Ocular and Periocular Metastasis in Breast Cancer: Clinical Characteristics, Prognostic Factors and Treatment Outcome.

BACKGROUND: Breast cancer remains a leading cause of cancer-related mortality and morbidity worldwide. Ocular and periocular metastasis present as a rare but clinically significant manifestation. This study aims to explore demographics and clinical aspects of ocular and periocular metastasis in breast cancer patients. METHODS: A retrospective cohort study comprising 45 breast cancer patients with ocular or periocular metastasis treated between 2013 and 2023. Patient demographics, tumor characteristics, diagnostic methods, treatment modalities, visual outcomes, and survival data were analyzed. RESULTS: Among 9902 breast cancer patients, 0.5% developed ocular or periocular metastasis, constituting 2.4% of metastatic cases. The median age was 50 years. Ocular metastasis timing varied: 5% before breast cancer, 24% concurrent, 22% within a year, and 49% after. The most common presentations included incidental MRI findings (42%) and vision decline (31%). Metastasis involved the orbit (47%), choroid (40%), optic nerve (11%), and iris (2%), with 44% having bilateral involvement. Predictive factors included invasive lobular carcinoma (ILC) (p < 0.0001) and brain metastasis (p < 0.0001), with ILC exhibiting a sixfold higher likelihood of ocular metastasis than invasive ductal carcinoma (IDC). Primary treatment was radiation therapy (89%), yielding a 55% maintenance of excellent vision (<0.5), with 93% developing dry eye disease. Patients with ocular metastasis faced an increased risk of disease-related mortality (p < 0.0001), with 71% succumbing within 10 months post-diagnosis. CONCLUSIONS: Ocular metastasis in breast cancer is rare (0.5%) but signifies poor outcome. It is linked to ILC and concurrent brain metastasis. Primary treatment involves radiation therapy, with a favorable visual prognosis.

The Impact of Tumor Laterality (Unilateral vs. Bilateral) on Presentation and Management Outcome in Patients with Retinoblastoma.

Background: This study compares the outcomes of managing retinoblastoma between patients with unilateral and bilateral presentations. Methods: The study, conducted at the King Hussein Cancer Center in Amman, Jordan, retrospectively analyzed cases of retinoblastoma treated between March 2003 and December 2019. Evaluation criteria included clinical features, disease stage, treatment methods, and overall management outcomes. Results: The study comprised 697 eyes from 478 patients with retinoblastoma, with 52% being males. Bilateral disease was observed in 70% of patients, and a family history of retinoblastoma was more prevalent in cases with bilateral disease (20%) compared to those with unilateral disease (4%). Unilateral cases had a median age at diagnosis of 28 months, whereas bilateral cases were diagnosed at a median age of 6 months. Extra-ocular retinoblastoma was detected in 1% of eyes. According to the International Intraocular Retinoblastoma Classification (IIRC), 88% of unilateral cases presented with advanced disease (IIRC group D/E), compared to 46% in bilateral cases. Primary enucleation was performed in 29% of unilateral cases and 16% of bilateral cases (p-value 0.0007). Eye salvage rates were 31% in unilateral cases and 68% in bilateral cases (p-value < 0.0001). At 120 months of follow-up, 5% of patients died from secondary neoplasms or metastases, 81% were alive, and 14% were lost to follow-up. There was no significant difference in metastasis, secondary neoplasms, or mortality between patients with unilateral and bilateral retinoblastoma. Conclusions: This study highlights the nuanced differences in clinical characteristics and outcomes between unilateral and bilateral retinoblastoma, emphasizing the necessity of customized management and early detection strategies. It demonstrates that while bilateral retinoblastoma benefits from earlier detection and has a higher rate of eye salvage, there is no significant difference in metastasis or mortality rates when compared to unilateral cases. The critical roles of primary enucleation in advanced cases, along with effective communication and patient education, are also underscored to improve treatment adherence. Overall, these findings point to the importance of tailored approaches in optimizing outcomes for the diverse patient population affected by retinoblastoma.

Causes of death and survival analysis for patients with retinoblastoma in Jordan.

Purpose: To analyze causes and prognostic factors for death among Retinoblastoma (Rb) patients treated at a single specialized tertiary cancer center in Jordan. Methods: We reviewed the mortality causes for all Rb patients who have been treated at the King Hussein Cancer Center between 2003 and 2019 and were followed for at least 3 years after diagnosis. The main outcome measures included demographics, laterality, tumor stage, treatment modalities, metastasis, survival, and causes of death. Results: Twenty-four (5%) of the 478 patients died from retinoblastoma and 5-year survival was 94%. The mean age at diagnosis was 15 months (median, 18 months; range, 4-38 months); eight (33%) received diagnoses within the first year of life. Eleven (46%) were boys, 16 (67%) had bilateral disease, and 3 (13%) had a positive family history. The stage for the worst eye was C for 1 (4%) patient, D in 6 (25%) patients, and E (T3) in 15 (63%) patients. Two patients had extraocular Rb at diagnosis, and four of the patients who had intraocular Rb at diagnosis refused treatment and then came back with extraocular Rb. In total, extraocular disease was encountered in six eyes (six patients). After a 120-month median follow-up period, 24 patients (5%) died of second neoplasms (n = 3) or metastases (n = 21). Significant predictive factors for metastasis and death included advanced IIRC tumor stage (p < 0.0001), the presence of high-risk pathological features in the enucleated eyes (p = 0.013), parental refusal of the recommended primary treatment plan (p < 0.0001), and extraocular extension (p < 0.0001). Conclusion: The 5-year survival rates of Rb patients in Jordan are as high as those in high-income countries. However, 5% are still dying from metastatic disease, prompting the need for awareness campaigns to educate the public about the high cure rates and to prevent treatment abandonment.

A comparison of high risk pathological features between primary and secondary enucleation for retinoblastoma.

AIM: To compare the risk and pattern of High-Risk Pathologic Features (HRPF) in retinoblastoma between primary and secondary enucleation. METHODS: A retrospective analysis of 121 eyes from 118 patients who underwent enucleation at the King Hussein Cancer Center (KHCC) Amman, Jordan, between November 2009 and January 2020. Demographic information, tumor stage, time from diagnosis-to-enucleation, results of pathology, metastasis, and mortality were retrieved. RESULTS: Patients in the secondary group (49/121 eyes, 40%) were considerably younger at diagnosis (p = 0.0014), had bilateral disease (p = 0.0001), and had less-progressed disease at presentation (p = 0.016) compared to the primary enucleation. Primarily enucleated eyes were more-likely to have massive choroidal invasion (p = 0.0315) and post-laminar optic nerve invasion (p = 0.027), in spite of the finding that the overall prevalence of HRPF was similar between the two groups (35.5 percent vs. 37.5 percent; p = 0.585). The likelihood of anterior chamber invasion, was considerably higher in secondary enucleated eyes (p = 0.013). We evaluated primary and secondary enucleation for each subgroup (D and E) of the International Intraocular Retinoblastoma Classification (IIRC) and found the prevalence of HRPF was comparable (p = 0.58, 1.0, respectively). The difference in time between diagnosis-to-enucleation in secondary enucleation did not predict HRPF (p = 0.50). There was no discernible difference between primary and secondary enucleated eyes in terms of metastasis or survival (p = 0.156 and 0.44, respectively). CONCLUSION: Systemic chemotherapy has the ability to reduce the extent of tumor expansion that has been pathologically identified. Primary and secondary enucleated eyes are comparable in low metastatic risk only when strict examination and management guidelines are followed.

Retinoblastoma and uveal melanoma in Jordan: incidence, demographics, and survival (2011-2020).

PURPOSE: We present an epidemiologic analysis of retinoblastoma (RB) and uveal melanoma (UM) in Jordan to aid national strategies for improved ocular cancer surveillance and control. METHODS: A retrospective cohort of all Jordanian patients with RB and UM diagnosed over 10 years (2011-2020). Outcome measures included incidence, demographics, and outcomes. RESULTS: Retinoblastoma (n = 124) was more common than UM (n = 82); there was no sex predilection for either group. The median age at diagnosis of RB was 15 months(Six and 28 months for bilateral and unilateral cases, respectively), and the mean age-adjusted incidence was 8.2 cases per-million-children per year for children aged five years or less(one per 15,620 newborn per year). Fifty-one(41%) had bilateral disease, and 18(15%) had familial disease. Ninety-six(55%) eyes were group D or E(78% were T3/T4), and the five-year survival rate was 96%.For UM, the median age at diagnosis was 45 years with an incidence of 1.39 new cases per year per one million population. All(100%) had nonfamilial unilateral disease. Seventy-three(89%) had the tumor in the choroid, and 48(58%) had an advanced tumor that had invaded the sclera or the orbit (T3/T4) tumor. Sixty-two(76%) were treated by I-125 radioactive plaque, with globe salvage in 59(95%); the five-year survival rate was 85%. CONCLUSION: In Jordan, RB is more common and has better survival than UM. RB in Jordan and Western countries is equal in terms of incidence, globe salvage, and survival. UM is less common, with lower age at diagnosis (that was associated with better survival) in Jordan than in Western countries.

Interim FDG-PET/CT for therapy monitoring and prognostication in Hodgkin's Lymphoma.

The aim of the study was to assess the predictive value of interim FDG-PET/CT (iPET) in patients with Hodgkin's lymphoma (HL) treated with Adriamycin, bleomycin, vinblastine and dacarbazine (ABVD) chemotherapy. A total of 245 consecutive patients with de novo HL between 12/2013 and 12/2017 were evaluated retrospectively. All patients were treated with upfront ABVD, performed PET/CT scans at baseline, after 2 cycles (interim PET, iPET2) or 4 cycles (iPET4) and at the end of therapy, and followed up for at least 6 months after therapy. The response status on iPET was defined according to the standard five-point Deauville scores (DS) as follows: complete metabolic response (CMR, DS 1-3) and non-complete metabolic response (nCMR) (DS 4 and 5). End-of-treatment (EoT) response was assessed by FDG-PET/CT and if needed biopsy confirmation of PET-positive findings. The association between iPET and EoT response was investigated using logistic regression analysis. Survival analysis was performed using the Cox regression hazard model and Kaplan-Meier methods. Sixty-nine patients underwent iPET-2 and 176 iPET-4. No association was found between the timing of iPET and iPET response status (P-value = 0.71). Two hundred and one patients (82%) had iPET-CMR and 44 (18%) iPET -nCMR. iPET was strongly associated with EoT response status: 194/201 (96 .5%) of iPET-CMR had a complete response at the EoT while only 21/44 (47.7%) of patients with iPET-nCMR presented a complete response at EoT (P-value < 0.0001). The median follow-up was 32 months (range 6-81). Patients with iPET-CMR presented a better outcome with 91% 3 y event-free-survival (EFS) and 95% 3 y overall survival (OS) than those with iPET-nCMR (41 and 86%, respectively, P-value < 0.0001). In multivariable analyses, iPET retained an independent prognostic factor of EFS and OS (P-value < 0.0001 and P-value = 0.002, respectively). iPET is highly predictive of outcome of HL patients treated with ABVD and allows to tailor therapy to the individual patient.

Pembrolizumab for the Treatment of Relapsed and Refractory Classical Hodgkin Lymphoma After Autologous Transplant and in Transplant-Naïve Patients.

INTRODUCTION: Checkpoint inhibitors demonstrated significant efficacy in relapsed/refractory Hodgkin's Lymphoma (R/R cHL) resulting in high responses and prolonged progression free survival in patients, who relapse after or are ineligible for autologous stem cell transplantation (auto-SCT). We aimed to assess the efficacy and toxicity of Pembrolizumab before auto-SCT and in transplant naïve patients and calculate survival outcomes. PATIENTS AND METHODS: Fifty-five patients with R/R cHL were included. Patients demographics, including age, sex, risk stratification, therapy received and details pertaining transplantation, were collected. RESULTS: Median age was 28 years (range, 16-62 years). The median follow-up was 15.3 months and the median number of previous treatments was 3 (1-10). The best objective response was 74.5% (CR 32.7%, SD 5.5%) with reasonable safety profile. Twenty-nine of the responding patients received subsequent auto-SCT and 9 allogeneic stem cell transplantation (allo-SCT), 6 are currently alive with ongoing response. At the time of analysis, 6 patients remained on Pembrolizumab and the rest discontinued. The main reason for discontinuation was disease progression (n-49). Twelve-months overall survival and progression free survival (PFS) was 92% (95% CI: 76%-95%) and 51% (95% CI, 39%-67%) respectively. Twelve-month PFS for patients, who achieved CR or PR or PD was 88% (95% CI: 07%-75%); PR 60% (95% CI: 21%-29%) and 5% (95% CI: 5%-0%). Though the number of patients who received auto-SCT after Pembrolizumab was small (n-15), 12 months overall survival and PFS 100% and PFS 92%. 11 patients (20%) deceased during the follow-up and none was regarded to be treatment-related. CONCLUSION: Checkpoint inhibitors are effective in heavily pretreated cHL patients with reasonable survival outcomes. The results supporting the concept of auto and/or allo-SCT after checkpoint inhibitors use.

A Proposal for Future Modifications on Clinical TNM Staging System of Retinoblastoma Based on the American Joint Committee on Cancer Staging Manual, 7th and 8th Editions.

Importance: The 8th edition of the American Joint Committee on Cancer (AJCC) staging manual incorporated new changes from its 7th edition for classifying retinoblastoma (RB). Objective: We assessed the comparative prognostic values of the 7th and 8th editions of the AJCC clinical (cTNM) staging manuals for RB and suggested modifications for future edition accordingly. Design: A retrospective, observational study. Setting: King Hussein Cancer Centre. Participants: A cohort of 478 patients and 565 eyes with RB. Main Outcomes and Measures: Main outcome measures included demographics; tumor features, AJCC cTNM stage, and eye salvage rates. The prognostic performance of the different staging systems was assessed with the concordance index (C-index) and likelihood ratio χ2 tests. Results: The overall eye salvage rate was 65%. Stage migration occurred for 330 (48%) eyes with the AJCC Staging Manual, 8th edition. Based on the 7th edition AJCC staging, the eye salvage rate was 94% (n=177) for T1 tumors (98% for T1a, 93%for T1b, and 90%for T1c), 69% (n=204) for T2 tumors (73% for T2a and 62%for T2b), and 51% (n=40) for T3 tumors. Based on the 8th edition AJCC staging, the eye salvage rate was 95% (n=139) for T1 tumors (98% for T1a and 93% for T1b), 68% (n=281) for T2 tumors (90%for T2a and 66%for T2b), and 12% (n=1) for T3 tumors. With our proposed cTNM modifications, the eye salvage rate was 94% (n=177) for T1 tumors (98%for T1a, 93%for T1b, and 90% for T1c), 66% (n=243) for T2 tumors (73% for T2a, 62% for T2b, and 55% for T2c), and 12% (n=1) for T3 tumors. As estimated by odds ratios, more advanced cTNM stage (regardless of the cTNM staging system) was significantly associated with an increased chance of treatment failure (P < .0001). The C-index for both the 8th edition and the proposed modifications were approximately equal, and both were higher than that of the 7th edition. However, the proposed modifications had the highest likelihood ratio χ2 value and the best bootstrap 95% confidence interval. Conclusions and Relevance: Our proposed modifications on the clinical TNM Staging System for RB harbor more detailed subgroup classification criteria that provides better prognostic value for eye globe salvage than the published similar (but not identical) AJCC Staging Manual, 7th and 8th editions, furthermore these modifications may resolve the discrepancies in the previously published different classification systems for RB.

Presentation and management outcomes of Retinoblastoma among Syrian refugees in Jordan.

Purpose: The humanitarian crisis in Syria has had a profound impact on the entire region. In this study, we report the patterns of presentation and management outcomes of Syrian patients with Retinoblastoma (Rb) treated at a single tertiary cancer center in Jordan. Methods and Materials: This is a retrospective comparative study of Syrian refugees and Jordanian citizens who had Rb between 2011 and 2020. Collected data included patient demographics, presentation, tumor stage, treatment modalities, eye salvage rate, metastasis, and mortality. Results: Thirty Syrian refugees (16 (53%) had bilateral disease) and 124 Jordanian citizens (51(41%) had bilateral disease) were diagnosed with Rb during this period. The median age at diagnosis for refugees was 10 and 32 months for patients with bilateral and unilateral Rb consecutively, compared to 6 and 28 months for citizens. The median lag time between signs of disease and initiation of treatment was 3 months for refugees, compared to 1 month for citizens.Refugees were more likely to present with a more advanced stage (p=0.046). Out of 46 affected eyes in refugees; 32 (70%) eyes were group D or E, while out of 175 affected eyes among citizens; 98 (56%) eyes were group D or E. Therefore, refugees with Rb were more likely to mandate primary enucleation (48%) compared to citizens (25%) (p=0.003). However, out of 24 eyes among refugees who received conservative therapy, 15 (62%) eyes were successfully salvaged, while out of 131 affected eyes among citizens who received conservative therapy, 105 (80%) eyes were successfully salvaged (p=0.06). Two (7%) of the refugees and four (3.2%) of the citizens with Rb died from metastasis. Conclusion: Syrian refugees with Rb presented with more advanced disease due to delay in diagnosis and referral that increased the treatment burden by decreasing the chance for eye globe salvage. However, patients who received the timely intervention had a similar outcome to citizens with Rb; probably a reflection of the management of all patients at a single specialized center. We advocate for the timely referral of refugees with this rare life-threatening tumor to a specialized cancer center for the best possible outcome.

The Predictive Value of the Eighth Edition of the Clinical TNM Staging System for the Likelihood of Eye Salvage for Intraocular Retinoblastoma by Systemic Chemotherapy and Focal Therapy.

BACKGROUND: The American Joint Committee on Cancer/Union for International Cancer Control (AJCC/UICC) cTNM staging is emerging as a universal staging for all cancers, including retinoblastoma. METHODS: Here we evaluated the predictive value of the eighth edition AJCC/UICC cTNM staging in comparison with the International Intraocular Retinoblastoma Classification for eye globe salvage by primary systemic chemotherapy and focal therapy (CRD) using logistic regression model for the probability of treatment failure. RESULTS: The eye salvage rate for 565 treated eyes was 95% (n=139/147) for T1 tumors (98% for T1a and 93% for T1b), 56% (n=230/410) for T2 (81% for T2a and 53% for T2b), and 0% for T3 tumors, and was 98%, 93%, 76%, and 44% for group A, B, C, and D tumors, respectively. As estimated by odds ratios, T2 were 13.6-fold more likely to fail treatment than T1, and T1b, T2a, and T2b were 2.8-, 9.4-, and 35.1-fold more likely to fail treatment than T1a, respectively. Group B, C, and D tumors were 2.8-, 12.7-, and 50.1-fold more likely to fail treatment than group A tumors, respectively. Eye salvage rate was 62% for eyes with focal seeds (3 mm close to the tumor), and 42% for eyes with diffuse seeds (clouds more than 3 mm from tumor edge) (P<0.0001). CONCLUSION: Both, the eighth edition cTNM classification and the International Intraocular Retinoblastoma Classification systems, can effectively predict eye salvage rates for retinoblastoma by CRD. Eyes with higher cT stages are more likely to experience treatment failure. Because the cT2b group is very heterogeneous, our findings suggest further division of this group based on the severity of vitreous/subretinal seeds, this should be revised in the next edition of cTNM system.

Management and Outcomes of Unilateral Group D Tumors in Retinoblastoma.

PURPOSE: Retinoblastoma presents most commonly as advanced unilateral disease, particularly in developing countries for which primary enucleation has been the preferred method of treatment. However, with the evolution of newer treatment modalities including intravitreal chemotherapy, intra-arterial chemotherapy and newer chemotherapeutic combinations, a trend towards more conservative approaches is being observed. Our aim is to evaluate outcomes of group D eyes following conservative and non-conservative treatment options. PATIENTS AND METHODS: The ocular oncology database was used to identify eyes with unilateral retinoblastoma that fulfilled the International Intraocular Retinoblastoma Classification (IIRC) group D criteria from August 2010 to August 2018 and these were retrospectively reviewed. Overall, 39 eyes were identified. RESULTS: Nineteen (49%) eyes underwent primary enucleation and 20 (51%) received eye-conserving treatment. Eye salvage was possible in 15 (75%) eyes in the attempted salvage group. None of the patient revealed signs of metastasis. All eyes received conventional chemotherapy (carboplatin, vincristine, etoposide) and focal laser therapy. Additional treatment modalities offered included intravitreal chemotherapy, intra-arterial chemotherapy and topotecan. Three (11%) eyes in the primary enucleation group showed high-risk features on histopathology and none developed metastasis. CONCLUSION: The results of the study seem promising and conservative measures can be adopted in selected unilateral group D eyes.

How Telemedicine and Centralized Care Changed the Natural History of Retinoblastoma in a Developing Country: Analysis of 478 Patients.

PURPOSE: To evaluate the efficacy of integrating a telemedicine-based twinning partnership and centralized care for retinoblastoma on survival and eye salvage. DESIGN: Four hundred seventy-eight retinoblastoma patients treated at a tertiary referral cancer center (King Hussein Cancer Centre [KHCC]) from 2003 through 2019. PARTICIPANTS: Four hundred seventy-eight retinoblastoma patients treated at KHCC after implementing a telemedicine-based program with St. Jude Children's Research Hospital. METHODS: We reviewed the outcomes of retinoblastoma patients who were treated at KHCC after implementing a telemedicine-based eye salvage program with St. Jude Children's Research Hospital, and we compared that with outcomes for retinoblastoma patients who were treated before implementing a telemedicine-based retinoblastoma service at KHCC. MAIN OUTCOME MEASURES: We analyzed patient demographics, clinical characteristics, treatments received, consultation type and duration, and long-term patient outcomes before and after implementing the twinning program. RESULTS: Over 17 years, 813 eyes from 478 children with retinoblastoma were treated at KHCC. Three hundred thirty-five patients (70%) had bilateral disease. Six patients (4%) with unilateral disease and 66 patients (20%) with bilateral disease had a family history of retinoblastoma. After the twinning program was established in 2003, the mortality rate decreased from 38% to 5% (P < 0.0001), and the overall eye salvage rate increased from 4% to 61% (98% for group A, 93% for group B, 81% for group C, and 48% for group D; P < 0.0001). Initially, all cases were discussed via telemedicine, but as knowledge transfer increased, the proportion of cases that required discussion decreased to less than 3% 10 years later. Similarly, treatment changes based on consultations decreased from 70% to 7% after 10 years. Both survival and eye-salvage rates were comparable at the early and later stages of implementing the twinning program. At a median follow-up of 120 months, 5% of patients had died of metastases or secondary neoplasms, 81% were alive, and 14% were lost to follow-up. CONCLUSIONS: Centralization of care at a single center in developing countries can achieve patient outcomes comparable with those of developed countries via twinning and telemedicine. This benefit can extend to a large region because two thirds of patients treated at KHCC were non-Jordanians.

Higher-dimensional physical models with multimemory indices: analytic solution and convergence analysis.

The purpose of this work is to analytically simulate the mutual impact for the existence of both temporal and spatial Caputo fractional derivative parameters in higher-dimensional physical models. For this purpose, we employ the γ̅-Maclaurin series along with an amendment of the power series technique. To supplement our idea, we present the necessary convergence analysis regarding the γ̅-Maclaurin series. As for the application side, we solved versions of the higher-dimensional heat and wave models with spatial and temporal Caputo fractional derivatives in terms of a rapidly convergent γ̅-Maclaurin series. The method performed extremely well, and the projections of the obtained solutions into the integer space are compatible with solutions available in the literature. Finally, the graphical analysis showed a possibility that the Caputo fractional derivatives reflect some memory characteristics.

Factors influencing the use of adaptive radiation therapy in vulvar carcinoma.

AIM: We aim to evaluate the variables affecting the frequency of adaptive radiotherapy (ART) in vulvar cancer. BACKGROUND: ART may be needed throughout a definitive RT course for vulvar carcinoma due to changes in patient's anatomy and tumor response. MATERIALS AND METHODS: Charts of patients charts who had been treated with definitive concurrent chemo-radiotherapy for vulvar carcinoma, between January 2015 and December 2019 were inquired. Radiation therapy was delivered using intensity modulated radiotherapy (IMRT) with daily image-guided radiotherapy (IGRT). ART was defined as re-simulation and re-planning based on deformation in the irradiated volume by more than 1 cm. Univariate analysis was conducted to study the impact of patient's demographics as well as tumor characteristics on the frequency of ART. RESULTS: 22 patients were eligible for analysis. Median age at diagnosis was 55 years (range 43-82). Radiotherapy dose was 60-66 Gy over 30-35 fractions (fx). Median primary tumor volume was 30cc (9-140). Median Body Mass Index (BMI) was 32 (range 21-40). Thirteen out of 22 patients (59%) required ART, with median timing at 25 fx (19-31). On univariate analysis, larger primary tumor volume (> = 30cc) was associated significantly with increased frequency of ART (p value = 0.0005). There was no significant impact of ART on the frequency with respect to patient's age, BMI, tumor stage, grade and location. CONCLUSION: Changes in radiation target volume are common among vulvar carcinoma patients who are treated with definitive radiotherapy, especially large primary tumors. This review highlights the importance of ART for patients with vulvar carcinoma treated with definitive radiotherapy.

Development of spreading symmetric two-waves motion for a family of two-mode nonlinear equations.

In this work, a functional operator extracted from Korsunsky's technique is used to produce new two-mode nonlinear equations. These new equations describe the motion of two directional solitary-waves overlapping with an increasing phase-velocity and affected by two factors labeled as the dispersion and nonlinearity coefficients. To investigate the dynamics of this two-mode family, we construct the two-mode KdV-Burgers-Kuramoto equation (TMKBK) and two-mode Hirota-Satsuma model (TMHS). Two efficient schemes are used to assign the necessary constraints for existence of solutions and to extract them. The role of the phase-velocity on the motion of the obtained two-wave solutions is investigated graphically. Finally, all the obtained solutions are categorized according to their physical shapes.

Programmed screening for retinoblastoma enhances early diagnosis and improves management outcome for high-risk children.

PURPOSE: To study the impact of a Retinoblastoma (Rb) screening program in the absence of genetic testing on the management and outcome of high-risk children. METHODS: This is a retrospective, clinical case series of 76 children from families involved in a Rb screening program as they had higher than normal risk as calculated by the conventional ways without genetic testing. Data included calculated risk, method of diagnosis, demographics, tumor features, treatment modalities, and management outcome. RESULTS: Out of the 76 children screened, 46 children were diagnosed with Rb (12 by screening and 34 had signs of Rb), the other 30 were free of disease. Patients diagnosed by screening were younger (mean; 2.4 months vs 15.8 months for the group with signs of Rb), had significantly earlier tumor stage at diagnosis (p = .0001), higher eye salvage rate (p = .0001), less need for systemic chemotherapy (p = .022), and better visual outcome (p = .0017) than the other group. None of the eyes were group D or E, enucleated or irradiated. Six (50%) patients were cured without chemotherapy, and the visual acuity was 0.5 or better in 55% of eyes. Of interest, 71% of tumors were diagnosed by the age of 6 months, 90% by the age of 1 year, and no new tumor appeared after the age of 2 years. CONCLUSION: Even in the absence of genetic testing, screening for children with high risk for Rb is effective in enhancing early diagnosis, improving visual outcome, and increasing eye salvage rate with limited exposure to treatment burden.

Impact of RB1 gene mutation type in retinoblastoma patients on clinical presentation and management outcome.

OBJECTIVE/BACKGROUND: Retinoblastoma (RB), the most common intraocular malignancy in children, is caused by biallelic inactivation of the human retinoblastoma susceptibility gene (RB1). We are evaluating the impact of the type of RB1 gene mutation on clinical presentation and management outcome. METHODS: A retrospective case series of 50 patients with RB. Main outcomes were clinical and pathologic features and types of RB1 gene mutations detected using quantitative multiplex polymerase chain reaction (PCR), allele-specific PCR, next-generation sequencing analysis, and Sanger sequencing. RESULTS: Twenty (40%) patients had unilateral RB and 30 (60%) had bilateral RB. Overall, 36 (72%) patients had germline disease, 17 (47%) of whom inherited the disease. Of these 17 inherited cases, paternal origin of the RB1 mutation was seen in 15 (88%). The overall eye salvage rate was 74% (n = 49/66; 100% for Groups A + B + C, and 79% for Group D eyes). The most frequent type of mutation was a nonsense mutation generating a stop codon (15/36, 42%). Other mutations that result in a premature stop codon due to deletions or insertions with donor splice site or receptor splice site mutations were detected in 7/36 (19%), 10/36 (28%), and 2/26 (6%) patients, respectively. The remaining two (6%) patients had frameshift mutation. Patients with deletion, acceptor splice site, and frameshift mutations presented with more advanced ICRB (International Classification of Retinoblastoma) stage (75% diagnosed with Group D or E), even though there was no significant difference in eye salvage rate or tumor invasiveness between patients with different types of mutations. CONCLUSION: Despite the heterogeneous nature of RB1 gene mutations, tumor stage remains the most important predictive factor for clinical presentation and outcome. Furthermore, acceptor splice site and frameshift mutations are associated with more advanced tumor stage at diagnosis.

Intravitreal Melphalan Chemotherapy for Vitreous Seeds in Retinoblastoma.

OBJECTIVE: To evaluate our experience with intravitreal melphalan chemotherapy as a second-line regimen for RB patients with refractory or recurrent vitreous seeds. METHODS: A retrospective case series of 16 eyes from 16 patients with intraocular RB who received intravitreal melphalan chemotherapy using the antireflux injection technique. Data included demographics, stage at diagnosis, treatment modalities, side effects, eye salvage, and survival. RESULTS: The total number of injections was 64 (median, 3 injections per eye; range, 3-8), and the median age at time of injection was 22 months (range, 9-63 months). Nine (56%) patients were males, and 13 (81%) patients had bilateral RB. Complete response was seen in 13 (81%) eyes: in 9 (100%) eyes with focal vitreous seeds and in 4 (57%) eyes with diffuse vitreous seeds (P=0.062). At a median follow-up of 18 months (range, 6-48 months), the eye salvage rate was 81%, local retinal toxicity confined to the site of injection was seen in 2/3 of the eyes, 2 (12%) eyes had cataract, and none of the patients had orbital recurrence and distant metastasis or was dead. CONCLUSION: Intravitreal melphalan is a promising modality for treatment of vitreous seeds, and the dose of 20-30 µg of melphalan sounds to be safe and effective for refractory and recurrent vitreous seeds.µg of melphalan sounds to be safe and effective for refractory and recurrent vitreous seeds.

The role of external beam radiation therapy for retinoblastoma after failure of combined chemoreduction and focal consolidation therapy.

Purpose: To study the role of external beam radiation therapy (EBRT) for the treatment of retinoblastoma eyes that were not cured by combined systemic chemotherapy and focal consolidation therapy.Methods and Materials: A retrospective case series of 28 eyes for 24 retinoblastoma patients treated by EBRT after the failure of tumor controlled by chemotherapy and focal therapy. The main outcome measures included: international intraocular retinoblastoma classification stage (IIRC) and Reese Ellsworth (RE) stage, tumor seeding, treatment modalities, eye salvage, and survival.Results: The median age at diagnosis was 11 months. There were 14 (58%) males and 20 (83%) bilateral cases. All eyes were treated initially by systemic chemotherapy (range; 6-8 cycles). The dose of radiation used for all eyes was 45 Gray (Gy).The mean follow-up was 75months, and the overall eye salvage rate after EBRT was 13 (46%) eyes: 67% (2/3) for IIRC group B, 71% (5/7) for group C, and 33% (6/18) for group D eyes. Vitreous seeds and tumor stage migration during management by chemotherapy were the most important significant predictive factors for tumor control (p = .001 and 0.033, respectively).Conclusion: Eyes with retinoblastoma that failed chemotherapy followed by focal therapy were controlled with EBRT. However, the presence of vitreous seeds, stage migration during the course of chemotherapy, as well as good vision in the other eye may not justify the known risks of EBRT.

Prognostic Factors for Eye Globe Salvage by External Beam Radiation Therapy for Resistant Intraocular Retinoblastoma.

PURPOSE: To analyse the prognostic factors for eye salvage for eyes with intra-ocular retinoblastoma (RB) that is resistant to systemic chemotherapy and focal therapy by external beam radiation therapy (EBRT). METHODS: A retrospective analysis of 28 eyes with intra-ocular RB that was resistant for systemic chemotherapy and focal consolidation therapy and received EBRT. Outcome measures included tumor stage at diagnosis, stage migration, type of tumor seeds, treatment modalities, eye globe salvage, metastasis, and survival. RESULTS: Most of the patients (83%) had bilateral RB, and 42% were females. All eyes were treated initially by combination of systemic chemotherapy and focal consolidation therapy. The dose of EBRT was 45 Gy. The mean follow-up was 6.5 years, and the overall eye globe salvage rate post EBRT was 46%: 67% (2/3) for group B, 71% (5/7) for group C, and 33% (6/18) for group D. Patient's gender, tumor site, laterality, and tumor stage at diagnosis were not significant prognostic factors (p> 0.05) for final outcome. The significant poor prognostic factors were tumor stage migration during systemic chemotherapy (p= 0.03) and presence of vitreous seeds at time of EBRT (p=0.001). Post EBRT complication rate was 68% (19/28) including; retinal detachment (3), vitreous hemorrhage (4), neovascular glaucoma (1), cataract (16), radiation retinopathy (2), and second malignancy (2). CONCLUSION: EBRT is an alternative for enucleation when RB is resistant to combined chemoreduction/focal consolidation therapy in absence in vitreous seeds. The known risks for EBRT are not justified for patients with unilateral RB and for those who have functional vision in the other eye.