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Biomedical subjects

Keiichi Nakagawa

Publications and source records attributed to Keiichi Nakagawa.

At least 19 recordsLinked to original sources
PubMed2007

[Radiation therapy in palliative care of cancer patients].

Since westernization of cancer profile and our aging society, the number of radiation therapy is increasing in this country. When compared to surgical operation and chemotherapy, the patient's adverse effects by radiation therapy are relatively limited. This is the reason why this treatment modality is used most frequently as a palliation of terminal-stage cancer patients. Radiation therapy gives not only pain relief of the tumor lesion, but also local control of the disease to prevent pathological fracture, spinal cord compression, or brain metastasis. Recently, technical innovations in this field actualizes pinpoint dose concentration to the cancer lesion, which benefits advanced or terminal cancer patients as well. Clinical usefulness of radiotherapy in the palliative medicine is documented.

Humans↗
PubMed2006

A retrospective study of radiotherapy for spinal bone metastases from hepatocellular carcinoma (HCC).

OBJECTIVE: To evaluate the therapeutic effects of radiotherapy on spinal bone metastases from hepatocellular carcinoma (HCC). METHODS: A retrospective review was conducted on 24 ambulatory patients with spinal bone metastases from HCC treated by radiotherapy from 1995 to 2004. Ambulatory rate and local progression-free rate after radiotherapy were analyzed. Eight (33%) of 24 patients had radiographic spinal cord compression from the spinal bone metastases before the treatment. Two (8.3%) of the 24 patients had some spinal deficits before the treatment. Biological equivalent dose (BED) with alpha/beta ratios of 10 ranged from 39 to 50.7 Gy (median 44.8 Gy). RESULTS: The median observation period was 5.1 months ranging from 0.9 to 36.0 months. Among the 24 patients, five (21%) underwent salvage therapies, while of the remaining 19 patients four (21%) became nonambulatory by the last follow-up. The ambulatory rates at 3 months and 6 months were 85 and 63%, respectively. The local progression-free rates at 3 months and 6 months were 53 and 47%, respectively. CONCLUSIONS: Radiotherapy with a BED of 39-50.7 Gy (median 44.8 Gy) is not sufficiently effective for the patients with spinal bone metastases from HCC to prevent paralysis. Dose escalation with a highly precise radiation technique will need to be evaluated.

Aged↗
PubMed2006

Relation between acute and late irradiation impairment of four basic tastes and irradiated tongue volume in patients with head-and-neck cancer.

PURPOSE: Taste loss is a major cause of morbidity in patients undergoing head-and-neck irradiation. The relationship between the time course and the degree of taste disorder was studied in both acute and late phases. METHODS AND MATERIALS: Taste ability was measured by the taste threshold for the four basic tastes using a filter paper disc method in patients before, during, and after radiotherapy. The subjects were divided into two groups. In Group A, the radiation fields included most of the tongue (n = 100), and in Group B the radiation fields did not include the tip of the tongue (n = 18). RESULTS: In Group A, there was a significant impairment of the threshold of all four basic tastes at 3 weeks after starting radiotherapy (RT), and this impairment remained at 8 weeks (p < 0.05). This was not seen in Group B. In Group A, there was no significant difference in the patterns of taste sensitivity change between the high-dose (>20 Gy) and low-dose (< or =20 Gy) groups. In the late phase, recovery of taste loss was seen in both groups since 4 months after completing RT. CONCLUSIONS: Unless the anterior part of the tongue was irradiated, taste loss was not observed during RT. When the anterior part of the tongue was irradiated, a difference by radiation dose was not observed in the taste loss pattern. Additionally, radiation-induced taste dysfunction appears to be a temporal effect.

Adult↗
PubMed2006

Radiophotoluminescence dosimetry using a small spherical glass: a preliminary phantom study.

A radiophotoluminescence dosimetry has been proposed using a spherical silver-activated phosphate glass with a diameter of 1.5 mm. A 6 MV photon dose of 2 Sv (2 Gy) was delivered to 14 spherical glass samples placed between two solid water phantoms at a depth of 10 cm. The samples were positioned within a 20 x 20 mm(2) centred at beam axis to ensure uniform dose absorption. A normalised output from a read-out system was obtained by simultaneously measuring luminescence from a non-irradiated reference and that from an irradiated reference to eliminate background contamination and time-varying fluctuation of the readout system, leading to a normalised standard deviation of 1.8%. A dose up to 3.5 Sv (3.5 Gy) was delivered to three spherical glass samples positioned between two solid water phantoms at a depth of 10 cm. The normalised output increased linearly with the applied dose.

Luminescent Measurements↗
PubMed2006

Human homolog of Drosophila tumor suppressor Scribble negatively regulates cell-cycle progression from G1 to S phase by localizing at the basolateral membrane in epithelial cells.

Drosophila tumor suppressor Scribble has been identified as an apical-basolateral polarity determinant in epithelia. A human homolog of Drosophila Scribble, human Scribble (hScrib), has been identified as a protein targeted by human papillomavirus E6 for the ubiquitin-mediated degradation dependent on E6AP, a cellular ubiquitin-protein ligase. Human Scribble is classified as a LAP protein, having leucine-rich repeats (LRRs) and PDZ domains. We investigated whether hScrib, which is thought to have a role in polarity determination based on the data of its Drosophila homolog, is involved in cell-cycle regulation and proliferation control of epithelia. Transfection of hScrib inhibits cell-cycle progression from G1 to S phase, and it up- and down-regulates expression of adenomatous polyposis coli and cyclins A and D1, respectively. Knockdown of hScrib expression by siRNA leads to cell-cycle progression from G1 to S phase. We explored functional domain mapping to reveal which domains of hScrib are critical for its cellular proliferation control and localization at the basolateral membrane. We found that LRRs and PDZ domain 1 are indispensable for hScrib to inhibit cell growth by blocking cell-cycle progression and to keep its proper localization. These data indicate that basolateral membrane localization of hScrib is closely related to its proliferation control. Our findings suggest the possibility that hScrib is involved in signal transduction to negatively regulate cell proliferation by localizing at the basolateral membrane of epithelial cells through LRRs and PDZ domains.

Animals↗
PubMed2006

Stereotactic radiosurgery plus whole-brain radiation therapy vs stereotactic radiosurgery alone for treatment of brain metastases: a randomized controlled trial.

CONTEXT: In patients with brain metastases, it is unclear whether adding up-front whole-brain radiation therapy (WBRT) to stereotactic radiosurgery (SRS) has beneficial effects on mortality or neurologic function compared with SRS alone. OBJECTIVE: To determine if WBRT combined with SRS results in improvements in survival, brain tumor control, functional preservation rate, and frequency of neurologic death. DESIGN, SETTING, AND PATIENTS: Randomized controlled trial of 132 patients with 1 to 4 brain metastases, each less than 3 cm in diameter, enrolled at 11 hospitals in Japan between October 1999 and December 2003. INTERVENTIONS: Patients were randomly assigned to receive WBRT plus SRS (65 patients) or SRS alone (67 patients). MAIN OUTCOME MEASURES: The primary end point was overall survival; secondary end points were brain tumor recurrence, salvage brain treatment, functional preservation, toxic effects of radiation, and cause of death. RESULTS: The median survival time and the 1-year actuarial survival rate were 7.5 months and 38.5% (95% confidence interval, 26.7%-50.3%) in the WBRT + SRS group and 8.0 months and 28.4% (95% confidence interval, 17.6%-39.2%) for SRS alone (P = .42). The 12-month brain tumor recurrence rate was 46.8% in the WBRT + SRS group and 76.4% for SRS alone group (P<.001). Salvage brain treatment was less frequently required in the WBRT + SRS group (n = 10) than with SRS alone (n = 29) (P<.001). Death was attributed to neurologic causes in 22.8% of patients in the WBRT + SRS group and in 19.3% of those treated with SRS alone (P = .64). There were no significant differences in systemic and neurologic functional preservation and toxic effects of radiation. CONCLUSIONS: Compared with SRS alone, the use of WBRT plus SRS did not improve survival for patients with 1 to 4 brain metastases, but intracranial relapse occurred considerably more frequently in those who did not receive WBRT. Consequently, salvage treatment is frequently required when up-front WBRT is not used. TRIAL REGISTRATION: umin.ac.jp/ctr Identifier: C000000412.

Adult↗
PubMed2006

Treatment results of chemoradiation therapy for localized aggressive lymphomas: A retrospective 20-year study.

In this study we analyzed our cases of localized aggressive lymphoma treated in our institution during the last 20 years to compare the finding of this study with those of previous studies. Forty patients with Ann Arbor stage I-II aggressive lymphoma were treated with 3-6 cycles of a CHOP regimen (cyclophosphamide, doxorubicin, vincristine, and prednisolone) and radiation therapy (30 or 40 Gy with involved field). Between 1985 and 2003, 40 patients with stage I (N = 25) or stage II (N = 15) disease were treated. Chemotherapy mainly preceded radiotherapy, although the sequence of radiotherapy and chemotherapy was determined by individual physicians and patients' choice. Median and mean age was 50.5 and 48.6 years, respectively, at the time of diagnosis, with a male to female ratio of 19:21. Analyses were undertaken to determine (1) response to treatment according to age, international prognostic index (IPI), lactate dehydrogenase (LDH) value, serum interleukin 2 receptor (sIL-2R) value, cell type, stage, extent of maximum local disease, with or without mediastinal lymph nodes, number of sites, anatomic distribution, and irradiation dose, and (2) relapse patterns. Complete follow-up was obtained in all patients. The follow-up period of surviving 33 patients ranged from 24.7 to 180 months with a median of 69 and a mean of 72.7 months. A complete remission (CR) was achieved in 37 patients (93%). A study of relapse patterns after a CR showed that four patients had a first relapse within a radiation field and the other one patient had an extranodal distant relapse. Significant prognostic factors were not identified by multivariate analysis. Combined chemotherapy and radiation therapy is safe, highly effective, and probably curative for most patients with stage I-II aggressive lymphoma.

Adult↗
PubMed2006

Src tyrosine kinase inhibitor PP2 suppresses ERK1/2 activation and epidermal growth factor receptor transactivation by X-irradiation.

Exposure of MDA-MB-468 cells to ionizing radiation (IR) caused biphasic activation of ERK as indicated by its phosphorylation at Thr202/Tyr204. Specific epidermal growth factor receptor (EGFR) inhibitor AG1478 and specific Src inhibitor PP2 inhibited IR-induced ERK1/2 activation but phosphatidylinositol-3 kinase inhibitor wortmannin did not. IR caused EGFR tyrosine phosphorylation, whereas it did not induce EGFR autophosphorylation at Tyr992, Tyr1045, and Tyr1068 or Src-dependent EGFR phosphorylation at Tyr845. SHP-2, which positively regulates EGFR/Ras/ERK signaling cascade, became activated by IR as indicated by its phosphorylation at Tyr542. This activation was inhibited by PP2 not by AG1478, which suggests Src-dependent activation of SHP-2. Src and PTPalpha, which positively regulates Src, became activated as indicated by phosphorylation at Tyr416 and Tyr789, respectively. These data suggest that IR-induced ERK1/2 activation involves EGFR through a Src-dependent pathway that is distinct from EGFR ligand activation.

Androstadienes↗
PubMed2006

Taste dysfunction in patients receiving radiotherapy.

BACKGROUND: Taste loss is a major cause of morbidity in patients undergoing head and neck irradiation. METHODS: In a prospective study, 51 patients undergoing radical head and neck irradiation at the Tokyo University Hospital were assessed for taste loss. Taste ability was measured by the taste threshold for the four basic tastes (sweet, sour, salt, and bitter qualities) plus another taste of "umami" quality using a filter-paper-disc method in patients before, during, and after radiotherapy (RT). RESULTS: All tastes declined on the fifth week after the start of RT and improved on the 11th week. Anatomic pathologic analyses in rats revealed that taste buds diminished completely on the sixth day after irradiation of 15 Gy in a single fraction, and the appearance of taste buds returned almost to the preirradiation state on the 28th day. CONCLUSIONS: The main cause of taste disorder resulting from RT was believed to be a disappearance of taste buds and not damage to the taste nerves.

Adult↗
PubMed2006

Involvement of a cellular ubiquitin-protein ligase E6AP in the ubiquitin-mediated degradation of extensive substrates of high-risk human papillomavirus E6.

Human scribble (hScrib), which was identified as substrate of human papillomavirus (HPV) E6 for ubiquitin-mediated degradation dependent on ubiquitin-protein ligase E6AP, is a human homolog of Drosophila neoplastic tumor suppressor scribble, in which mutation causes loss of polarity and overgrowth of epithelia. Drosophila discs large (Dlg) is one of neoplastic tumor suppressors, which genetically links to scribble. E6 also targets human Dlg (hDlg) for ubiquitin-mediated degradation. Ubiquitin-protein ligase involved in this process has not been identified thus far. Here we investigated mechanism underlying degradation of three target proteins of E6, hScrib, hDlg, and p53 by using eighteen HPV 16 E6 mutants with single amino acid substitution. In vitro degradation ability of each E6 mutant was equivalent for these tumor suppressors. We investigated whether E6AP is involved in ubiquitin-mediated degradation of hDlg. In vitro binding assay revealed that hDlg formed ternary complex with E6-E6AP complex. The ability of E6 mutants to degrade these tumor suppressors was correlated with their ability to interact with E6AP. Furthermore, hDlg was targeted for in vitro ubiquitination in the presence of both E6 and E6AP. These data revealed that E6AP is extensively involved in the ubiquitin-mediated degradation of E6-dependent substrates as a cellular E3 ubiquitin-protein ligase.

Adaptor Proteins, Signal Transducing↗
PubMed2006

Treatment planning and dosimetry of a multi-axis dynamic arc technique for prostate cancer: A comparison with IMRT.

PURPOSE: Intensity-modulated radiation therapy (IMRT) allows greater dose conformity to the tumor target. However, IMRT, especially static delivery, usually requires more time to deliver a dose fraction than conventional external beam radiotherapy (EBRT). The authors have been using a "two-axis dynamic arc therapy" (2A-DAT) technique for prostate cancer treatment to make a concave dose distribution to spare the rectum and bladder while working with limited time and human resources. The objectives of this study were to (1) clinically implement the 2A-DAT technique, (2) evaluate the dosimetry in comparison with IMRT, and (3) analyze the initial treatment outcome. MATERIALS AND METHODS: The 2A-DAT consists of two dynamic arc therapies (DATs) with half rotation around two isocenters each in two separate symmetrical rhombi. Treatment planning is forward and on a trial-and-error basis. Thirty-four patients received 2A-DAT with a median prescribed dose of 70 Gy. RESULTS: Although inferior in dose uniformity, the 2A-DAT provided equivalent sparing of normal structures to IMRT. Daily fraction delivery time for the 34 patients ranged from 6.4 to 9.6 minutes, with an average of 7.4 minutes. Five-year survival and five-year prostate specific autigen (PSA) failure-free survival were 89.3% and 79.5%, respectively. Three patients developed grade 2 proctitis. CONCLUSION: This technique is a possible alternative to IMRT in EBRT of prostate cancer.

Aged↗
PubMed2006

Treatment results of preoperative concurrent chemoradiotherapy followed by surgery for stage III or IV esophageal squamous cell carcinoma.

PURPOSE: To evaluate the treatment outcome of preoperative neoadjuvant radiotherapy combined with chemotherapy (CTx) for 17 esophageal cancer patients. MATERIALS AND METHODS: Between 1992 and 2004, patients with locally advanced esophageal cancer (stage III or IV) before curative-intent surgery received radiotherapy (RT) combined with CTx (Cisplatin: 75 mg/m2, bolus infusion, and 5-fluorouracil (5-FU): 1,000 mg/m2/24 h, continuous infusion for 4 days) at a median total dose of 30 Gy (n=17). RESULTS: The median survival period was 13.8 months. The overall survival rates at 1, 2, and 3 years were 75%, 40%, and 20%, respectively. According to univariate analysis, no factor of worse prognosis was found. Pathological markedly (Grade 3) or moderately (Grade 2) effects were observed in 4 patients (24%) and 8 patients (47%), respectively. CONCLUSION: These results indicate that, although this regimen was effective in terms of pathological effect, it is unclear whether it made a contribution to the improvement of survival

Aged↗
PubMed2006

Human scribble, a novel tumor suppressor identified as a target of high-risk HPV E6 for ubiquitin-mediated degradation, interacts with adenomatous polyposis coli.

Recently, we have identified human scribble (hScrib), human homolog of the Drosophila tumor suppressor Scribble, as a substrate of human papillomavirus E6 oncoproteins for ubiquitin-mediated degradation dependent on ubiquitin-protein ligase E6AP. Human Scribble, classified as a LAP protein containing leucine-rich repeats and PDZ domains, interacts with E6 through its PDZ domains and C-terminal PDZ domain-binding motif of E6 protein. Interaction between human Discs Large (hDlg), which is a substrate of E6 for the ubiquitin-mediated degradation, and adenomatous polyposis coli (APC) has been shown. Here, we investigated whether hScrib and APC interact with each other in vitro and in vivo. Interaction between hScrib and APC is mediated by the PDZ domains 1 and 4 of hScrib and C-terminal PDZ domain-binding motif of APC. Human Scribble co-localized with APC at the synaptic sites of hippocampal neuron and at the tip of membrane protrusion in the epithelial cell line. Interference of the interaction between hScrib and APC caused disruption of adherens junction. Knockdown of hScrib expression by RNAi disrupts localization of APC at the adherens junction. These data suggest that hScrib may participate in the hDlg-APC complex through its PDZ domains and regulate cell cycle and neural function by associating with APC.

Adenomatous Polyposis Coli Protein↗
PubMed2006

External beam radiotherapy to treat intra- and extra-hepatic dissemination of hepatocellular carcinoma after radiofrequency thermal ablation.

BACKGROUND: Radiofrequency ablation (RFA) is an alternative to percutaneous ethanol injection therapy (PEIT) for single non-surgical hepatocellular carcinoma. However, the risk of seeding along the needle track has been reported. METHODS: Seven patients presenting with neoplastic seeding after RFA or PEIT were treated with external beam radiotherapy using conventional fractionation. All patients underwent irradiation with a total dose in the range of 44-61 Gy (median and mode value: 50 Gy). RESULTS: An objective response to treatment was achieved in six of seven patients (86%). A complete response was obtained in two patients (29%). The median survival time was 14.7 months and the actuarial 1- and 2-year survivals were 67% and 50%, respectively. CONCLUSIONS: The response to treatment was relatively good without serious complications. Seeding from hepatocellular carcinoma is sensitive to external beam radiotherapy. It is useful in the treatment of these patients with 50 Gy in 25 fractions.

Aged↗
PubMed2006

Small bowel perforation without tumor recurrence after radiotherapy for cervical carcinoma: report of seven cases.

AIM: We describe the clinical presentation, evaluation, management and outcome of patients experiencing small bowel perforation following radiation therapy for cervical cancer. METHODS AND MATERIALS: A database consisting of 95 Japanese women with stage 0-4 A cervix cancer treated between 1991 and 2004 contained seven patients (7.4%) with small bowel perforation. RESULTS: The median age at the time of perforation was 72.5 years (range 62-78). The median time from completion of radiotherapy to perforation was 6 months (range 2-58). Surgery (one small bowel resection and anastomosis with diversion; six small bowel resection and anastomosis) was performed immediately in all seven patients. One of seven patients died of small bowel perforation (i.e. mortality rate was 14%). Bowel adhesion was detected during the operation in only three cases (43%). Signs of peritonitis were absent in six cases (86%). Severe abdominal pain was seen in all seven patients. The perforation site was ileum in all seven cases. In all patients, pathological changes were compatible with postirradiation injury of the gastrointestinal tract. CONCLUSIONS: The presenting complaints of patients with bowel perforation following radiotherapy vary, and signs of peritonitis may be absent. Emergency physicians must be alert for these complications in patients who have been treated with radiotherapy.

Aged↗