Selective ophthalmic arterial injection using a balloon catheter for retinoblastoma: a seven-year clinical evaluation.

PURPOSE: To evaluate the effectiveness and safety of selective ophthalmic arterial injection (SOAI) for retinoblastoma utilizing a microballoon catheter system with an M chamber. STUDY DESIGN: Retrospective analysis. METHODS AND PATIENTS: This study was sanctioned by theNational Cancer Center Hospital' Independent Ethics Committee. The surgeon was a general interventional radiologist. After confirming that the distal internal carotid artery was not delineated by balloon occlusion and the ophthalmic artery was visualized using digital subtraction angiography, melphalan was manually administered. Notably, in cases presenting bilateral retinoblastoma, both eyes received treatment in a singular, low-dose procedure. Between July 2015 and December 2021, 125 patients with retinoblastoma (68 boys and 57 girls) underwent SOAI at our facility. The average age at initial treatment was 19.3 months. The study covered 250 procedures, with patients undergoing an average of 3.7 procedures. RESULTS: The success rate of the procedure was 99.2%, with a mean procedure duration of 18.3 min. Two distinct technical failures were recorded: one attributed to an internal carotid artery having a wide lumen and the other due to the ophthalmic artery remaining undetected on angiography post-balloon occlusion of the internal carotid artery. Adverse events were minimal but included bronchospasm post-procedure and severe orbital inflammation in 0.8% and 0.4% of cases, respectively. CONCLUSION: SOAI using the microballoon catheter with the M chamber is a feasible and safe procedure for the treatment of retinoblastoma. The success rate was 99.2%. This system can be recommended as intra-arterial chemotherapy for retinoblastoma.

Technical Feasibility and Safety of Central Venous Ports for Intravenous Chemotherapy in Infants With Retinoblastoma: A Retrospective Study.

PURPOSE: The central venous port (CVP) is widely used for intravenous chemotherapy (IVC) in adult patients because of its lower infection rates and easier management than that of a central venous catheter. However, the feasibility and safety of the CVP for IVC in infants remain unknown. This study evaluated the usefulness of CVP for IVC in infants with retinoblastoma. METHODS: The usefulness of CVP was retrospectively evaluated using technical success rates, the safety of CVP placement, and postoperative procedure-related complications in 18 infants with retinoblastoma. This study was conducted at the National Cancer Center Hospital, Chuo-Ku, Tokyo, Japan. RESULTS: The technical success rate was 100% (18/18) without any procedure-related complications. The sum duration of CVP implantation was 12,836 days (mean: 713 ± 453 days, range: 10-1,639 days). Postoperative complications were observed in two cases; one was a port reversal after 20 days, which was reversed by incisional surgery, and another was a catheter-related bloodstream infection after eight days, resulting in CVP removal. The total incidence of CVP-related infections was 5.6% (1/18) and 0.08/1000 catheter days. No other CVP-related complications were noted. CONCLUSION: The use of the CVP for IVC in infants with retinoblastoma was feasible with few complications.

A novel de-novo RB1 mutation identified in a patient with bilateral retinoblastoma.

Retinoblastoma manifests as ocular malignancy due to mutations in the RB1 gene. A 17-month-old girl with bilateral retinoblastoma having no family history was admitted to our hospital. The right eye was enucleated but the other was preserved with systemic chemotherapy and topical treatment. The patient has been tumor-free for over 7 years since diagnosis. All exons of RB1 were sequenced and a novel 1-base pair deletion (NM_000321.2:c.2409del, p.Asn803Lysfs*7) was detected.

Encorafenib, binimetinib, and cetuximab in BRAF V600E-mutated colorectal cancer: an early post-marketing phase vigilance study.

BACKGROUND: Triplet and doublet regimens of encorafenib plus cetuximab with and without binimetinib, respectively, were approved in Japan for unresectable, metastatic, BRAF V600E-mutated colorectal cancer (mCRC) that had progressed after 1-2 prior chemotherapies. This early post-marketing phase vigilance (EPPV) study collected adverse drug reactions (ADRs) from Japanese patients to ensure safety measures as appropriate. METHODS: Patients with BRAF V600E mCRC who received the triplet or doublet regimens in Japan were selected for this study. ADRs were collected as spontaneous reports between November 27, 2020 and May 26, 2021. Serious ADRs were evaluated according to guidelines of the International Council for Harmonisation and the EudraVigilance list of Important Medical Event Terms. RESULTS: An estimated 550 Japanese patients with mCRC received the triplet or doublet regimens during the 6-month EPPV period. Overall, 101 and 42 patients reported ADRs and serious ADRs, respectively. No ADRs leading to death were reported. The most frequently reported ADRs were nausea (17 patients), serous retinal detachment (16), decreased appetite (12), diarrhea (11), and vomiting (11). Among the important identified/potential risks that are defined in the risk management plans for encorafenib and binimetinib, eye disorder-related ADRs were observed in 32 patients, rhabdomyolysis-related ADRs in 12, hemorrhage-related ADRs in 7, and hepatic dysfunction-related ADRs in 7. Of 22 patients with serious eye disorders, 20 recovered or were recovering during the EPPV period. CONCLUSION: The safety profile in this EPPV study was similar to that from the phase III BEACON CRC study and no new safety concerns were identified.

Ocular toxicity of investigational anti-cancer drugs in early phase clinical trials.

Ocular toxicities arising from anti-cancer drugs occur sporadically and are sometimes underestimated because they are not life-threatening. Reports focusing on ocular toxicities from cancer therapy are limited. We investigated the detailed progress of ocular toxicities of anti-cancer drugs including first-in-class ones. A retrospective review of medical records was conducted for patients who were involved in early phase clinical trials with scheduled ophthalmologic examinations according to their protocols between January 2014 and August 2021. Patients with ocular toxicity suspected to be related to the investigational drugs in the ophthalmic examination were investigated in detail. In total, 37 ocular toxicities related to investigational drugs occurred in 7.6% of patients (33/434). The median age of the 33 patients was 61 years (range, 33-76 years), and 20 were male. Causal drugs with a high incidence of ocular toxicities were HSP90 inhibitors and FGFR inhibitors. Retinopathy was most frequent, while conjunctivitis, dry eye, keratitis, keratopathy, and uveitis were also observed. Dim vision as a subjective finding was a unique adverse event. Most patients developed ocular toxicities even though their dose was below the drug's maximum tolerated dose. Except for one case, all ocular toxicities occurred bilaterally. About 60% (22/37) of ocular toxicity cases needed a temporary hold of the drug. All except for three cases fully recovered. This study reported the risks and timing of the onset of a variety of ocular toxicities of anti-cancer drugs, which were fundamentally controllable. (Trial registration number. Retrospectively registered).

Granular cell tumour in the ciliary body.

Granular cell tumours (GCTs) are benign tumours that rarely develop in intraocular regions. We report a rare case of intraocular GCT in the ciliary body. A woman in her 20s with a history of bone marrow transplantation for malignant lymphoma in early childhood was referred to our department for bilateral proliferative diabetic retinopathy. A yellowish-white ciliary tumour was observed in the temporal periphery of the patient's left eye during routine ophthalmological examination. As the tumour enlarged, we performed total resection combined with vitrectomy, silicone oil tamponade and cataract surgery. Histopathological examination revealed tumour cells with small, round or oval nuclei with eosinophilic cytoplasm. Positive immunohistochemical staining for S-100 and vimentin led to a diagnosis of ciliary GCT. No retinal detachment, proliferative membrane formation or tumour recurrence was observed 4 years postoperatively. Intraocular GCT should be considered a differential diagnosis of ciliary tumours.

A case of retinoblastoma resulting in phthisis bulbi after proton beam radiation therapy.

Purpose: Proton beam radiation therapy (PBRT) is a treatment option for advanced retinoblastoma (RB) resistant to chemotherapy and focal ophthalmic treatment. Here we report a case of RB with phthisis bulbi following PBRT. Observations: A 16-day-old boy with a family history of RB was referred to our institution. Initial examination revealed an extensive white mass in the right eye and a small tumor near the optic disk of the left eye. The patient was diagnosed with bilateral RB and treated with chemotherapy and focal ophthalmic therapy. The right eye showed shrinkage in the treatment course. The tumor control was not achieved bilaterally, and, therefore, PBRT was performed to preserve the eyes. However, the right eye became significantly phthisical following PBRT and ultimately required enucleation. Conclusions and importance: PBRT for RB may result in phthisis bulbi. Further investigations of its role and possible complications are warranted.

Pars plana vitrectomy for vitreoretinal complications in only seeing eyes after treatment for retinoblastoma.

PURPOSE: To report the outcomes of two only seeing eyes of two cases with retinoblastoma in which vitrectomy was performed to treat vitreous hemorrhage or rhegmatogenous retinal detachment after treatment for retinoblastoma. OBSERVATIONS: Case 1 was an 8-month-old girl whose bilateral retinoblastoma (group D, OU) was treated by chemotherapy and focal ablation therapy. As the tumor size increased, enucleation was required in the right eye. At 4 years of age, about 1 year after the last treatment for retinoblastoma, lens-sparing vitrectomy was performed for dense, nonclearing vitreous hemorrhage, which had occurred 6 months previously. No recurrence of the tumor was found, and the patient's visual acuity improved to 0.9 postoperatively. Case 2 was a 4-month-old boy who was diagnosed with bilateral retinoblastoma (group D, OD; group C, OS) and underwent treatment, including systemic and local chemotherapy and proton beam therapy. Because large, regressed tumor masses were present in the posterior pole of the right eye, the left eye was the only seeing eye. At the age of 1 year 7 months, retinal detachment developed in the left eye 1 month after cryotherapy was performed for tumor recurrence. Although a scleral buckling procedure without drainage was performed, the retina was not reattached. The retina was reattached after vitrectomy with melphalan irrigation and silicone oil tamponade. However, recurrence was noted 6 months after the operation, and enucleation was required. CONCLUSION AND IMPORTANCE: Vitrectomy appears to be beneficial for the treatment of vision-threatening complications after retinoblastoma treatment. However, vitrectomy may be associated with the potential spread of tumor cells and/or tumor recurrence and therefore should be reserved as the last treatment modality for only seeing eyes. Careful postoperative follow-up is mandatory.

Monte Carlo simulation of tilted contact plaque brachytherapy placement for juxtapapillary retinoblastoma.

BACKGROUND: The 106-Ruthenium contact plaque applicator is utilized for the treatment of intraocular tumor within a thickness of less than 6 mm. If anything obstructs the placement of the plaque applicator, the treatment is generally difficult because the applicator has to be temporarily located just on the opposite side of the retinal tumor. Furthermore, the plaque applicator edge of approximately 1 mm does not contain 106Ru, estimating the delivered radiation dose for eccentric tumor is challenging because the lateral dose profile is inadequately provided by the manufacture's certification. This study aims to simulate tumor coverage of the tilted applicator placement for treating an infant with juxtapapillary retinoblastoma and to achieve the effective treatment. CASE PRESENTATION: We present an infant with retinoblastoma whose tumor involved macular and was invading just temporal side of the optic disc. Additionally, posterior staphyloma was induced by a series of previous treatments, making it more difficult to treat the standard plaque placement. Thus, the applicator type of CCA was intentionally tilted to the eyeball and the distance between the posterior edge of the applicator and the eyeball had to be then equal to or more than 2 mm based on the dose distribution of the applicator calculated using Monte Carlo simulation to minimize damage to surrounding tissues while covering the tumor. It was then comparable to the certification and previous reports. Based on the acquired dose distribution, the optimal placement of the applicator was derived from varying the distance between the applicator's edge and the eyeball, and the distance was then determined to be 2 mm. In this case, the minimum dose rate in the tumor was 25.5 mGy/min, and the time required to deliver the prescribed dose was 26.2 h. Therefore, the tilted 106Ru plaque applicator placement could deliver the required dose for the treatment. The physical examination revealed no active tumor as a result of the treatment. CONCLUSIONS: Optimizing the placement of the 106Ru plaque applicator, it was possible to guarantee that the prescribed dose will be delivered to the tumor even if the standard placement is not possible for the juxtapapillary tumor.

Patients presenting with metastases: stage IV uveal melanoma, an international study.

OBJECTIVE: To analyse ocular and systemic findings of patients presenting with systemic metastasis. METHODS AND ANALYSIS: It is an international, multicentre, internet-enabled, registry-based retrospective data analysis. Patients were diagnosed between 2001 and 2011. Data included: primary tumour dimensions, extrascleral extension, ciliary body involvement, American Joint Committee on Cancer (AJCC)-tumour, node, metastasis staging, characteristics of metastases. RESULTS: Of 3610 patients with uveal melanoma, 69 (1.9%; 95% CI 1.5 to 2.4) presented with clinical metastasis (stage IV). These melanomas originated in the iris, ciliary body and choroid in 4%, 16% and 80% of eyes, respectively. Using eighth edition AJCC, 8 (11%), 20 (29%), 24 (35%), and 17 (25%) belonged to AJCC T-categories T1-T4. Risk of synchronous metastases increased from 0.7% (T1) to 1.5% (T2), 2.6% (T3) and 7.9% (T4). Regional lymph node metastases (N1a) were detected in 9 (13%) patients of whom 6 (67%) had extrascleral extension. Stage of systemic metastases (known for 40 (59%) stage IV patients) revealed 14 (35%), 25 (63%) and 1 (2%) had small (M1a), medium-sized (M1b) and large-sized (M1c) metastases, respectively. Location of metastases in stage IV patients were liver (91%), lung (16%), bone (9%), brain (6%), subcutaneous tissue (4%) and others (5%). Multiple sites of metastases were noted in 24%. Compared with the 98.1% of patients who did not present with metastases, those with synchronous metastases had larger intraocular tumours, more frequent extrascleral extension, ciliary body involvement and thus a higher AJCC T-category. CONCLUSIONS: Though higher AJCC T-stage was associated with risk for metastases at diagnosis, even small T1 tumours were stage IV at initial presentation. The liver was the most common site of metastases; however, frequent multiorgan involvement supports initial whole-body staging.

Defining High-risk Retinoblastoma: A Multicenter Global Survey.

IMPORTANCE: High-risk histopathologic features of retinoblastoma are useful to assess the risk of systemic metastasis. In this era of globe salvage treatments for retinoblastoma, the definition of high-risk retinoblastoma is evolving. OBJECTIVE: To evaluate variations in the definition of high-risk histopathologic features for metastasis of retinoblastoma in different ocular oncology practices around the world. DESIGN, SETTING, AND PARTICIPANTS: An electronic web-based, nonvalidated 10-question survey was sent in December 2020 to 52 oncologists and pathologists treating retinoblastoma at referral retinoblastoma centers. INTERVENTION: Anonymized survey about the definition of high-risk histopathologic features for metastasis of retinoblastoma. MAIN OUTCOMES AND MEASURES: High-risk histopathologic features that determine further treatment with adjuvant systemic chemotherapy to prevent metastasis. RESULTS: Among the 52 survey recipients, the results are based on the responses from 27 individuals (52%) from 24 different retinoblastoma practices across 16 countries in 6 continents. The following were considered to be high-risk features: postlaminar optic nerve infiltration (27 [100%]), involvement of optic nerve transection (27 [100%]), extrascleral tissue infiltration (27 [100%]), massive (≥3 mm) choroidal invasion (25 [93%]), microscopic scleral infiltration (23 [85%]), ciliary body infiltration (20 [74%]), trabecular meshwork invasion (18 [67%]), iris infiltration (17 [63%]), anterior chamber seeds (14 [52%]), laminar optic nerve infiltration (13 [48%]), combination of prelaminar and laminar optic nerve infiltration and minor choroidal invasion (11 [41%]), minor (<3 mm) choroidal invasion (5 [19%]), and prelaminar optic nerve infiltration (2 [7%]). The other histopathologic features considered high risk included Schlemm canal invasion (4 [15%]) and severe anaplasia (1 [4%]). Four respondents (15%) said that the presence of more than 1 high-risk feature, especially a combination of massive peripapillary choroidal invasion and postlaminar optic nerve infiltration, should be considered very high risk for metastasis. CONCLUSIONS AND RELEVANCE: Responses to this nonvalidated survey conducted in 2020-2021 showed little uniformity in the definition of high-risk retinoblastoma. Postlaminar optic nerve infiltration, involvement of optic nerve transection, and extrascleral tumor extension were the only features uniformly considered as high risk for metastasis across all oncology practices. These findings suggest that the relevance about their value in the current scenario with advanced disease being treated conservatively needs further evaluation; there is also a need to arrive at consensus definitions and conduct prospective multicenter studies to understand their relevance.

Small Symptomatic Unilateral Choroidal Osteoma Diagnosed with Enhanced-Depth Imaging Optical Coherence Tomography and Thin-Slice Computed Tomography: 2 Clinical Cases.

BACKGROUND: Choroidal osteoma is a rare, benign, ossifying intraocular tumor of unknown etiology. While patients with choroidal osteoma usually show distinct large yellowish subretinal lesions, some could have small lesions, making the differential diagnosis difficult. We experienced 2 cases of small symptomatic unilateral osteoma approximately 1.0-mm disc diameter in size. METHODS: Retrospective medical charts of 2 patients with small symptomatic unilateral osteoma were reviewed. Fundus examination, spectral domain enhanced-depth optical coherence tomography (EDI-OCT), fluorescein angiography, indocyanine green angiography, B-scan ultrasonography (USG), and X-ray computed tomography (CT) were performed. RESULTS: Case 1: a case of a 41-year-old male. Fundus examination revealed a yellowish-white lesion of 1.0-mm disc diameter in size. EDI-OCT of the lesion shows sub-RPE elevation. B-scan USG was not definite for diagnosis. Thin-slice (2 mm) CT scan revealed a choroidal osteoma. Case 2: a case of a 70-year-old male. Fundus examination revealed a yellowish-white lesion of 0.9-mm disc diameter. EDI-OCT showed sub-RPE elevation without serous retinal detachment and horizontal lamellar-like structure within the lesion. B-scan USG suggested acoustic shadowing, but it was unclear. The thin-slice CT scan confirmed bony tissue at the lesion. CONCLUSIONS: We report 2 cases of small choroidal osteoma. Diagnosis of small yellowish subretinal lesions is sometimes difficult. Characteristic findings with EDI-OCT may sometimes suggest this disease, and thin-slice CT could help to diagnose choroidal osteoma.

Survival and ocular preservation in a long-term cohort of Japanese patients with retinoblastoma.

BACKGROUND: Retinoblastoma is an ocular tumor in infants with cancer predisposition. Treatment of the rare tumor needs to be optimized for ocular preserved survival without second primary malignancy (SPM). METHODS: We studied the outcomes of all patients with retinoblastoma at a tertiary center in 1984-2016, when preservation method changed from radiotherapy (1984-2001) to systemic chemotherapy (2002-2016). RESULTS: One-hundred sixteen infants developed unilateral- (n = 77), bilateral- (n = 38), or trilateral-onset (n = 1) tumor. Ten (8.6%) had a positive family history, despite a few studies on RB1 gene. Contralateral disease occurred in one unilateral-onset case. One-hundred eight of 155 eyes (70%) were enucleated. Nine binocular survivors were from 5 bilateral- and 4 unilateral-onset cases. Two survivors received bilateral enucleation. Six deaths occurred; brain involvement (including 3 trilateral diseases) in 4 bilateral-onset, systemic invasion in a unilateral-onset, and SPM (osteosarcoma) in a bilateral-onset case(s). Two others survived SPM of osteosarcoma or lymphoma. The 10-year overall survival (OS: 98.5% vs. 91.3%, p = 0.068) and binocular survivors (13.2% vs. 5.2%, p = 0.154) between bilateral- and unilateral-onsets did not differ statistically. The 10-year OS and cancer (retinoblastoma/SPM)-free survival (CFS) rates of all patients were 94.9 and 88.5%, respectively. The proportion of preserved eyes did not differ between radiotherapy and chemotherapy eras. The CFS rate of bilateral-onset cases in systemic chemotherapy era was higher than that in radiotherapy era (p = 0.042). The CFS rates of bilateral-onset patients with neoadjuvant chemotherapy (upfront systemic therapy for preservation) was higher than those without it (p = 0.030). CONCLUSIONS: Systemic chemotherapy and local therapy raised OS and binocular survival rates of bilateral-onset patients similarly to those of unilateral-onset patients. All but one death was associated with a probable germline defect of the RB1 gene. Neoadjuvant stratified chemotherapy may support the long-term binocular life with minimized risk of SPM.

Nivolumab for patients with metastatic uveal melanoma previously untreated with ipilimumab: a single-institution retrospective study.

We evaluated the efficacy of nivolumab in patients with metastatic uveal melanoma previously untreated with ipilimumab. We performed a retrospective study at the National Cancer Center Hospital in Tokyo, Japan, where nivolumab was approved 1 year earlier than ipilimumab. Clinical efficacy outcomes were determined by assessing best overall response according to the Response Evaluation Criteria in Solid Tumors (version 1.1), progression-free survival and overall survival. Fourteen patients were analyzed; none had received any prior systemic therapies although eight had undergone transarterial chemoembolization. The median follow-up period was 15 months. The objective response and disease control rates were 7.1% and 42.9%, respectively (one partial response and five stable diseases). The median progression-free survival and overall survival were 10 (range, 4-105) and 60 (range, 5-105) weeks, respectively. Liver metastases in three patients were all programmed cell death-1 ligand negative. Lower lactate dehydrogenase, development of vitiligo, and a neutrophil-to-lymphocyte ratio less than 5 at week 6 were associated with favorable progression-free survival and overall survival; of these, only a neutrophil-to-lymphocyte ratio less than 5 at week 6 was statistically significant. Even with the use of nivolumab before ipilimumab, metastatic uveal melanoma appears to remain refractory to nivolumab monotherapy. However, because one patient in our cohort achieved an objective response, and the median overall survival exceeded 1 year, treatment strategies that incorporate anti-PD1 antibody should be further investigated. Whether a neutrophil-to-lymphocyte ratio less than 5 at week 6 is a favorable early on-treatment marker should be validated in larger cohorts.

High-dose-rate interstitial brachytherapy for a bulky sebaceous carcinoma of the eyelid: A case report.

High-dose-rate interstitial brachytherapy (HDR-ISBT) achieved excellent local control of the bulky sebaceous carcinoma of the eyelid. However, we must pay attention to dose of eyelid and cornea about late toxicity of HDR-ISBT.

Radiotherapy for localized sebaceous carcinoma of the eyelid: a retrospective analysis of 83 patients.

The current study retrospectively analyzed the results of radiotherapy for clinically localized sebaceous carcinoma of the eyelid.We reviewed records of 83 patients with histologically confirmed sebaceous carcinoma who were treated radiotherapeutically between 1983 and 2015. Sixty-five patients (78%) were initially treated with radiotherapy of curative intent, while the remaining 18 patients underwent postoperative radiotherapy due to tumor recurrence or positive surgical margins. Thirty-seven patients belonged to T1-2, while 46 belonged to T3-4. All 83 patients were treated with radiotherapy with a median radiation dose of 60 Gy. The median follow-up period was 92.1 months (range, 2.8-310.3 months). At the time of analysis, 13 patients (15.1%) died, and 36 patients (43.3%) had local recurrence. The 7-year overall survival, freedom from neck lymph node recurrence, and local control (LC) rates for all patients were 83.5%, 75.5%, and 52.3%, respectively. Patients with a tumor size ≤10 mm had a higher 7-year LC rate than those with a tumor size >10 mm (58.8% vs 46.6%, P = 0.054). Neck lymph node recurrence was observed in 17 patients (20%) and significantly related to the tumor size. Late toxicity of an eyelid dysfunction of grade 3 was observed in 1 patient with T3 tumor. Radiotherapy for sebaceous carcinoma of the eyelid is a reasonable alternative to surgical resection for tumors <10 mm in size with few severe complications, while larger tumors should be treated with surgery if feasible.

First-in-Human Phase I Study of an Oral HSP90 Inhibitor, TAS-116, in Patients with Advanced Solid Tumors.

HSP90 is involved in stability and function of cancer-related proteins. This study was conducted to define the MTD, safety, pharmacokinetics, pharmacodynamics, and preliminary antitumor efficacy of TAS-116, a novel class, orally available, highly selective inhibitor of HSP90. Patients with advanced solid tumors received TAS-116 orally once daily (QD, step 1) or every other day (QOD, step 2) in 21-day cycles. Each step comprised a dose escalation phase to determine MTD and an expansion phase at the MTD. In the dose escalation phase, an accelerated dose-titration design and a "3+3" design were used. Sixty-one patients were enrolled in Japan and the United Kingdom. MTD was determined to be 107.5 mg/m2/day for QD, and 210.7 mg/m2/day for QOD. In the expansion phase of step 1, TAS-116 was administered 5 days on/2 days off per week (QD × 5). The most common treatment-related adverse events included gastrointestinal disorders, creatinine increases, AST increases, ALT increases, and eye disorders. Eye disorders have been reported with HSP90 inhibitors; however, those observed with TAS-116 in the expansion phases were limited to grade 1. The systemic exposure of TAS-116 increased dose-proportionally with QD and QOD regimens. Two patients with non-small cell lung cancer and one patient with gastrointestinal stromal tumor (GIST) achieved a confirmed partial response. TAS-116 had an acceptable safety profile with some antitumor activity, supporting further development of this HSP90 inhibitor.This is a result from a first-in-human study, in which the HSP90 inhibitor TAS-116 demonstrated preliminary antitumor efficacy in patients with advanced solid tumors, including those with heavily pretreated GIST.

SOX10 Expression as Well as BRAF and GNAQ/11 Mutations Distinguish Pigmented Ciliary Epithelium Neoplasms From Uveal Melanomas.

Purpose: Adenocarcinomas or adenomas derived from pigmented ciliary epithelium (APCE) are exceptionally rare ocular tumors. These tumors have pigmented and epithelioid features, and some APCEs are negative for keratin markers and positive for melanocytic markers. It is especially difficult to distinguish APCEs from uveal melanoma (UM). Accordingly, we examined protein expression and genetic mutations associated with APCE to facilitate diagnosis. Methods: Five APCE and 11 UM samples were obtained from patients during surgical resection at our institute. APCE and UM ocular structures were compared comprehensively. Protein expression and genetic alterations involved in malignant melanoma were evaluated. Results: SOX10 was expressed diffusely in all 11 UMs and in surrounding uveal or choroidal melanocytes, but not in the APCEs or nontumorous pigmented epithelia. Additionally, the expression patterns of cytokeratins and melanocytic markers differed between UMs and APCEs. We identified BRAF V600E mutations in four of five APCE samples, but not in the 11 UM samples. Moreover, GNAQ or GNA11 mutations were found in 10 of the 11 UM samples, but not in APCE samples. NRAS mutations were not observed in either tumor group examined. Conclusions: APCE is a separate entity distinguished from UM by the absence of SOX10 expression and presence of the BRAF V600E mutation. These results have implications for diagnosis, providing a means to distinguish between UM and APCE.

Related visual impairment to mother-infant interaction and development in infants with bilateral retinoblastoma.

PURPOSE: This study was conducted with infants diagnosed with bilateral retinoblastoma (RB) and their mothers. It explored characteristics of the mother-infant interaction, the infants' developmental characteristics and related risk factors. METHOD: Cross-sectional statistical analysis was performed with 18 dyads of one-year-old infants with bilateral RB and their mothers. RESULTS: Using the Japanese Nursing Child Assessment Teaching Scale (JNCATS) results showed that infants with RB had significantly lower scores compared to normative Japanese scores on all of the infants' subscales and "Child's contingency" (p < 0.01). Five infants with visual impairment at high risk of developmental problems had a pass rate of 0% on six JNCATS items. There were positive correlations between Developmental quotients (DQ) and JNCATS score of "Responsiveness to caregiver" (ρ = 0.50, p < 0.05) and DQ and "Child's contingency" (ρ = 0.47, p < 0.05). CONCLUSIONS: Infants with visual impairment were characterized by high likelihood of developmental delays and problematic behaviors; they tended not to turn their face or eyes toward their mothers, smile in response to their mothers' talking to them or the latter's changing body language or facial expressions, or react in a contingent manner in their interactions. These infant behaviors noted by their mothers shared similarities with developmental characteristics of children with visual impairments. These findings indicated a need to provide support promoting mother-infant interactions consistent with the developmental characteristics of RB infants with visual impairment.

Efficacy and toxicity of transarterial chemoembolization therapy using cisplatin and gelatin sponge in patients with liver metastases from uveal melanoma in an Asian population.

BACKGROUND: Although both immune-checkpoint inhibitors and targeted therapies such as MEK inhibitors have been evaluated in metastatic uveal melanoma, the efficacy of these therapies is modest to date. The purpose of this study was to evaluate the efficacy and toxicity of transarterial chemoembolization (TACE) therapy for liver metastasis from uveal melanoma in an Asian population. METHODS: We retrospectively assessed the clinical data of patients with liver metastases from uveal melanoma who received TACE therapy using cisplatin (70 mg/m2) and gelatin sponge between 1997 and 2008. RESULTS: We identified 29 eligible patients. The overall response rate was 21%. The median survival time was 23 months, and the 1-, 2-, and 5-year survival rates were 72.4, 39.4, and 0%, respectively. The favorable prognostic factors were partial response and stable disease, <25% of the tumor volume within the liver at baseline, and normal serum lactate dehydrogenase (LDH) and normal alkaline phosphatase at baseline. Among them, normal LDH at baseline was the only independent prognostic factor in multivariate analysis. The common adverse events (AEs) were liver enzyme elevation (100%), nausea (72.4%), abdominal pain (65.5%), vomiting (55.2%), post-embolization syndrome (34.5% of patients, 9.6% of TACE procedures), and pyrexia (24.1%). Grade ≥3 AEs consisted of aspartate aminotransferase elevation (34.5%), alanine aminotransferase elevation (51.7%), and serum creatinine elevation (3.4%). CONCLUSION: TACE therapy has a certain degree of clinical efficacy with a tolerable toxicity and, therefore, can still be one of the treatment options. However, considering the lack of long-term efficacy of this therapy, further treatment strategies need to be developed.