Real-World Experience of Vismodegib in Advanced Basal Cell Carcinoma at a Canadian Cancer Center.

BACKGROUND: Vismodegib is a novel Hedgehog pathway inhibitor that has revolutionized the treatment of patients with advanced basal cell carcinoma (BCC) who are poor candidates for surgery or radiation. Few studies have explored the use of vismodegib to facilitate further surgery or radiotherapy, and the optimal treatment duration to balance outcomes with adverse effects. OBJECTIVES: To characterize the disease response, progression, and recurrence outcomes of BCC patients, and to report the impact of subsequent therapies. METHODS: We performed a retrospective study of 46 adult patients with advanced basal cell carcinoma (aBCC), including both locally advanced (laBCC) and metastatic (mBCC) disease, treated with vismodegib at a single center from 2012 to 2019. RESULTS: Thirty-six had laBCC, and 10 had mBCC. Treatment was given over a mean of 21.9 months. Twenty-three (50%) had a complete response (CR), and 19 (41.3%) achieved partial response (PR). Median time to maximal response was 5.3 months. Eleven (23.9%) had resected disease at median 17.2 months, and 11 patients (23.9%) received radiotherapy. Thirty-two (69.6%) experienced progressive disease after achievement of CR or PR. Among 17 CR patients, who stopped treatment, 14 (82.3%) experienced subsequent relapse; 6 (85%) attained a repeat response. Twenty (43.5%) discontinued treatment at least once due to adverse effects. CONCLUSIONS: With a response rate of 91%, London Regional Cancer Center's (LRCP)'s experience with vismodegib supports its effectiveness in treatment of aBCC. Moreover, a significant number of patients treated with vismodegib became amenable to surgery or radiotherapy. Toxicity remained an important factor that limited treatment duration.

Epidemiology and clinical outcome of intraocular foreign bodies in Hong Kong: a 13-year review.

The purpose of this study was to describe the epidemiology, visual outcome and prognostic factors of intraocular foreign body (IOFB) injuries in a tertiary centre in Hong Kong. A retrospective review of 21 eyes in 21 patients with IOFB that presented to United Christian Hospital from January 2001 to July 2014 was performed. IOFB represented 16 % of all open-globe traumas. There was a high male predominance (90 %). The mean age was 42. Work-related injuries (86 %) were the main cause, where only 10.5 % had eye protection. Hammering was the commonest mechanism of injury (43 %). Most IOFBs were metallic (67 %). The IOFB was found in the anterior segment in 31 % and posterior segment in 69 %. 57 % presented with an initial visual acuity of ≥0.1, and up to 24 % of patients had an initial visual acuity of better than or equal to 0.5. Most cases (76 %) received prompt surgical intervention within 24 h, and there was a low (0 %) endophthalmitis rate. Forty-eight percent had an improvement in visual acuity, defined as final visual acuity more than or equal to 2 lines of improvement from initial visual acuity, and 48 % attained a final visual acuity of better than or equal to 0.5. One case underwent evisceration. A smaller IOFB size (<5 mm) was associated with a good final visual acuity of better than or equal to 0.5 (p = 0.048). It was also found that a posterior segment IOFB was more likely to give a final VA of less than 0.5 (p = 0.035). IOFB remains a significant complication of work-related injuries in Hong Kong. This is the first local study that explores the epidemiology of IOFB injuries in Hong Kong. The favourable visual outcome and low endophthalmitis rate may be related to early removal of IOFB. Despite legal ordinances for mandatory eye protection, the uptake of eye protection was low.

FACTORS INFLUENCING NEED FOR RETREATMENT AND LONG-TERM VISUAL OUTCOME AFTER INTRAVITREAL BEVACIZUMAB FOR MYOPIC CHOROIDAL NEOVASCULARIZATION.

PURPOSE: To evaluate the efficacy and the predictive factors associated with the need for retreatment and long-term visual outcome after intravitreal bevacizumab for myopic choroidal neovascularization (CNV). METHODS: Retrospective cohort study of 93 eyes with subfoveal or juxtafoveal myopic CNV treated initially with either 3-monthly or single intravitreal bevacizumab injections followed by pro re nata retreatment. The efficacy was evaluated by the best-corrected visual acuity (BCVA) during follow-up visits. Backward stepwise multiple linear regression analyses were performed to evaluate the potential predictive factors on final BCVA, change in BCVA, and number of injections. Multiple logistic regression was performed to evaluate the potential predictive factors for retreatment. RESULTS: The mean follow-up duration was 25.12 ± 11.18 (SD) months. The mean logMAR BCVA at baseline was 0.72 ± 0.58 logMAR (20/100 Snellen equivalent) and was maintained at 0.39 ± 0.46 logMAR (20/50 Snellen equivalent) at the last follow-up (P < 0.001). The mean number of injections was 3.53 ± 1.70 (range, 3-10), and a total of 25 eyes (26.9%) received retreatment. Patients who received single loading injection had significantly lower mean total number of injections (1.50 ± 0.73 vs. 3.96 ± 1.53). Both subfoveal and juxtafoveal myopic CNV eyes had significant improvement in BCVA (0.28 ± 0.43 vs. 0.22 ± 0.32 [20/40 vs 20/30 Snellen equivalent], P = 0.506), and juxtafoveal myopic CNV eyes had significantly better BCVA at baseline and at the last follow-up than the subfoveal group. Treatment-naive eyes had significant improvement from baseline BCVA, and the amount of improvement was significantly more than those who received previous photodynamic therapy (0.31 ± 0.43 vs. 0.06 ± 0.11 [20/40 vs 20/25 Snellen equivalent], P < 0.001). Multivariate stepwise regression analysis showed that the baseline CNV size (P < 0.05), baseline BCVA (P < 0.001), and duration of symptoms (P < 0.05) were significant predictive factors for final BCVA, and BCVA improvement. Multiple logistic regression analysis identified that CNV size (P = 0.014) and follow-up duration (P = 0.017) were significant predictive factors for retreatment. No significant association was found for number of injections. CONCLUSION: Intravitreal bevacizumab seems to be an effective treatment for both subfoveal and juxtafoveal myopic CNV in the long term. Patients presented with shorter duration of symptoms and smaller CNV size before treatment as significant prognostic factors that predict better visual outcome. Eyes with longer follow-up duration and larger baseline CNV size may have higher risk for retreatment.

Survivals following discontinuation of PD-1 inhibitor treatment in advanced melanoma patients.

The aim of this study was to evaluate overall survival post-treatment discontinuation survival (OS PTD ) in advanced melanoma patients started on immunotherapy. This retrospective study included all unresectable advanced or metastatic melanoma patients who had permanent treatment discontinuation after receiving at least one cycle of palliative-intent programmed death-1 ± cytotoxic T-lymphocyte associated protein-4 inhibitor treatment from 2014 to 2019. Indications of permanent treatment discontinuation included treatment completion, toxicity or progression. OS PTD was defined as a time of permanent treatment discontinuation to the time of death. Our study ( N = 96) had 27, 12 and 57 patients who discontinued PD-1 inhibitor treatment due to treatment completion, toxicity and progression, respectively. Median treatment durations received for the treatment completion, toxicity and progression groups were 24, 6 and 3 months, respectively. As expected those patients who had disease progression on immunotherapy had very poor survival compared to those that completed treatment or stopped due to toxicity. A multivariable Cox model excluding the patients who progressed indicated no significant OS PTD differences between the toxicity and treatment completion group (HR, 0.894; 95% CI, 0.232-3.449; P = 0.871) who received single or dual immunotherapy. Our real-world study highlighted similar, durable survival at PD-1 inhibitor discontinuation due to either toxicity or treatment completion, despite longer treatment duration received in the completion group than toxicity group. Patients with progression on PD-1 inhibitor treatment have very poor survival. Our findings must be interpreted with caution due to its retrospective nature and small sample size.

Priapism in a Patient with Rectal Adenocarcinoma.

BACKGROUND: Priapism is a very rare complication of malignancy and is usually accompanied by locally advanced or widely metastatic disease. We describe a case of priapism arising in a 46-year-old male with localised rectal cancer that was responding to therapy. CASE PRESENTATION: This patient had just completed two weeks of neoadjuvant, long-course chemoradiation when he presented with persistent painful penile erection. Assessment and diagnosis were delayed for more than 60 h, and although a cause could not be determined from imaging, a near complete radiological response of the primary rectal cancer was seen. His symptoms were refractory to urologic intervention and were associated with extreme psychological distress. He re-presented shortly thereafter with extensively metastatic disease in the lungs, liver, pelvis, scrotum, and penis; additionally, multiple venous thromboses were identified, including in the dorsal penile veins. His priapism was not reversible and was associated with a considerable symptom burden for the remainder of his life. His malignancy did not respond to first-line palliative chemotherapy or radiation, and his clinical course was further complicated by obstructive nephropathy, ileus, and genital skin breakdown with a suspected infection. We initiated comfort measures, and he ultimately died in hospital less than five months after his initial presentation. CONCLUSION: Priapism in cancer is usually related to tumour infiltration of the penis and corporal bodies resulting in poor venous and lymphatic drainage. The management is palliative and can include chemotherapy, radiation, surgical shunting, and potentially penectomy; however, conservative penis-sparing therapy may be reasonable in patients with limited life expectancy.

Association of circadian timing of initial infusions of immune checkpoint inhibitors with survival in advanced melanoma.

Aims: Chronomodulation of immune checkpoint inhibitors (ICIs) is not well understood. The authors evaluated the circadian timing of initial ICI infusions. Patients & methods: A retrospective cohort study of patients with advanced melanoma (n = 121) was conducted. Results: Exclusive afternoon timing of the first four infusions was associated with worse overall survival (5.5 vs 24.9 months; p < 0.001) and progression-free survival (3.3 vs 7.6 months; p = 0.009) on Kaplan-Meier curves. In multivariable Cox analysis, the rate of overall survival was lower in patients who received all first four ICI infusions in the afternoon versus patients who received ≥1 of the first four infusions in the morning (hazard ratio: 2.4; p = 0.004). Conclusion: Deliberate morning scheduling for the first several ICI treatments may improve patient-centered outcomes.

Long-Term Toxicities of Immune Checkpoint Inhibitor (ICI) in Melanoma Patients.

ICI therapy has greatly improved patient outcomes in melanoma, but at the cost of immune-related adverse events (irAEs). Data on the chronicity of irAEs, especially in real-world settings, are currently limited. We performed a retrospective chart review of 161 adult patients with melanoma treated with at least one cycle of ICI regimen in the adjuvant or metastatic setting: 129 patients received PD-1 inhibitor monotherapy and 32 received dual immunotherapy. Patients were grouped by duration of irAE: permanent (no complete resolution), long-term (resolution over a period ≥ 6 months), transient (resolution over a period < 6 months), or no irAEs. A total of 283 irAEs were reported in the whole patient population. Sixty-six (41.0%) patients developed permanent irAEs, fifteen (9.3%) experienced long-term irAEs as their longest-lasting toxicity, thirty-four (21.1%) developed transient irAEs only, and forty-six (28.6%) experienced no irAEs. Permanent irAEs occurred in 21 (65.6%) patients treated with dual immunotherapy and in 45 (34.9%) patients treated with monotherapy. The majority of permanent irAEs were endocrine-related (36.0%) or skin-related (32.4%). Grade 3-4 permanent irAEs occurred in 20 (12.4%) patients and included toxicities such as adrenal insufficiency, myocarditis, and myelitis. Fifty-three (32.9%) patients were still requiring treatment for long-term or permanent irAEs 6 months or more following the completion of ICI therapy, including twenty-four patients on thyroid hormone replacement and twenty-two on oral steroids. ICI treatment was temporarily interrupted for 64 (22.6%) irAEs and permanently discontinued due to irAEs in 38 patients (13.6% of irAEs, 23.6% of patients); additionally, 4 (2.5%) patients died of irAEs. Our findings show that ICI treatment in melanoma is associated with a wide range of toxicities that can be permanent and may have long-lasting impacts on patients, which should therefore be discussed when obtaining consent for treatment.

Ocular Features and Autism Spectrum Disorder: A 10-Year Retrospective Review.

We reviewed the medical records of our pediatric ophthalmology and strabismus clinic of our hospitals for the period 1 January, 2009 to 31 December, 2018, to identify children with autism spectrum disorder (ASD). We found that refractive errors (62%) and strabismus (63%) were the most common ocular manifestations in children with ASD. With timely management, amblyopia and strabismus could have favorable outcome. As amblyopia was significantly associated with intellectual disability (P=0.02), early ophthalmic monitoring via multidisciplinary approach is warranted.

C. elegans electrotaxis behavior is modulated by heat shock response and unfolded protein response signaling pathways.

The nematode C. elegans is a leading model to investigate the mechanisms of stress-induced behavioral changes coupled with biochemical mechanisms. Our group has previously characterized C. elegans behavior using a microfluidic-based electrotaxis device, and showed that worms display directional motion in the presence of a mild electric field. In this study, we describe the effects of various forms of genetic and environmental stress on the electrotactic movement of animals. Using exposure to chemicals, such as paraquat and tunicamycin, as well as mitochondrial and endoplasmic reticulum (ER) unfolded protein response (UPR) mutants, we demonstrate that chronic stress causes abnormal movement. Additionally, we report that pqe-1 (human RNA exonuclease 1 homolog) is necessary for the maintenance of multiple stress response signaling and electrotaxis behavior of animals. Further, exposure of C. elegans to several environmental stress-inducing conditions revealed that while chronic heat and dietary restriction caused electrotaxis speed deficits due to prolonged stress, daily exercise had a beneficial effect on the animals, likely due to improved muscle health and transient activation of UPR. Overall, these data demonstrate that the electrotaxis behavior of worms is susceptible to cytosolic, mitochondrial, and ER stress, and that multiple stress response pathways contribute to its preservation in the face of stressful stimuli.

Microfluidic Device for Microinjection of Caenorhabditis elegans.

Microinjection is an established and reliable method to deliver transgenic constructs and other reagents to specific locations in C. elegans worms. Specifically, microinjection of a desired DNA construct into the distal gonad is the most widely used method to generate germ-line transformation of C. elegans. Although, current C. elegans microinjection method is effective to produce transgenic worms, it requires expensive multi degree of freedom (DOF) micromanipulator, careful injection alignment procedure and skilled operator, all of which make it slow and not suitable for scaling to high throughput. A few microfabricated microinjectors have been developed recently to address these issues. However, none of them are capable of immobilizing a freely mobile animal such as C. elegans worm using a passive immobilization mechanism. Here, a microfluidic microinjector was developed to passively immobilize a freely mobile animal such as C. elegans and simultaneously perform microinjection by using a simple and fast mechanism for needle actuation. The entire process of the microinjection takes ~30 s which includes 10 s for worm loading and aligning, 5 s needle penetration, 5 s reagent injection and 5 s worm unloading. The device is suitable for high-throughput and can be potentially used for creating transgenic C. elegans.

CITROBACTER ENDOGENOUS ENDOPHTHALMITIS: A CASE REPORT AND REVIEW OF THE LITERATURE.

PURPOSE: We present a case of endogenous endophthalmitis because of an unusual bacterium, Citrobacter koseri. PATIENT: A 57-year-old woman without previous history of eye surgery or trauma presented with diabetic ketoacidosis and a painful right eye with the reduction of vision. C. koseri was identified in blood culture; thus, a diagnosis of right eye endogenous endophthalmitis was made. Intravenous and intravitreal antibiotics were both started, and vitreous culture further confirmed C. koseri as the causative organism. Computed tomography of the abdomen and pelvis revealed a right C-shaped perinephric abscess, which was drained under ultrasound guidance. RESULTS: Because of rapid progression to corneal melting, evisceration was performed. CONCLUSION: Cases of endogenous endophthalmitis caused by Citrobacter are very limited, and a review of all published cases in the English literature and the present case revealed that endogenous Citrobacter endophthalmitis arose almost entirely from Citrobacter renal infection. Early recognition and drainage of renal abscess may lower the chance of uncontrolled infection and endogenous spread to the eyes. Despite prompt and intensive treatment, the clinical outcome of Citrobacter endogenous endophthalmitis seems to be poor.

Bevacizumab for neovascular age-related macular degeneration in Chinese patients in a clinical setting.

AIM: To determine the outcome of non-investigational treatment with intravitreal bevacizumab (IVB) in neovascular age-related macular degeneration (AMD) patients. METHODS: Retrospective chart review of 81 eyes with neovascular AMD followed-up for at least 12mo and received 3-monthly loading IVB injections. Re-treat was based upon the individual clinician's judgment. Best-corrected visual acuity (BCVA) and optical coherence tomography measurements of central foveal thickness outcomes were evaluated at 12, 24mo. RESULTS: Eighty-one eyes (of 75 patients) completed 12mo of follow-up and 44 eyes (of 41 patients) completed 24mo of follow-up. The mean baseline logMAR BCVA significantly improved from 0.94±0.69 to 0.85±0.68 at 12mo (P<0.001) and from 0.91±0.65 to 0.85±0.60 (P=0.004) at 24mo. The proportion of eyes that lost <15 logMAR letters at 12mo was 90.1% and at 24mo was 81.8%. IVB was effective in improving visual acuity in both treatment naïve and previous photodynamic therapy (PDT)-treated subgroups. Treatment naive patients required significantly fewer injections than patients with prior PDT. Multiple regression analysis identified that poorer baseline visual acuity was associated with greater improvement in visual acuity (P=0.015). CONCLUSION: Fewer injections in clinical practice may result in suboptimal visual outcomes compared with clinical trials of IVB in neovascular AMD patients. Poor baseline visual acuity and prior PDT treatment may also improve vision after IVB. The safety and durability of effect was maintained at 24mo.

Defining a new testosterone threshold for medical castration: Results from a prospective cohort series.

BACKGROUND: We seek to determine if testosterone levels below the accepted castration threshold (50 ng/dL) have an impact on time to progression to castrate-resistant prostate cancer (CRPC). METHODS: This is a prospective cohort series of patients undergoing androgen deprivation therapy (ADT) with luteinizing hormone-releasing hormone agonist or antagonist at a tertiary centre from 2006 to 2011. Serum testosterone level was assessed every 3 months. Patients with any testosterone >50 ng/dL were excluded. Patients were stratified into groups based on those achieving mean testosterone levels <20 ng/dL and <32 ng/dL. Progression to CRPC was assessed with the Kaplan-Meier method and compared with the log-rank test. RESULTS: A total of 32 patients were included in this study. Mean patient follow-up was 25.7 months. Patients with a 9-month serum testosterone <32 ng/dL had a significantly increased time to CRPC compared to patients with testosterone 32 to 50 ng/dL (p = 0.001, median progression-free survival (PFS) 33.1 months [<32 ng/dL] vs. 12.5 months [>32 ng/dL]). Patients with first year mean testosterone <32 ng/dL also had a significantly increased time to CRPC compared to 32 to 50 ng/dL (p = 0.05, median PFS 33.1 months [<32 ng/dL] vs. 12.5 months [32-50 ng/dL]). A testosterone <20 ng/dL compared to 20 to 50 ng/dL did not significantly predict with time to CRPC. CONCLUSION: This study supports a lower testosterone threshold to define optimal medical castration (T <32 ng/dL) than the previously accepted standard of 50 ng/dL. Testosterone levels during ADT serve as an early predictor of disease progression and thus should be measured in conjunction with prostate-specific antigen.

Microfluidic-based electrotaxis for on-demand quantitative analysis of Caenorhabditis elegans' locomotion.

The nematode Caenorhabditis elegans is a versatile model organism for biomedical research because of its conservation of disease-related genes and pathways as well as its ease of cultivation. Several C. elegans disease models have been reported, including neurodegenerative disorders such as Parkinson's disease (PD), which involves the degeneration of dopaminergic (DA) neurons (1). Both transgenes and neurotoxic chemicals have been used to induce DA neurodegeneration and consequent movement defects in worms, allowing for investigations into the basis of neurodegeneration and screens for neuroprotective genes and compounds (2,3). Screens in lower eukaryotes like C. elegans provide an efficient and economical means to identify compounds and genes affecting neuronal signaling. Conventional screens are typically performed manually and scored by visual inspection; consequently, they are time-consuming and prone to human errors. Additionally, most focus on cellular level analysis while ignoring locomotion, which is an especially important parameter for movement disorders. We have developed a novel microfluidic screening system (Figure 1) that controls and quantifies C. elegans' locomotion using electric field stimuli inside microchannels. We have shown that a Direct Current (DC) field can robustly induce on-demand locomotion towards the cathode ("electrotaxis") (4). Reversing the field's polarity causes the worm to quickly reverse its direction as well. We have also shown that defects in dopaminergic and other sensory neurons alter the swimming response (5). Therefore, abnormalities in neuronal signaling can be determined using locomotion as a read-out. The movement response can be accurately quantified using a range of parameters such as swimming speed, body bending frequency and reversal time. Our work has revealed that the electrotactic response varies with age. Specifically, young adults respond to a lower range of electric fields and move faster compared to larvae (4). These findings led us to design a new microfluidic device to passively sort worms by age and phenotype (6). We have also tested the response of worms to pulsed DC and Alternating Current (AC) electric fields. Pulsed DC fields of various duty cycles effectively generated electrotaxis in both C. elegans and its cousin C. briggsae (7). In another experiment, symmetrical AC fields with frequencies ranging from 1 Hz to 3 KHz immobilized worms inside the channel (8). Implementation of the electric field in a microfluidic environment enables rapid and automated execution of the electrotaxis assay. This approach promises to facilitate high-throughput genetic and chemical screens for factors affecting neuronal function and viability.