be caused by microscopic dissemination of the exfoliated cancer cells from primary tumors to serosal surfaces at the time of operation, not detectable with conventional diagnostic tools. We applied the reverse transcriptase-polymerase chain reaction (RT-PCR) for carcinoembryonic antigen (CEA) and cytokeratin 20 (CK 20) to detect micrometastatic foci in the peritoneal cavity of colon cancer patients. Cytological samples taken by peritoneal lavage from a series of 79 colon cancer patients were analyzed microscopically, for CEA levels, and by RT-PCR analysis using nested primers for CEA and CK 20. Cases with both CEA and CK 20 signals were defined as PCR-positive. This RT-PCR method proved both sensitive (1 tumor cell/10(6) non-tumor cells on preparation of serial colorectal cancer cell dilutions) and specific (no false positive results, 0/23 tested in our control experiment). Intraperitoneal micrometastatic cells were detected in peritoneal lavage 7.6% by cytology, 17.7% by CEA levels, and 24.1% by RT-PCR (significantly higher than by cytology: p=0.0046). RT-PCR detection rate increased in parallel with pathological depth of tumor invasion, and also a pathological stage-dependence was suggested according to the tumor-node-metastasis classification of the International Union Against Cancer. Our results suggest that CEA and CK 20 mRNA identification by RT-PCR appeared to be reliable and may be useful for early diagnosis in peritoneal dissemination of colon cancer.

[Therapeutic effect of multimodal therapy, such as cryosurgery, locoregional immunotherapy and systemic chemotherapy against far advanced breast cancer].

A total of 6 breast cancer patients, 5 with local recurrent tumors on their anterior chest wall and 1 with far advanced primary breast tumor, underwent multimodal therapy in which cryosurgery was performed in combination with local injection of the non-specific immunopotentiator OK-432. This multimodal therapy was repeated as many times as possible. In addition, 3 patients whose general condition was relatively good were treated with mild chemotherapy. In every patient who underwent cryosurgery combined with locoregional immunotherapy, eradication or reduction of tumor was observed for several months. Of 3 patients who underwent cryosurgery, locoregional immunotherapy and systemic chemotherapy, the tumor burden decreased markedly in 2 patients and rapid tumor growth was suppressed in 1 patient, even though the diameter of tumor was over 5 cm in all cases. There were no side effects caused by either cryosurgery or locoregional immunotherapy. Little toxicity was observed throughout the mild chemotherapy. These results indicated that cryosurgery in combination with local injection of OK-432 should be a feasible modality against unresectable breast cancer on the chest wall, and that this therapeutic effect might be augmented by mild chemotherapy.

[Significance of detection of micrometastases in regional lymph nodes in cancer patients using RT-PCR].

Lymph node metastasis is the most important predictor of prognosis, and lymph node dissection is indispensable in achieving curative resection. However, even in patients who undergo curative resection, 20-30% experience relapse, which may be due to micrometastases that are undetectable by conventional histologic methods. Recently, more specific and sensitive genetic methods, including the reverse-transcriptase polymerase chain reaction (RT-PCR), have been introduced to detect micrometastases. We review the literature to evaluate the significance of detecting micrometastases in lymph nodes by RT-PCR. Since the first study by Smith in 1991, many authors have reported molecular diagnoses in the lymph nodes, blood, and bone marrow in patients with various types of cancer using markers such as CEA and cytokeratins. Many researchers have found RT-PCR to be more sensitive than conventional histological methods in detecting lymph node metastases. Molecular diagnosis will become a powerful tool for predicting prognosis and determining who should receive postoperative adjuvant chemotherapy. However, reports on the relationship between molecular diagnosis and prognosis are still few. It will be important to clarify this relationship in large-scale clinical trials to evaluate the significance of detecting micrometastases in the lymph nodes.

A ruptured pancreaticoduodenal artery aneurysm associated with a splenic artery aneurysm: report of a case.

True pancreaticoduodenal artery (PDA) aneurysms are extremely rare. We report herein a case of a ruptured PDA aneurysm associated with a nonruptured splenic artery aneurysm which was successfully treated by surgery. A 55-year-old man was admitted to a local hospital complaining of sudden abdominal and back pain, and thereafter he was transferred to our university hospital. Abdominal computed tomography revealed retroperitoneal hematoma and an enhanced round spot suggesting a peripancreatic aneurysm. Emergency angiography showed a 20-mm-sized aneurysm in the inferior PDA and a 10-mm-sized aneurysm in the splenic artery. The patient underwent an emergency laparotomy with a diagnosis of a ruptured PDA aneurysm. After evacuating a large volume clot in the right retroperitoneal space and the peritoneal cavity, we detected an index finger-sized aneurysm with arterial bleeding in the right inferioposterior aspect of the pancreas. Hemostasis was obtained by oversewing the aneurysm and a ligation of the feeding arteries. A prophylactic splenectomy was performed for the nonruptured splenic artery aneurysm. This case indicates that emergency angiography is indispensable for both a definitive diagnosis and adequate surgical treatment of PDA aneurysms.

Rapid growth of a retroperitoneal rhabdomyosarcoma following right hemicolectomy for ascending colon cancer: report of a case.

We report herein the case of a 69-year-old man in whom rapid growth of a retroperitoneal rhabdomyosarcoma occurred following hemicolectomy for ascending colon cancer. On his first admission for surgery, a small lesion, 1.5 cm in diameter, was detected adjacent to the inner side of the left kidney by abdominal axial computed tomography (CT), which was initially suspected to be a benign lesion; however, a postoperative follow-up CT scan done 5 months later revealed that the lesion had enlarged remarkably to 8 cm in diameter. Thus, total resection was performed under the presumed diagnosis of a malignant retroperitoneal tumor. The tumor was found to be adjacent to the inner portion of the left kidney and covered by Gerota's fascia. As it involved the ileolumbar muscle and had a metastatic lymph node, complete resection was performed. The resected specimen was 8.5 x 6.5 x 5 cm in size and was histologically confirmed as a retroperitoneal rhabdomyosarcoma of embryonal type. Two courses of adjuvant chemotherapy with adriamycin, vincristine, and cyclophosphamide were given, and the patient has shown no signs of recurrence for 2 years since his second operation.

Detection of lymph-node metastases in patients with gastric carcinoma: comparison of three MR imaging pulse sequences.

BACKGROUND: To compare the diagnostic accuracy of magnetic resonance (MR) images obtained with three different pulse sequences for lymph-node metastases in patients with gastric cancer. METHODS: T1-weighted spin-echo (SE), breath-hold T2-weighted fast SE, and triphasic gadolinium-enhanced dynamic gradient-recall-echo (GRE) MR images obtained in 16 patients with gastric carcinoma were retrospectively reviewed. Regional lymph nodes were assigned to four different groups, and image review was conducted on a lymph-node group-by-group basis; 64 lymph-node groups were reviewed by two radiologists. Relative sensitivity, specificity, and accuracy were determined based on the findings with definitive surgery and follow-up imaging. Diagnostic accuracy was determined by means of receiver-operating-characteristic (ROC) analysis. RESULTS: Relative sensitivities for lymph-node metastases with T1-weighted SE, breath-hold T2-weighted fast SE, and dynamic GRE images were 61%, 94%, and 59%, respectively. Relative sensitivity with breath-hold T2-weighted fast SE images was significantly greater than that with T1-weighted SE (p < 0.05) and dynamic GRE (p < 0.05) images. Diagnostic accuracy determined by ROC analysis was marginally higher with breath-hold T2-weighted fast SE (area under ROC curve [Az] = 0.87) than with T1-weighted SE (Az = 0.78, p = 0.08) and dynamic GRE (Az = 0.79, p = 0.12) images. CONCLUSION: Breath-hold T2-weighted fast SE sequence is useful in the detection of regional lymph-node metastases in patients with gastric carcinoma.

Recurrence of giant adrenocortical carcinoma in the contralateral adrenal gland 6 years after surgery: report of a case.

We report herein the case of a patient in whom a giant adrenocortical carcinoma was found to have recurred in the contralateral adrenal gland and intrapelvic cavity 6 years after his initial operation. A 52-year-old man had consulted our hospital complaining of right upper abdominal pain and weight loss, and was subsequently diagnosed as having a giant adrenal tumor by computed tomography scans and echography. A laparotomy was performed and the tumor, located in the right retroperitoneal cavity and infiltrating the liver and right kidney, was surgically removed. The lesion, 29 x 19 x 10 cm in size and 4700 g in weight, was histopathologically diagnosed as an adrenocortical carcinoma. Adjuvant chemotherapy with mitotane was given for 3 months and his postoperative course was uneventful until a recurrence in the contralateral adrenal gland and peritoneal cavity was found 6 years later. The second resection was successful, and he is currently alive with no further sign of recurrence 8 years after his first operation. We report this unusual case as it provides much useful information on the biological features of adrenocortical carcinomas and the state of tumor dormancy.

Therapeutic effect of TNP-470 on spontaneous liver metastasis of colon tumors in the rabbit.

Even though angiogenesis inhibitor is thought to be one of the promising agents in tumor dormancy therapy, its optimal administration is still unknown. Therefore, the efficient protocol using TNP-470 was examined regarding its treatment affect against spontaneous liver metastases of colon tumors in the rabbit. A spontaneous liver metastases model was established in the rabbit by the inoculation of VX-2 tumors into the subserosal space of the colon. The therapeutic effect of TNP-470 was then investigated by monitoring both the number of metastatic nodules in the liver and the microvessel density (MVD) in the tumor by immunohistochemical staining using anti-CD31 monoclonal antibody. TNP-470 did not show any effect on the primary tumor. It was able to reduce the metastatic spread to liver when it was administered at the microscopic metastatic stage. Treatment at this stage, however, was not able to sufficiently control the disease. These results indicated that TNP-470 could efficiently cause the tumor to enter into a dormant state by inhibiting angiogenesis when it was used at the initial stage of the metastatic process in the liver. Regarding its clinical application, TNP-470 might be useful for preventing the metachronous liver metastases of colorectal cancer when it is administered as adjuvant therapy after curative surgery.

[Clinical evaluation of intermittent hepatic arterial infusion therapy with CDDP and 5-FU for liver metastasis of colorectal cancer].

Twenty-seven patients with liver metastasis from colorectal cancer were treated with intermittent intra-arterial infusion chemotherapy for 5 years starting from 1993. Five to ten mg of CDDP, 250 mg of 5-FU and/or 3-6 mg of Leucovorin were administered weekly. In the case of nonresponders, the dose of 5-FU was allowed to increase toward 500 mg. The above schedule was repeated as long as possible. The average number of administrations in 12 out of 27 unresectable patients was 28.7. The response rate was 50% (CR; 4 cases, PR; 2), with 2 NC and 3 PD. Four patients given 500 mg of 5-FU showed some response. The 50% survival period was 466 days, and the 1- and 3-year survival rates were 66.7% and 18.3%, respectively. The average number of administrations in the group of patients who underwent prophylactic treatment and resection of the metastasis was 33.1. During an average observational period 681 days, 7 patients (46.7%) had a recurrence in the liver. The 5-year survival rate was 85.7%. The patients who were treated with 250 mg 5-FU experienced no severe side effects, but one who was given 500 mg 5-FU developed a duodenal ulcer.

[A recurrent case of esophageal cancer in which metastatic skin tumor disappeared after local injection of activated lymphocytes with tumor-pulsed dendritic cells].

We examined the effect of activated lymphocytes stimulated with tumor-pulsed dendritic cells (DC-K), and found that such stimulation enhanced the cytotoxity of the activated lymphocytes. Furthermore, in applying DC-K to a recurrent case of esophageal cancer, the skin tumors disappeared after local injection of DC-K. The only adverse effect of this treatment was pyrexia. Although no general effect was observed, the local effect was satisfactory. This suggests that DC-K might be useful for local treatment or postoperative adjuvant therapy.

An abdominal desmoid tumor involving the xyphoid and costal chondrium associated with pregnancy: report of a case.

We report herein the case of a 27-year-old woman found to have an abdominal desmoid tumor involving the xyphoid and costal chondrium associated with pregnancy. The patient was referred to our department on the third day after delivery for investigation of a fist-sized, firm tumor in the infrasternal angle, first noticed during the eighth month of gestation. Computed tomography and magnetic resonance imaging revealed a well-defined mass, 9 x 7.5 cm in size, invading the xyphoid. The tumor could be radically excised with the xyphoid, a lower part of sternum, and the chondrium of the bilateral sixth and seventh ribs, including 1.5 cm of free margin. The resected specimen measured 10 x 11.5 x 11.5 cm and weighed 395 g. Histological examination revealed the lesion to be a desmoid tumor consisting of spindle cells with small, elongated nuclei infiltrating dense collagenous fibers. The patient had an uneventful postoperative course and was discharged on the 11th postoperative day. There has been no evidence of recurrence in the 6 months since her operation. This case is of interest with regard to the possible contribution of sex hormones, especially estrogen, to desmoid tumor development.

[Recent progress in biological therapies for cancer].

After approval of national health insurance for non-specific immunomodulation such as OK-432 (1978) and PSK (1980), lentinan, SPG, bestatin and dried BCG vaccine have been tried. Including cytokines such as IL-2, IL-12, IFN, TNF or monoclonal antibodies, they have been widely used as biological response modifiers (BRM). Progress in BRM therapy may be broken down into the first 10 years as development, the next 10 years as disappointment and the most recent 5 years as dream-like progress owing to molecular biological techniques. An interdisciplinary approach has been taken by the Japanese Research Society for Surgical Cancer Immunology, founded in 1980, and the Japanese Society of BRM founded in 1988. Many investigations have been performed on issues such as the clinical evaluation or criteria for responder cases, host immunocompetency, post-operative adjuvant immuno-chemotherapy, locoregional immunotherapy, cytokine therapy, adoptive immunotherapy, and tumor specific immunotherapy. Attention has also focused on malignant tumor injury, surgical stress, the advantages or disadvantages of splenectomy, and discussions of the current status and future prospects in the next century for new BRM therapy.

Impact of splenectomy and immunochemotherapy on survival following gastrectomy for carcinoma: covariate interaction with immunosuppressive acidic protein, a serum marker for the host immune system. Tumor Marker Committee for the Study Group of Immunochemotherapy with PSK for Gastric Cancer.

The role of the spleen in tumor immunology is still controversial in that it can either enhance or suppress the antitumor immune response depending on the tumor-bearing host. To clarify this biphasic effect of the spleen, a clinical evaluation of splenectomy in conjunction with immunotherapy and the host immune status was performed in gastric cancer patients. The effect of splenectomy and immunotherapy in 253 gastric cancer patients enrolled in a prospective randomized trial (SIP) was analyzed using the Cox's proportional hazards model in terms of the covariate interaction of the preoperative immunosuppressive acidic protein (IAP) level. In patients with high IAP levels (>580 microg/ml) with predicted negative antitumor immune reactions, splenectomy improved the prognosis. In patients with lower IAP values, conversely, the preservation of the spleen and immunotherapy demonstrated a significant benefit to survival. The spleen was shown to have a biphasic activity in terms of its antitumor immune response depending on the IAP level of the patient. The effect of immunotherapy is significantly influenced by the activity of spleen cells. The preoperative IAP level is therefore considered to be a possible indicator for the effectiveness of splenectomy and immunotherapy in curatively resected gastric cancer patients.