Current understanding of the epidemiologic and clinical characteristics of optic neuritis.

Optic neuritis is an ocular disorder whose pathogenesis has not been fully determined, although autoimmune mechanisms have been suggested to be involved in its development. In recent years, anti-aquaporin-4 antibody (AQP4-Ab) and anti-myelin oligodendrocyte glycoprotein antibody (MOG-Ab) have been shown to play major roles in the development of optic neuritis. Because these two antibodies target different tissues, optic neuritis can be classified by the type of antibody. AQP4-Ab-positive optic neuritis responds poorly to steroid therapy and has a poor prognosis in terms of visual acuity. On the other hand, MOG-Ab-positive optic neuritis responds favorably to steroid therapy but is likely to recur when the dosage of steroids is reduced or discontinued. We first present the high incidence of idiopathic optic neuritis and discuss these relatively newer disease concepts of AQP4-Ab-positive optic neuritis and MOG-Ab-positive optic neuritis.

Shape analysis of rectus extraocular muscles with age and axial length using anterior segment optical coherence tomography.

PURPOSE: This study aimed to evaluate the shape of the extraocular muscles (EOMs) in normal subjects using the en-face images of anterior segment optical coherence tomography (AS-OCT). The EOM insertion and the direction of the muscle fibers were investigated. SUBJECTS AND METHODS: A total of 97 healthy normal subjects (194 eyes) at Okayama University Hospital (age, 47.1±21.5 years; range, 8-79 years) participated in the study. A series of 256 tomographic images of the rectus EOMs were captured using the C-scan function of the AS-OCT (CASIA2, TOMEY Co., Japan), and the images were converted to en-face images in multi-TIFF format. The anterior chamber angle to EOM insertion distance (AID) and the angle of the muscle fibers from the insertion site (angle of muscles) were measured from the images. The correlations of AID and angle of muscles with age and axial length were investigated and evaluated. RESULTS: AID and angle of muscles were significantly correlated with age or axial length in some EOMs. The AIDs of medial rectus (MR) (P = 0.000) and superior rectus (SR) (P = 0.005) shortened with age. The AIDs of MR (P = 0.001) and inferior rectus (IR) (P = 0.035) elongated with axial length, whereas lateral rectus (LR) (P = 0.013) shortened. The angles of MR (P = 0.001) and LR (P = 0.000) were found to have a more downward direction toward the posterior in older subjects. CONCLUSION: En-face images can be created by AS-OCT, and the shape of the EOMs in normal subjects using these image measurements was available. With the ability to assess the EOMs, AID and angle of muscles are expected give useful information for treating and diagnosing strabismus-related diseases.

Long-term results of a multicenter phase II study of preoperative chemoradiotherapy with S-1 plus oxaliplatin for locally advanced rectal cancer (JACCRO CC-04: SHOGUN Trial).

PURPOSE: The study was designed to evaluate the safety and efficacy of adding oxaliplatin to py (CRT) with S-1 in patients with locally advanced rectal carcinoma (LARC). We report here the final results of the study. PATIENTS AND METHODS: Patients with histopathologically confirmed LARC (cT3-T4, any N) were eligible. They received oral S-1 (80 mg/m2/day on days 1-5, 8-12, 22-26, and 29-33) and infusional oxaliplatin (60 mg/m2/day on days 1, 8, 22, 29) plus radiotherapy (1.8 Gy/day, total dose of 50.4 Gy in 28 fractions), with a chemotherapy gap in the third week of radiotherapy. Primary endpoint of the study was pathological complete response (pCR) rate. Secondary endpoints were rates of R0 resection, down-staging, cumulative 3-year local recurrence, 3-year disease-free survival (DFS), and toxicity. RESULTS: Forty-five patients were enrolled at six centers in Japan. All patients received CRT, and 44 underwent operation. The pCR rate was 27.3% (12/44). The R0 resection rate was 95.5% (42/44). T-down-staging rate was 59.1% (26/44), and N-down staging rate was 65.9% (29/44); the combined pathological down-staging rate was 79.5% (35/44). There were no grade 4 adverse events, but 11.1% of the patients had grade 3 adverse events. Cumulative 3-year local recurrence rate was 0%. However, 13 (30.0%) patients suffered from distant metastasis, and one patient suffered from secondary esophageal cancer that was unrelated to rectal cancer. Eight patients had lung metastasis, 4 had liver metastasis, and 3 patients died of the metastatic disease. The 3-year DFS rate of the 44 patients was 67.5% (median follow-up 36.3 months), and the 3-year overall survival (OS) rate was 93.0% (median follow-up 39.6 months). The patients were then divided into the pCR (12 patients) group and non pCR (32 patients) group. The 3-year rate of DFS for each group was 91.7% and 58.1% and that of OS was 100% and 90.3%, respectively. CONCLUSIONS: The study showed a high pCR rate with no severe toxicity, good follow-up results, and good loco-regional control. Therefore, addition of oxaliplatin to preoperative CRT with S-1 in patients with LARC might be feasible and lead to better local control than standard treatment.

Changes in visual field defects during 10-year follow-up for indocyanine green-assisted macular hole surgery.

PURPOSE: To determine whether the visual field defects detected within 3 months of indocyanine green (ICG)-assisted inner-limiting membrane (ILM) peeling continue to worsen over longer periods. METHODS: This was a retrospective observational case series. Four eyes with visual field defects that developed within 3 years of ICG-assisted ILM peeling for a macular hole (MH) were examined yearly for 10 years. The main outcome measures were the degree of mean deviation (MD) determined by Humphrey perimetry with the 30-2 SITA-Fast program and the best-corrected visual acuity (BCVA). RESULTS: Four patients were examined yearly for more than 10 years, with a mean duration of follow-up of 139.5 months (11.6 years) and a range of follow-up of 137-156 months (11.4-13 years). The mean (±standard deviation) preoperative MD value was -4.99 ± 3.26 dB, and the mean postoperative MD values were -12.9 ± 1.29 dB after 1 year, -14.1 ± 0.75 dB after 3 years, and -12.73 ± 2.65 dB after 10 years. The mean preoperative BCVA was 0.65 ± 0.26 logarithm of the minimal angle of resolution (logMAR) units, and the postoperative BCVA was 0.21 ± 0.07 logMAR units at 1 year, 0.28 ± 0.21 logMAR units at 3 years, and 0.14 ± 0.06 dB logMAR units at 10 years. CONCLUSIONS: The visual field defects detected soon after ICG-assisted ILM peeling continued to worsen for 3 years, but not thereafter.

A multicenter phase II study of preoperative chemoradiotherapy with S-1 plus oxaliplatin for locally advanced rectal cancer (SHOGUN trial).

PURPOSE: This study was designed to evaluate the safety and efficacy of adding oxaliplatin to preoperative chemoradiotherapy (CRT) with S-1 in patients with locally advanced rectal carcinoma (LARC). PATIENTS AND METHODS: This was a multicenter phase II study in patients with histologically proven clinical stage T3 or T4 (any N, M0) LARC. Patients preoperatively received oral S-1 (80 mg/m(2)/day on days 1-5, 8-12, 22-27, and 29-33) and infusional oxaliplatin (60 mg/m(2) days on 1, 8, 22, and 29) plus radiotherapy (50.4 Gy), with a chemotherapy gap in the third week of radiotherapy. Pathological complete response (pCR) was the primary endpoint. Secondary endpoints included toxicity, compliance, R0 resection rate, and downstaging rate. RESULTS: A total of 45 patients were enrolled at six centers in Japan. All 45 patients received CRT, and 44 underwent operation. A pCR was achieved in 12 (27.3%) of the 44 patients who underwent surgery. Near-total tumor regression was confirmed in 47.7%. There were no grade 4 adverse events, and 11.1% of the patients had grade 3 adverse events. R0 resection was achieved in 95.5% of the patients. CONCLUSION: Preoperative CRT with S-1 plus oxaliplatin had a high pCR rate and a favorable toxicity profile.

Successful radiotherapy for repeated recurrent uterine clear cell adenocarcinoma.

Uterine clear cell adenocarcinoma (UCCA) is rare and resistant to treatment. We report a UCCA patient who responded to radiotherapy on each relapse. The first relapse was detected in the vaginal wall after the first course of postoperative adjuvant chemotherapy. Radiotherapy was conducted. Recurrent tumors were detected in the left lung after 5 months and in the right lung after 8 months. Partial resection of the lungs was performed. After 5 months, relapse was detected in the left pulmonary apex. Stereotactic radiotherapy was conducted. After 7 months, relapse was detected in the left pulmonary apex outside the irradiation field, and stereotactic radiotherapy was performed. During the subsequent 36-month follow-up, there has been no relapse. Although UCCA is resistant to treatment, radiotherapy is effective in some cases, as demonstrated in this patient. Even when relapse is repeated, radiotherapy may be considered as a treatment option if the recurrent focus is localized.

A phase I dose escalation study of oxaliplatin plus oral S-1 and pelvic radiation in patients with locally advanced rectal cancer (SHOGUN trial).

BACKGROUND: The objective of this phase I study was to determine the maximum tolerated dose (MTD) and recommended dose (RD) of preoperative chemoradiotherapy (CRT) with S-1 plus oxaliplatin in patients with locally advanced rectal cancer. METHODS: Patients received radiotherapy in a total dose of 50.4 Gy in 28 fractions. Concurrent chemotherapy consisted of a fixed oral dose of S-1 (80 mg/m(2)/day) on days 1-5, 8-12, 22-27, and 29-33, plus escalated doses of oxaliplatin as an intravenous infusion on days 1, 8, 22, and 29. Oxaliplatin was initially given in a dose of 40 mg/m(2)/week to three patients. The dose was then increased in a stepwise fashion to 50 mg/m(2)/week and the highest dose level of 60 mg/m(2)/week until the MTD was attained. RESULTS: Thirteen patients were enrolled, and 12 received CRT. Dose-limiting toxicity (DLT) occurred in two of six patients (persistent grade 2 neutropenia, delaying oxaliplatin treatment by more than 3 days) at dose level 3; there were no grade 3 or 4 adverse events defined as DLT. The RD was 60 mg/m(2)/week of oxaliplatin on days 1, 8, 22, and 29. Twelve patients underwent histologically confirmed R0 resections, and two out of six patients (33%) given dose level 3 had pathological complete responses. CONCLUSIONS: The RD for further studies is 80 mg/m(2) of S-1 5 days per week plus 60 mg/m(2) of oxaliplatin on days 1, 8, 22, and 29 and concurrent radiotherapy. Although our results are preliminary, this new regimen for neoadjuvant chemoradiotherapy is considered safe and active. TRIAL REGISTRATION: This trial was registered with Clinicaltrials.gov (identifier: NCT01227239 ).

[Analysis of initial treatment only by linac-based stereotactic radiosurgery for a metastatic brain tumor from non-small cell lung cancer].

A patient who receives stereotactic radiosurgery(SRS)alone for treating the brain metastatic lesion has a risk of tumor recurrence in the brain. Thus, some patients undergo prophylactic whole brain radiotherapy(WBRT)in addition to the SRS. However, the usefulness of adding WBRT is still debatable. In our hospitals, we initially treat metastatic brain tumors with SRS alone, and have experienced 2 long-surviving cases. Here, we report our treatment outcomes, including those for these 2 cases, and discuss the treatment plan for non-small cell lung cancer(NSCLC)with brain metastases. Forty-two brain metastatic cases were studied. Median survival(MS), tumor control rate(TCR), and recurrence ratio at distant site(RRDS)in the brain were analyzed. Age, Karnofsky performance status(KPS), and recursive partitioning analysis(RPA)class were analyzed as prognostic factors. We present 2 cases of a 42- and a 56-year-old man, surviving for more than 100 months. MS, TCR, and RRDS at 1 year in our hospitals were 20 months, 89.1%, and 25.6%, respectively. The prognostic factors were good KPS and RPA class and younger age. Our data showed a good MS among some reliable random controlled trials. Our strategy of SRS alone preserves the possibility to treat new lesions with WBRT. Prognosis was mainly defined by the systemic condition of the patient and activity of the primary lesion. Thorough treatment of the primary lesion with addition of SRS for initial treatment of metastatic lesions and scheduled MRI follow-up will provide for longer survival times.

Protection of ovarian function by two distinct methods of ovarian shielding for young female patients who receive total body irradiation.

To prevent ovarian dysfunction due to total body irradiation, we started ovarian shielding at our center (Saitama Medical Center, Jichi Medical University (SMC-JMU)) with a long source axis distance, which is different from the original method used at the University of Tokyo Hospital (UTH). We retrospectively analyzed the outcome of eight patients with a median age of 20.5 years from SMC-JMU and compared the results with the published data for eight patients with a median age of 22 years from UTH. The recovery of ovarian function was observed in five and six patients, respectively. The cumulative incidence of ovarian recovery, while treating relapse and death without ovarian recovery as competing risks, was 68.8 % at 2 years after transplantation in the total population, and there was no statistically significant difference between the two institutions (p = 0.85). Age and the history of previous chemotherapy did not affect the incidence of ovarian recovery. Two patients from each center had a relapse of leukemia. Overall, among the 11 patients who have survived without relapse, only one has not achieved ovarian recovery. In conclusion, ovarian shielding with both methods strongly protected ovarian function. However, we should continue to monitor the relapse rate among patients who undergo this procedure.

Multidisciplinary therapy consisting of minimally invasive resection, irradiation, and intra-arterial infusion of 5-fluorouracil for maxillary sinus carcinomas.

BACKGROUND: Current goals for the treatment of maxillary sinus carcinoma include the preservation of vision, eating, communication, and appearance, as well as the achievement of a cure. METHODS: Japanese patients (n = 121) with maxillary sinus carcinoma were analyzed retrospectively. All patients underwent multidisciplinary therapy including minimally invasive resection, 20 Gy irradiation, and intra-arterial infusion of 5-fluorouracil. RESULTS: The 5- and 10-year overall survival rates were 73% and 68%, respectively. In 97 patients with squamous cell carcinoma (SCC), the 5- and 10-year overall survival rates were 76% and 70%, respectively. All 29 patients with orbital invasion retained the orbital contents, and 21 of these patients demonstrated adequate visual acuity. There were 16 complications, including trismus (5 patients), double vision (5 patients), fistula formation (3 patients), and cataract (3 patients). CONCLUSION: A multidisciplinary therapy, consisting of minimally invasive resection, irradiation, and regional chemotherapy, can yield good patient prognosis and quality of life after treatment.

Successful treatment of esophageal squamous cell carcinoma in a patient with Fanconi anemia.

Fanconi anemia is a congenital syndrome characterized by hypoplasia of bone marrow and the development of aplastic anemia in childhood, followed by myelodysplastic syndrome and acute myelogenous leukemia in later life. We report here a patient first diagnosed with Fanconi anemia at age 10. Bone marrow transplantation was performed at age 23 and repeated after an episode of rejection at age 25. Hematologic findings returned to normal, but chronic graft-versus-host disease persisted. Esophageal cancer developed at age 35. Invasion of the bronchus and aorta by the tumor was suspected on computed tomography. Chemoradiotherapy was administered to down-stage the tumor, using low-dose cisplatin and 5-fluorouracil. After two courses of chemotherapy with cisplatin (total dose, 100 mg) and 5-fluorouracil (5000 mg) plus radiotherapy (30 Gy), Grade 3 diarrhea and bone marrow suppression developed, and treatment was discontinued. After resolution of toxicity, a good response to the neoadjuvant therapy was seen on computed tomography scan, and a subtotal esophagectomy was performed which demonstrated a complete response in the resected specimen. However, tongue cancer developed at age 40 years, and hemiglossectomy was performed. Patients with Fanconi anemia have a high risk of developing esophageal cancer while they are still young. Reduced doses of alkylating agents and radiotherapy are used in patients with Fanconi anemia. However, the optimal dosage of chemoradiotherapy and the treatment strategy for esophageal cancer in patients with Fanconi anemia remain unclear, and outcomes are generally extremely poor. In this patient, esophageal cancer associated with Fanconi anemia responded well to multidisciplinary therapy.

[Accelerated fractionation].

Accelerated repopulation is a reason for loco-regional failure after radiotherapy for head and neck carcinoma. Accelerated fractionation(AF) is a radiotherapy regimen reducing the total treatment time, with the aim of counteracting tumor cell repopulation. AF administers the same or a similar total dose as conventional treatment in a reduced overall time by giving conventionally-sized or smaller fractions more than once daily. Several different clinical trials on AF have proved to be of benefit in loco-regional control, although no benefit in survival was generally detected. The metaanalysis of altered fractionated radiotherapy in head and neck cancer has showed a benefit with AF with conventional fractionation(CF). However, the magnitude of the survival benefit is lower with AF than with hyperfractionation (HF). In particular, AF using reduced total doses or a split course does not improve treatment benefits. AF that employs continuous RT schedules, without compromising the total dose, improves local control. More data on this AF regimen are needed. Acute morbidity is significantly more frequent with AF. Whether late toxicity is also worse with AF is unclear. Some trials suggest no increase in late toxicity, while others suggest the opposite. The effect of AF seems to be greater for the primary tumor than for the metastatic lymph-nodes. Also, the reduction of the treatment time is more beneficial in well- to moderately-differentiated tumors.

A multicenter phase II study of local radiation therapy for stage IEA mucosa-associated lymphoid tissue lymphomas: a preliminary report from the Japan Radiation Oncology Group (JAROG).

PURPOSE: The aim of this study was to evaluate the efficacy and toxicity of moderate dose radiation therapy (RT) for mucosa-associated lymphoid tissue (MALT) lymphoma in a prospective multicenter phase II trial. METHODS AND MATERIALS: The subjects in this study were 37 patients with MALT lymphoma between April 2002 and November 2004. There were 16 male and 21 female patients, ranging in age from 24 to 82 years, with a median of 56 years. The primary tumor originated in the orbit in 24 patients, in the thyroid and salivary gland in 4 patients each, and 5 in the others. The median tumor dose was 30.6 Gy (range, 30.6-39.6 Gy), depending on the primary site and maximal tumor diameter. The median follow-up was 37.3 months. RESULTS: Complete remission (CR) or CR/unconfirmed was achieved in 34 patients (92%). The 3-year overall survival, progression-free survival, and local control probability were 100%, 91.9%, and 97.3%, respectively. Thirteen patients experienced Grade 1 acute toxicities including dermatitis, mucositis, and conjunctivitis. One patient developed Grade 2 taste loss. Regarding late toxicities, Grade 2 reactions including hypothyroidism, and radiation pneumonitis were observed in three patients, and Grade 3 cataract was seen in three patients. CONCLUSIONS: This prospective phase II study demonstrated that moderate dose RT was highly effective in achieving local control with acceptable morbidity in 37 patients with MALT lymphoma.

Initial experience with the quality assurance program of radiation therapy on behalf of Japan Radiation Oncology Group (JAROG).

BACKGROUND: We evaluated the efficacy of our quality assurance (QA) program of radiation therapy (RT) in a prospective phase II study. This is the first description of the experience of the Japan Radiation Oncology Group (JAROG) with this program. METHODS: Clinical records, all diagnostic radiological films or color photos that depicted the extent of disease of 37 patients with stage IEA extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue (MALT lymphoma) were collected for review. Radiation therapy charts, simulation films or digitally reconstructed radiographs, portal films and isodose distributions at the central axis plan were also reviewed. All documents were digitally processed, mounted on Microsoft PowerPoint, and for security returned from researchers by mail in CD-ROM format. The QA committee members reviewed all documents centrally, utilizing the slide show functionality. RESULTS: All patients were prescribed their specified dose to the dose specification point in accordance with the protocol. Three patients were regarded as deviations, because of a smaller margin than that specified in the protocol (n = 2) or a prolonged overall treatment time (n = 1). No violations were observed in this study. CONCLUSIONS: This is the first report with regard to the QA program in MALT lymphoma. We demonstrated that our QA program was simple and inexpensive. We also confirmed that the radiation oncologists in Japan adhered closely to the protocol guidelines.