Long-term follow-up of the randomized trial of mesorectal excision with or without lateral lymph node dissection in rectal cancer (JCOG0212).

BACKGROUND: Japan Clinical Oncology Group (JCOG) 0212 (ClinicalTrials.gov NCT00190541) was a non-inferiority phase III trial of patients with clinical stage II-III rectal cancer without lateral pelvic lymph node enlargement. The trial compared mesorectal excision (ME) with ME and lateral lymph node dissection (LLND), with a primary endpoint of recurrence-free survival (RFS). The planned primary analysis at 5 years failed to confirm the non-inferiority of ME alone compared with ME and LLND. The present study aimed to compare ME alone and ME with LLND using long-term follow-up data from JCOG0212. METHODS: Patients with clinical stage II-III rectal cancer below the peritoneal reflection and no lateral pelvic lymph node enlargement were included in this study. After surgeons confirmed R0 resection by ME, patients were randomized to receive ME alone or ME with LLND. The primary endpoint was RFS. RESULTS: A total of 701 patients from 33 institutions were assigned to ME with LLND (351) or ME alone (350) between June 2003 and August 2010. The 7-year RFS rate was 71.1 per cent for ME with LLND and 70·7 per cent for ME alone (hazard ratio (HR) 1·09, 95 per cent c.i. 0·84 to 1·42; non-inferiority P = 0·064). Subgroup analysis showed improved RFS among patients with clinical stage III disease who underwent ME with LLND compared with ME alone (HR 1·49, 1·02 to 2·17). CONCLUSION: Long-term follow-up data did not support the non-inferiority of ME alone compared with ME and LLND. ME with LLND is recommended for patients with clinical stage III disease, whereas LLND could be omitted in those with clinical stage II tumours.

ANTECEDENTES: El JCOG0212 (ClinicalTrials.gov: NCT00190541) fue un ensayo fase III de no inferioridad en pacientes con cáncer de recto en estadio clínico II/III sin ganglios linfáticos aumentados de tamaño en la pared pélvica lateral. El ensayo comparó la escisión del mesorrecto (mesorectal excision, ME) con la ME con disección de los ganglios linfáticos laterales (lateral lymph node dissection, LLND), siendo el criterio de valoración principal la supervivencia libre de recidiva (recurrence free survival, RFS). El análisis primario planificado a los 5 años de seguimiento no pudo confirmar la no inferioridad de la ME frente a la ME con LLND. Este estudio tuvo como objetivo comparar la ME como procedimiento único y la ME con LLND utilizando datos de seguimiento a largo plazo del ensayo JCOG0212. MÉTODOS: En este estudio se incluyeron pacientes con cáncer de recto en estadio clínico II/III por debajo de la reflexión peritoneal sin ganglios linfáticos aumentados de tamaño en la pared pélvica lateral. Después de que los cirujanos confirmaran la resección R0 mediante la ME, los pacientes fueron asignados al azar al brazo de ME sola o al brazo de ME con LLND. El criterio de valoración principal fue la supervivencia libre de recidiva (RFS). RESULTADOS: Un total de 701 pacientes de 33 instituciones fueron asignados al azar para ser tratados mediante una ME con LLND (n = 351) o EM sola (n = 350) entre junio de 2003 y agosto de 2010. Las tasas de RFS a 7 años fueron del 71,1% para ME con LLND y 70,7 % para ME sola (cociente de riesgos instantáneos, hazard ratio, HR: 1,09 (i.c. del 95% 0,84-1,42), no inferioridad P = 0,064)). El análisis de subgrupos mostró una mejor RFS entre los pacientes en estadio clínico III que se sometieron a ME con LLND en comparación con ME sola (HR: 1,49 (i.c. del 95%: 1,02-2,17)). CONCLUSIÓN: Los datos de seguimiento a largo plazo no justificaron la no inferioridad de la ME en comparación con la ME con LLND. Se recomienda la ME con LLND para pacientes en estadio clínico III, mientras que LLND podría omitirse para pacientes en estadio clínico II.

Differences between primary central nervous system lymphoma and glioblastoma: topographic analysis using voxel-based morphometry.

AIM: To evaluate the diagnostic feasibility of probabilistic analysis using voxel-based morphometry (VBM) in differentiating primary central nervous system lymphoma (PCNSL) from glioblastoma (GBM). MATERIALS AND METHODS: In total, 118 patients with GBM (57 males, 61 females; mean [± standard deviation] age, 56.9±19.3 years; median, 61 years) and 52 patients with PCNSL (37 males, 15 females; mean age, 62±13.3 years, median, 66 years) were studied retrospectively. Each patient underwent preoperative contrast-enhanced T1-weighted imaging (CE-T1WI) using a 1.5 or 3 T magnetic resonance imaging (MRI) system. To assess preferential occurrence sites, images from CE-T1WI were co-registered and spatially normalised using the MNI152 T1 template. Subsequently, a region of interest (ROI) was placed in the centre of the enhancing tumour in normalised images with 1-mm isotropic resolution. The same ROI between normalised and T1 template images was set up using an ROI manager function in ImageJ software. A spherical volume of interest (VOI) with a radius of 10 mm was determined. A probability map was created by overlaying each image with the VOI. Each VOI was removed from T1 template images for VBM analysis. VBM analysis was performed using statistical parametric mapping (SPM) 12 software under default settings. RESULTS: VBM analysis showed significantly higher frequency in the splenium of the corpus callosum among PCNSL patients than among GBM patients (p<0.05; family-wise error correction). CONCLUSION: Topographic analysis using VBM provides useful information for differentiating PCNSL from GBM.

Navigation surgery for intraoperative sentinel lymph node detection using Indocyanine green (ICG) fluorescence real-time imaging in breast cancer.

A new sensitive fluorescence imaging system was developed for the real-time identification of sentinel lymph nodes (SLNs) in patients with early breast cancer. The purpose of this study was to evaluate the utility of a color charge-coupled device camera system for the intraoperative detection of SLNs and to determine its clinical efficacy and sensitivity in patients with operable breast cancer. We assessed a total of 168 patients diagnosed with or suspected of having early-stage breast cancer without metastasis in SLNs. The intraoperative detection of SLNs was performed using the conventional Indigo Carmine dye (indigotindisulfonate sodium) technique combined with a new Indocyanine green (ICG) imaging system (HyperEye Medical System: HEMS, MIZUHO IKAKOGYO, Japan) to map SLNs, in which the lymphatic vessels and SLNs were visualized transcutaneously with illuminating ICG fluorescence. Between January 2012 and May 2013, SLNs were successfully identified in all 168 patients (detection rate: 100%). By histopathology, the sensitivity was 93.8% for the detection of the metastatic involvement of SLNs (15 of 16 nodal-positive patients). After a median follow-up of 30.5 months, none of the patients presented with axillary recurrence. These results suggest that the HEMS imaging system is a feasible and effective method for the detection of SLNs in breast cancer. Furthermore, the HEMS device permitted the transcutaneous visualization of lymphatic vessels under light conditions, thus facilitating the identification and detection of SLNs without affecting the surgical procedure, together with a high sensitivity and specificity.

Endovascular Treatment for Very Early Hepatic Artery Stenosis Following Living-Donor Liver Transplantation: Report of Two Cases.

BACKGROUND: Some literature has reported on endovascular treatment for very early hepatic artery stenosis (HAS; within 2 weeks after liver transplantation, and has deemed endovascular treatment to be a contraindication because out of serious complications associated with the procedure. We report on 2 cases of very early HAS successfully treated with endovascular treatment after living-donor liver transplantation (LDLT). CASE 1: A 54-year-old woman underwent LDLT with a left liver graft. The native right gastric artery and left hepatic artery (LHA) of the donor were anastomosed. On postoperative day (POD) 13, HAS was suspected and multidetector computerized tomographic angiography (MDCTA) was performed, which revealed 90% stenosis of the arterial anastomosis and 50% stenosis of the LHA in the graft. We performed percutaneous balloon arterioplasty (PBA) without any complications. The artery was patent with a postoperative follow-up of 60 months without the need for repeat intervention. CASE 2: A 67-year-old woman with a history of repeated transarterial chemoembolization for hepatocellular carcinoma underwent LDLT with a left liver graft. The native A4 and LHA of the donor were anastomosed. We performed MDCTA on POD 11, which revealed 70% stenosis of the native hepatic artery. We performed PBA followed by stent placement on POD 11 without complication. The artery was patent with a postoperative follow-up of 40 months without the need for repeated intervention. CONCLUSIONS: Endovascular treatment has the potential to avoid the need for repeated surgical interventions or retransplantation, and it can be safely performed in carefully selected patients.

Metronomic chemotherapy using weekly low-dosage CPT-11 and UFT as postoperative adjuvant therapy in colorectal cancer at high risk to recurrence.

This study was designed to evaluate the antitumor efficacy and feasibility of postoperative adjuvant metronomic chemotherapy using weekly low-dosage CPT-11 and UFT in colorectal cancer at high risk to recurrence. A total of 49 patients (24 stage IIIb and 25 distant metastasis) who underwent a R0 operation were enrolled in this prospective study. Forty mg/m2 of CPT-11 were administered on day 1, day 8, and on day 15 in 28-day cycles. A dosage of 335 mg/m2/day of UFT was given perorally on daily schedule. Cycles were repeated for 6 months, and were followed by UFT alone for further 6 months. One or more adverse effects were seen in 43 of the 49 patients. However, most of these effects were mild at grade 1 or 2: with only nausea in 3 patients, vomiting in 2, leucopenia in 2 and neutropenia in 2 at grade 3. The overall survival rates were favorable both in the stage IIIb group (5-year: 73%) and in the distant metastases group (5-year: 62%). Postoperative adjuvant metronomic chemotherapy using weekly low-dosage CPT-11 and UFT might be safe and feasible and prolong survival time in colorectal cancer at high risk to recurrence.

Axial length, myopia, and the severity of lens opacity at the time of cataract surgery.

OBJECTIVE: To investigate the relationship between axial length, myopia of the eye, and the severity of lens opacity at the time of cataract surgery. METHODS: We retrospectively reviewed a consecutive series of 198 eyes of patients aged older than 50 years at Fukui University Hospital (Fukui, Japan) from June 2004 to December 2005. Patient age at the time of surgery, axial length, spherical equivalent, and the subtypes and severity of cataract (as classified according to the modification of the Lens Opacities Classification System, version III) were recorded. RESULTS: Axial length was significantly associated with age at the time of cataract surgery (P<.001). Regarding the severity of nuclear cataract, a significant correlation was seen between a higher score of nuclear cataract and longer axial length (P<.001). The relationship between the severity of nuclear cataract and spherical equivalent at the time of surgery showed a significant association between grading nuclear color and nuclear opalescence 4-6 and higher myopia (P<.001). CONCLUSION: An increase in axial length or myopia of the eye was associated with a lower mean age at the time of surgery and higher grade of nuclear cataract.

Regulation of vascular endothelial growth factor expression in human colon cancer by insulin-like growth factor-I.

We investigated the role of insulin-like growth factor (IGF)-I and IGF-binding proteins (IGFBPs) in the regulation of vascular endothelial growth factor (VEGF) expression in colon cancer cells and the mechanism by which this regulation occurs. HT29 human colon cancer cells were treated with IGF-I for various time periods. VEGF mRNA expression increased within 2 h and peaked at 24 h. SW620 colon cancer cells exhibited a peak induction of VEGF mRNA 8 h after IGF-I treatment. IGF-I induction of VEGF was confirmed at the protein level. In experiments using transient transfection of VEGF promoter-reporter constructs into HT29 cells, IGF-I increased the activity of the VEGF promoter, and pretreatment of HT29 cells with dactinomycin abrogated the induction of VEGF mRNA by IGF-I. The half-life of VEGF mRNA was not prolonged by treatment with IGF-I. Blocking the activity of IGFBP-4 did not significantly modulate the effect of IGF-I induction of VEGF mRNA in HT29 cells. Treating cells with des-(1-3)-IGF-I (an active derivative of IGF-I that does not bind to binding proteins) had effects on VEGF mRNA expression that were similar to those of IGF-I. These findings suggest that IGF-I regulates VEGF expression in human colon cancer cells by induction of transcription of the VEGF gene. IGFBPs do not significantly affect IGF-I induction of VEGF.

Evaluation of resectability after neoadjuvant chemotherapy for primary non-resectable colorectal liver metastases: A multicenter study.

BACKGROUND/AIM: The Kyushu Study Group of Clinical Cancer (KSCC) previously reported the safety and efficacy of neoadjuvant chemotherapy with mFOLFOX6 + bevacizumab for H2/H3 liver metastases of colorectal cancer. The aim of the current study was to evaluate the resectability of these metastases before and after chemotherapy as determined by independent liver surgeons. METHODS: Between May 2008 and April 2010, 40 patients were registered in a multicenter phase 2 trial of neoadjuvant chemotherapy (KSCC 0802). In Study 1, 5 independent liver surgeons from five different KSCC centers evaluated the resectability of liver metastases of colorectal cancer based on imaging studies performed before and after chemotherapy. Each surgeon was blinded to the other surgeons' evaluations. In addition, no information about the patients' characteristics was provided. In Study 2, 3 surgeons evaluated the resectability of these lesions based on imaging studies with discussion with each other, with the surgeons being provided with information on the patients' characteristics. RESULTS: In Study 1, 13 patients (36.1%) were evaluated to be resectable at baseline, whereas 17 patients (47.2%) were evaluated to be resectable after chemotherapy. In Study 2, 4 patients (11.1%) were evaluated to be resectable at baseline, compared to 23 patients (63.9%) after chemotherapy. CONCLUSION: Neoadjuvant chemotherapy with mFOLFOX6 + bevacizumab was confirmed to increase the resectability of non-resectable liver metastases of colorectal cancer according to the independent assessments of surgeons.

Localization of aldose reductase in the human eye.

The presence of the enzyme aldose reductase is increasingly being linked to diabetic complications. The distribution of this enzyme in human cornea, lens, retina, and optic nerve has been studied using specific antibodies against purified human placental aldose reductase raised in both rabbit and goat. The antisera from both animals gave equal, specific reactions. In frozen sections of ocular tissues, significant aldose reductase localization was reproducibly demonstrated in the endothelium and epithelium of the cornea and in the basal cell layers of the conjunctiva. In the lens, staining was observed in the epithelium and superficial lens fibers. In retinal sections, the presence of aldose reductase was demonstrated in the Mueller's cells, especially near the inner limiting membrane. It was also found in some ganglion and cone cells. In the optic nerve, positive staining was observed in the axon. All other cells of the tissues examined revealed only weak, nonspecific staining.

Prevention of basement membrane thickening in retinal capillaries by a novel inhibitor of aldose reductase, tolrestat.

A diabetic-like thickening of retinal capillary basement membranes induced in rats fed for 207 consecutive days a diet containing 50% galactose was prevented by the addition to the diet of tolrestat, a potent, structurally novel inhibitor of aldose reductase. Analysis of electron micrographs (X 25,000) of capillaries from the outer plexiform layer of the retina by computer planimetry showed that the basement membranes were approximately twofold thicker in rats fed galactose than in those fed either a standard diet or a diet containing galactose and tolrestat in doses of 43 or 57 mg/kg/day. The thickening of basement membranes in galactose-fed rats was accompanied by other ultrastructural alterations mimicking changes typical of diabetic microangiopathy, such as multilamination and the formation of vacuoles and dense inclusions. Therefore, the galactosemic rat represents a useful model for studying basement membrane-related complications of diabetes and their possible prevention by aldose reductase inhibitors.

Transactivation of involucrin, a marker of differentiation in keratinocytes, by lens epithelium-derived growth factor (LEDGF).

Human involucrin (hINV), first appears in the cytosol of keratinocytes and ultimately cross-linked to membrane proteins via transglutaminase and forms a protective barrier as an insoluble envelope beneath the plasma membrane. Although the function and evolution of involucrin is known, the regulation of its gene expression is not well understood. An analysis of the hINV gene sequence, upstream of the transcription start site (-534 to +1 nt) revealed the presence of potential sites for binding of lens epithelium-derived growth factor (LEDGF); stress response element (STRE; A/TGGGGA/T) and heat shock element (HSE; nGAAn). We reported earlier that LEDGF activates stress-associated genes by binding to these elements and elevates cellular resistance to various stresses. Here, gel-shift and super-shift assays confirm the binding of LEDGF to the DNA fragments containing HSEs and STREs that are present in the involucrin gene promoter. Furthermore, hINV promoter linked to CAT reporter gene, cotransfected in human corneal simian virus 40-transformed keratinocytes (HCK), was transactivated by LEDGF significantly. In contrast, the activity of hINV promoter bearing mutations at the WT1 (containing HSE and STRE), WT2 (containing STRE) and WT3 (containing STRE) binding sites was diminished. In addition, in HCK cell over-expressing LEDGF, the levels of hINV mRNA and hINV protein are increased by four to five-fold. LEDGF is inducible to oxidants. Cells treated with 12-O-tetradecanoyl-phorbol-13-acetate (TPA), known to stimulate production of H(2)O(2), showed higher levels of LEDGF mRNA. Furthermore, our immunohistochemical studies revealed that hINV protein is found in the cytoplasm of HCK cells over-expressing LEDGF, but not detectable in the normal HCK cells or HCK cells transfected with vector. This regulation appears to be physiologically important, as over-expression of HCK with LEDGF increases the expression of the endogenous hINV gene and may provide new insight to understand the molecular mechanism of transcriptional regulation of this gene. LEDGF may play an important role in establishing an important barrier in corneal keratinocytes by maintaining epidermal turn-over rate, and protecting HCKs against stress.

Significance of platelet-derived endothelial cell growth factor in the angiogenesis of human gastric cancer.

We have previously shown that platelet-derived endothelial cell growth factor (PD-ECGF) is associated with angiogenesis of human colon cancer; this factor is expressed at high levels in vascular tumors that express low levels of vascular endothelial growth factor (VEGF). In these colon cancers, the major source of PD-ECGF is the infiltrating cells. In this study, we examined the role of PD-ECGF in the angiogenesis of human gastric cancer. Immunostaining for PD-ECGF was done on 93 gastric cancers previously stained for VEGF, basic fibroblast growth factor, and factor VIII-related antigen (specific for endothelial cells). To determine the cell type expressing PD-ECGF, double staining was done using antibodies to both PD-ECGF and CD68 (specific for macrophages). PD-ECGF was expressed more frequently in infiltrating cells (positive CD68 staining; 53.8%) than in tumor epithelium (9.7%; P < 0.0001). Infiltrating cells simultaneously stained positive for both PD-ECGF and CD68. An association between PD-ECGF expression in infiltrating cells, VEGF expression in tumor epithelium, and vessel count was observed in intestinal-type gastric cancer but not in diffuse-type gastric cancer. Vessel count was greater in tumors with high expression of both PD-ECGF and VEGF than in those with high expression of either factor alone (P = 0.002). Multiple angiogenic factors expressed by both tumor cells and infiltrating cells may play a role in the regulation of angiogenesis in intestinal-type gastric cancer.

The localization of the motor neurons innervating the extraocular muscles in the oculomotor nuclei of the cat and rabbit, using horseradish peroxidase.

The localization of the motor neurons innervating the extraocular muscles in the oculomotor nuclei of adult cats and rabbits was investigated by means of retrograde labelling with horseradish peroxidase (HRP). The groups consisting of the motor neurons innervating an individual muscle lay in the nucleus as elongated columns extending in a longitudinal direction. The position of each group in the transverse section varied according to the rostro-caudal level of the nucleus. In the cat and rabbit, entire contralateral innervation of the superior rectus and entire ipsilateral innervation of three muscles of the inferior rectus, medial rectus and inferior oblique were similarly observed. However, the arrangement of individual motor groups differed considerably in both animals except for the group innervating the inferior rectus which was generally found in the ventral position running through the rostral two-thirds of the oculomotor nucleus. In the case of cats, the central caudal nucleus bilaterally innervated the levator palpebrae superioris. The motor neurons innervating this muscle in the rabbit (which lacks the central caudal nucleus) formed a rostro-caudal club-shaped column close to the group innervating the superior rectus. The aberrant cellular mass in the adjoining medial longitudinal fasciculus which belongs to the medial rectus appears to play an important role in the eye movement, because it commonly appears in various animals.

Treatment results of stage I and II oral tongue cancer with interstitial brachytherapy: maximum tumor thickness is prognostic of nodal metastasis.

PURPOSE: To evaluate the prognostic importance of T classification and maximum tumor thickness (MTT) on the treatment results of Stage I and II oral tongue cancer treated with interstitial brachytherapy. METHODS AND MATERIALS: Between January 1981 and December 1993, 173 cases were eligible for this retrospective analysis. Of 173 patients, 75 were classified as Stage I and 98 as Stage II: maximum tumor length ranged from 6 to 40 mm. MTT, which ranged from 2 to 38 mm, was measured with ultrasonography and/or palpation. Brachytherapy was performed with iridium hairpins or radium needles following external irradiation in 66 patients, or exclusively in 107 patients. RESULTS: The 5-year local recurrence rates were Stage I, 7%; Stage II, 22%; MTT < 8 mm, 8%; and MTT > or = 8 mm, 28%. The 5-year regional recurrence rates were Stage I, 15%; Stage II, 29%; MTT < 8 mm, 18%; and MTT > or = 8 mm, 31%, respectively. The 5-year local recurrence rates of the patients with Stage I and MTT < 8 mm of the brachytherapy only group were significantly better than those of Stage II and MTT > or = 8 mm (5% and 6% vs. 16% and 24%). The 5-year regional recurrence rates of the patients with Stage I and MTT < 8 mm of the brachytherapy-only group were significantly better than those of Stage II and MTT > or = 8 mm (14% and 16% vs. 34% and 46%). There was no significant difference in the 5-year regional recurrence rates between the two groups of Stage I and Stage II, MTT < 8 mm. However, there was a significant difference in the 5-year regional recurrence rates between the two groups of MTT > or = 8 mm (p < 0.005). CONCLUSIONS: For patients with Stage I and II oral tongue cancer, tumor thickness as well as T classification were prognostic for nodal metastasis and prognosis. Patients with MTT > or = 8 mm are more likely to fail in the neck region. These findings suggest that MTT should be considered along with T stage in determining strategies for Stage I and II oral tongue cancer.

Interstitial brachytherapy for stage I and II squamous cell carcinoma of the oral tongue: factors influencing local control and soft tissue complications.

PURPOSE: Our aim was to study the treatment parameters that influence local control and soft tissue complications (STC) in a series of 207 Stage I and II squamous cell carcinomas of the oral tongue treated by interstitial brachytherapy (BRT) alone (127 patients), or by a combination using external beam irradiation (EBI) (80 patients) between 1980 and 1993. METHODS AND MATERIALS: The patient distribution was 93 T1, 72 T2a, and 42 T2b. The prescribed BRT dose at the plane 5 mm from the plane of the radioactive sources was 65-70 Gy in BRT alone, and 50-60 Gy in the combined treatment using EBI. Generally, an EBI dose of 30 Gy was used. No prophylactic neck treatment was performed. RESULTS: The 5-year local recurrence-free rate for T1, T2a, and T2b was 92.9%, 81.9%, and 71.8%, respectively (p < 0.05). The lesions of endophytic appearance and those located in the posterior half of the mobile tongue had a significantly lower local control rate than those of other macroscopic appearances (p = 0.02) and those in other localizations (p < 0.01). Most local recurrences (66.7%) occurred within 2 years after treatment. However, 8 of 14 recurrences of T1 and 6 of 15 recurrences among patients treated by BRT alone occurred after 5 years. Statistical analysis showed that, in BRT alone treatment, a dose rate < = 1.0 Gy/h was related to better local control (p = 0.04). There was no significant relationship between BRT dose and local control; however, the incidence of local recurrence was lowest in a BRT dose 65-70 Gy. In the combined treatment, a total dose > 85 Gy (p = 0.01), BRT dose > 55 Gy (p = 0.04), and a dose rate < 0.55 Gy/h (p = 0.03) were significantly related to better local control. The incidence of more severe STC were 11.5% and was significantly higher in T2a (p = 0.03) and T2b (p < 0.01) than in T1. Statistical analysis revealed that a dose rate > = 0.6 Gy/h was significantly related to more STC in BRT alone (p = 0.03), and that a dose rate > = 0.55 Gy/h (p < 0.03) and a BRT dose > 70 Gy ( < 0.05) and a total dose > 100 Gy (p < 0.05) were significantly related to more STC in the combined treatment. Neck metastases occurred in 25% in T1N0, 27% in T2aN0, and 31% in T2bN0 (NS). Eighty-eight percent were found within 12 months. Thirty-three secondary cancers including 12 head and neck, 8 esophageal, and 3 gastric were found after treatment. The 5-year crude survival rate for T1, T2a, and T2b was 83.4%, 66.0%, and 70.9%, respectively. CONCLUSION: To acheive better local control and fewer STC, we recommend the following relationships between dose and dose rate. In BRT alone, dose rate should be maintained at < 0.6 Gy/h with a preferable BRT dose 65-70 Gy. In the combined treatment, total dose, BRT dose and dose rate should be kept between > 85 Gy and < = 100Gy, between > 55 Gy and < = 70 Gy, and < 0.55 Gy/h, respectively. We also recommend longer follow-up periods; more than 5 years might be necessary for late local recurrences and for secondary cancers.

An analysis of mandibular bone complications in radiotherapy for T1 and T2 carcinoma of the oral tongue.

PURPOSE: To examine the incidence of mandibular bone complication in patients who underwent radiotherapy for T1 and T2 carcinomas of the oral tongue and to analyze the factors contributing to its occurrence. METHODS AND MATERIALS: The clinical records of 148 patients with T1 and T2 carcinoma of the oral tongue treated with radiotherapy alone between 1978 and 1989 were examined retrospectively. Interstitial brachytherapy, used as the major treatment modality, was performed using cobalt needles, radium needles, or iridium hairpins. The prescribed dose at the plane 5 mm from the plane of the radioactive sources was 65-70 Gy in interstitial brachytherapy alone, and 50-60 Gy in the combined treatment with external irradiation. An external irradiation dose of 30 Gy was usually used. RESULTS: Eleven of the patients showed radiation-induced mandibular bone complication. Two (1 T1, 1 T2) had been treated with interstitial brachytherapy alone, and nine (2 T1, 7 T2) with the combination of external irradiation and interstitial brachytherapy. The incidence of radiation complication of bone was significantly higher in the patients with T2 tumors (p = 0.04) and in those who received the combined treatment (p < 0.01). Multivariate analysis revealed that the total dose (p = 0.04) and dose rate of interstitial brachytherapy (p = 0.03) were significant factors contributing to radiation bone complication. A significant difference in the incidence of bone complication was also seen between patients who received a total dose of 90 Gy or more and those who received less than 90 Gy (p < 0.01), as well as between patients who were treated with 0.55 Gy/h or higher and those who were treated with less than 0.55 Gy/h (p = 0.03). CONCLUSION: A significant increase in the incidence of bone complication was found at the total dose of 90 Gy or more and at the dose rate of 0.55 Gy/h or higher. In combined treatment with external irradiation and interstitial brachytherapy, the interstitial brachytherapy dose of 60 Gy appears to be the threshold at which mandibular bone complication is induced when the external irradiation dose is 30 Gy.

Optimum fractionation for high-dose-rate endoesophageal brachytherapy following external irradiation of early stage esophageal cancer.

PURPOSE: To establish the optimum fractionation for high-dose-rate (HDR) endoesophageal brachytherapy (EBT) for early stage esophageal cancer from retrospective data of patients treated with different HDR schedules following external beam irradiation (EBI). METHODS AND MATERIALS: The study population consisted of 35 consecutive early stage esophageal cancer patients who received EBI to the mediastinum, plus EBT, between May 1992 and November 1995 at the Hiroshima University Medical Center and Hiroshima City Hospital. All patients were treated with EBI, with doses ranging from 50 to 61 Gy. The spinal cord was spared after 44-45 Gy. HDR EBT was performed using a double-balloon applicator in conjunction with an Ir-192 remote afterloading system. One group of 10 patients was given a weekly endoesophageal boost of 4 or 5 Gy at a distance of 5 mm from the applicator surface over a period of 1-2 weeks. Another group of 25 patients was treated with 4 or 5 endoesophageal boosts with a fraction dose of either 2.5 or 2 Gy for 1 week. The linear quadratic (LQ) formula was used to calculate the biologically effective dose (BED) for tumor (Gy10) and esophageal mucosa (Gy3); Gy10 means alpha/beta equals 10 Gy, and Gy3 means alpha/beta equals 3 Gy. The Kaplan-Meier method was used to calculate the local control and late complication rates, while the Cox-Mantel test was used to evaluate statistical significance (p < 0.01). RESULTS: Nine (26%) of the 35 patients recurred locally and 7 (20%) had late complications (esophageal ulcer grade by RTOG/EORTC criteria > 1). The 5-year overall survival, local control, and late complication rates were 38%, 57%, and 26%, respectively. The probability of local recurrence was not affected by the treatment parameters. Results from the LQ formula significantly correlate with data on late complications. A BED > 134 Gy3 and a fraction number = < 3 were associated with late complications (grade > 1). BED analysis showed that the fractionation dose should be decreased to 2.5 or 2.0 Gy at a distance of 5 mm from the applicator surface, and the number of doses increased to 4 or 5, respectively, to yield a satisfactory BED (< 134 Gy3). CONCLUSION: A significant reduction in endoesophageal brachytherapy dose per fraction is necessary to reduce late complications. Our current treatment protocol for early-stage esophageal cancer consists of EBI of 60 Gy followed by 4 EBT doses at a fraction dose of 2.5 Gy applied over 1 week.

Immunohistochemical localization for aldose reductase in diabetic lenses.

Sugar cataract formation has been demonstrated to result from lenticular sorbitol accumulation. In the lens, the activity of aldose reductase has been observed to increase with the onset of diabetes, while the activity of sorbitol dehydrogenase decreases. This shift in activities of these two Sorbitol Pathway enzymes favors the increased accumulation of sorbitol. Immunohistochemical studies with antibodies prepared against purified rat lens aldose reductase reveal a striking increase in immunoreactive positive staining for aldose reductase in lenses from diabetic rats. Two weeks after the onset of diabetes, increased immunohistochemical staining for aldose reductase appears beneath the epithelial region where water cleft formation occurs, and the intensity of this staining increases with the formation of vacuoles. By 6-8 weeks, the presence of large vacuoles and areas of liquifaction containing dense immunoreactive stain can be observed. Examination of human cataractous lenses with antibodies prepared against purified human placenta aldose reductase suggest similar increases in immunoreactive staining in the human diabetic lens. Cataractous lenses from diabetic patients revealed increased immunoreactive staining for aldose reductase, which was associated with the presence of vacuoles in both the anterior or posterior superficial cortical layers. Examination of similar vacuole containing regions from non-diabetic cataractous lenses revealed no increase in immunoreactive staining for aldose reductase. These results suggest that the enhanced activity of aldose reductase observed in diabetes is due to an increased amount of enzyme, rather than enzyme activation.

Aldose reductase localization in human retinal mural cells.

A hallmark of early diabetic retinopathy is the selective loss of the retinal mural cells (pericytes) from vessels. Using antibodies prepared against purified human placental aldose reductase, the presence of the enzyme aldose reductase can be demonstrated immunohistochemically in the cytoplasm of retinal mural cells of trypsin-digested human retinal vessels. This enzyme, which reduces various hexose sugars to their sugar alcohols, has been implicated in the pathogenesis of several diabetic complications.

3-FG as substrate for investigating flux through the polyol pathway in dog lens by 19F-NMR spectroscopy.

PURPOSE: To investigate flux through the polyol pathway in the dog lens by 19F-nuclear magnetic resonance (19F-NMR) spectroscopy, using 3-fluoro-3-deoxy-D-glucose (3-FG) as a substrate. METHODS: 3-FG metabolism was monitored by 19F-NMR analysis. Dog lenses were incubated in Dulbecco's modified Eagle's medium containing 10 mM 3-FG. Enzymatic reductase and dehydrogenase activities were spectrophotometrically determined, whereas the analyses of 3-FG metabolites were conducted by 19F-NMR analysis. Aldose reductase (AR) was immunohistochemically localized in dog lens with antibodies raised against dog kidney AR. RESULTS: 19F-NMR spectra indicate that incubation of purified dog lenses AR with 3-FG results in the formation of 3-fluoro-3-deoxy-D-sorbitol (3-FS) and that incubation of dog liver sorbitol dehydrogenase (SDH) with 3-FS results in the formation of 3-fluoro-3-deoxy-D-fructose (3-FF). This confirms that 3-FG is metabolized to 3-FF by the polyol pathway enzymes. The affinity (Km) of AR for 3-FG is approximately 20-fold better than that for D-glucose, whereas the Km of SDH for 3-FS was fourfold less than for D-sorbitol. 3-FG in cultured dog lenses is metabolized primarily to 3-FS; however, small amounts of 3-FF and 3-fluoro-3-deoxy-D-gluconic acid (3-FGA) are also formed. 3-FS formation was reduced by the AR inhibitor AL 1576, and 3-FF formation was eliminated by the SDH inhibitor CP-166,572. In dog lens epithelial cells cultured with 3-FG, only 3-FS is formed. Similarly, only 3-FS is formed when lens capsule containing primarily epithelial lens contaminated with superficial epithelial cells was incubated in 3-FG. Similar incubation of the remaining cortex resulted primarily in the formation of 3-FS and 3-FGA. This enzymatic distribution was confirmed by spectrophotometric activity analysis and the immunohistochemical localization of AR. CONCLUSIONS: The data confirm that flux through the polyol pathway primarily results in sorbitol accumulation. The absence of fructose and gluconic acid from cultured lens epithelium suggests that the epithelial cells primarily contain AR, whereas differentiated fiber cells also contain SDH and glucose dehydrogenase.