Central Pigment Research Articles

6609 Central Serous Chorioretinopathy in the Eyes of the Beholder of Testosterone Depot Injection

Abstract Disclosure: H. Ni: None. D. Kankanamge: None. J. Jabbour: None. V.A. Preda: None. Background: Central serous chorioretinopathy (CSC) is a characterised by subretinal fluid accumulation causing detachment of the neurosensory retina and visual disturbance[1]. It has been postulated that increased focal choriocapillaris permeability results in leakage of interstial fluid into the subretinal space[1]. CSC is a rare side effect of testosterone therapy, the exact mechanism is unclear. Case : We present a 32-year-old male gym manager who has been self-administering anabolic steroids with testsoterone ethanoate IM injections every 14 days for body building. He reported left blurred vision for 8 weeks. He was normotensive and reported taking doxycycline and azithromycin for mycoplasma genitalia. There was no history of glucocorticoid exposure, smoking, alcohol use, gastoesophageal reflux disease, hypertension, shift work, sleep apnoea, nor other established risk factors for CSC. The visual acuity was OD 6/6 and OS 6/9 with intraocular pressures of 12mmHg on the right and 15mmg on the left. Fundoscopy revealed a left serous macular elevation involving the left fovea. A macular OCT confirmed the left acute central serous chorioretinopathy and right retinal pigment epithelial changes. The latter were suggestive of right CSC in the past. Discussion: Androgens have been associated with CSC in the literature. It has been hypothesised that exogenous testosterone may cause increased choriodal blood flow and permeability, promote atheroscleorsis, cause sodium retention and potentially interact with retinal pigment epithelium (RPE) via androgen receptors4. Intramuscular testosterone therapy causes fluctuation in plasma testosterone concentration (which is thought to be more relevant than absolute value of testosterone). Most cases (60%) of CSC resolve spontaneously, and appear to coincide with cessation of testosterone therapy5. Conclusion: Clinicans need to be alert to the use of testosterone and other anabolic steroids, prescribed or self administered, particularly in their patients with CSC or who have other risk factors for CSC, such as corticosteroids, smoking and hypertension.

One-Year Real-World Outcomes of Intravitreal Faricimab for Previously Treated Neovascular Age-Related Macular Degeneration.

This study assessed the efficacy, durability, and safety of faricimab in patients with neovascular age-related macular degeneration (nAMD), previously treated with aflibercept or ranibizumab with unsatisfactory results. This was a single-center, prospective cohort study of all consecutive patients with nAMD switched to intravitreally administered faricimab from traditional anti-vascular endothelial growth factor (anti-VEGF) treatments between September 2022 and April 2023 because of unsatisfactory response (maximal fluid-free interval ≤ 8weeks). Faricimab was administered with a loading dose of four 4-weekly injections, followed by a treat-and-extend regimen. The primary outcome measures were maximum fluid-free interval after the switch and last assigned treatment interval. Secondary outcome measures included best-corrected visual acuity (BCVA) and structural optical coherence tomography parameters. Thirty-three eyes of 33 patients were included. Patients were followed for a median of 72weeks [interquartile range 61, 76]. Median maximum fluid-free treatment interval after switch to faricimab and the last assigned interval were significantly longer than before the switch (7 vs. 4weeks, p < 0.001 and 8 vs. 5weeks, p < 0.001, respectively). Significant improvements in central subfield thickness (353 vs. 281µm), macular volume (2.46 vs. 2.16mm3), and pigment epithelial detachment height (198 vs. 150µm) were observed (all p < 0.001). BCVA remained stable at 0.4 versus 0.3logMAR before switch (p = 0.190). One eye (3%) developed intraocular inflammation and one eye (3%) developed a retinal pigment epithelium tear. Faricimab improved anatomical outcomes and allowed longer treatment intervals in patients with nAMD previously treated with other anti-VEGF therapies with unsatisfactory response, reducing treatment burden. A favorable safety profile was observed.

Case Report: Gastric Metastasis revealing a Disseminated Skin Melanoma: A Case Report and Literature Review

Abstract Background Melanoma, an aggressive malignant skin cancer, has the ability to spread both locoregionally and to distant sites. The risk of metastasis is correlated to invasion depth and the presence of ulceration. Although gastrointestinal (GI) metastases are uncommon, gastric involvement is particularly rare. Case presentation We report a case of a 62-year-old male who presented with abdominal pain, dyspepsia, anorexia, and weight loss. On physical examination abdominal masses and hepatomegaly were detected. Radiological imaging showed widespread masses in the abdominal and thoracic regions. Upper GI endoscopy identified an umbilicated protruded lesion with central dark pigmentation at the antro-fundic junction. Histopathological examination and immunohistochemical staining were consistent with melanoma. A subsequent rigorous skin examination uncovered a primary malignant skin melanoma. Due to worsening general condition, the patient received palliative hospice care. Conclusion This report highlights the critical need for vigilant skin examination when encountering gastric lesions with dark pigmentation, which led to the identification of initially undetected cutaneous melanoma.

An anthocyanin activation gene underlies the purple central flower pigmentation in wild carrot.

Many organisms have complex pigmentation patterns. However, how these patterns are formed remains largely unknown. In wild carrot (Daucus carota subsp. carota), which is also known as Queen Anne's lace, one or several purple central flowers occur in white umbels. Here, we investigated the unique central flower pigmentation pattern in wild carrot umbels. Using wild and cultivated carrot (Daucus carota subsp. sativus L.) accessions, transcriptome analysis, protein interaction, stable transformation, and CRISPR/Cas9-mediated knockout, a anthocyanin-activating R2R3-myeloblastosis (MYB) gene, Purple Central Flower (DcPCF), was identified as the causal gene that triggers only central flowers to possess the purple phenotype. The expression of DcPCF was only detected in tiny central flowers. We propose that the transition from purple to nonpurple flowers in the center of the umbel occurred after three separate adverse events: insertion of transposons in the promoter region, premature termination of the coding sequence (caused by a C-T substitution in the open reading frame), and the emergence of unknown anthocyanin suppressors. These three events could have occurred either consecutively or independently. The intriguing purple central flower pattern and its underlying mechanism may provide evidence that it is a remnant of ancient conditions of the species, reflecting the original appearance of Umbelliferae (also called Apiaceae) when a single flower was present.

Short-term outcomes of treatment switch to faricimab in patients with aflibercept-resistant neovascular age-related macular degeneration

PurposeTo report short-term outcomes of treatment switch to faricimab in real-world patients with aflibercept-resistant neovascular age-related macular degeneration (AMD).MethodsSingle-center, retrospective cohort study with chart-review using electronic injection database, electronic medical records, and optical coherence tomography (OCT) data from May to September 2023.ResultsA total of 50 eyes of 46 patients were analyzed. Faricimab treatment led to absence of fluid in 32% of the eyes and a reduction of fluid in 84% of the eyes. There was a statistically significant decrease in central retinal thickness (CRT) and pigment epithelial detachment (PED) height in those that responded to the switch (median difference: − 31 μm, IQR: 55, p < 0.0001 and median difference: − 21 μm, IQR: 36, p < 0.0001, respectively) and a statistically significant increase in CRT (median difference: + 19 μm, IQR: 20, p = 0.0143) and no change in PED height (median difference: + 22 μm, IQR: 64, p = 0.1508) in those that did not.Best-corrected visual acuity (BCVA) showed marginal decrease with low statistical significance. No ocular or systemic safety events were observed.ConclusionsOur findings suggest that switching to faricimab is generally safe and effective in patients with neovascular AMD who are otherwise difficult to treat and have residual fluid despite frequent injections with aflibercept. We observed a high rate of morphological response to the treatment switch, improvement of anatomical parameters with about one-third of patients having dry macula following a single injection, and a marginal change in BCVA. Sustainability of these results requires further investigation.Study registrationClinicalTrials.gov registration number: NCT06124677. Date of registration: 09/11/2023, retrospectively registered.

Functional and anatomical outcomes of brolucizumab for nAMD in a real-life setting

To report long-term outcomes of brolucizumab in neovascular age-related macular degeneration (nAMD) treatment. Records from 74 patients were retrospectively reviewed. Both naïve eyes and those previously treated with other antiVEGF agents were included. Primary outcomes included variation in best corrected visual acuity (BCVA), central subfield thickness (CST), intraretinal fluid (IRF), subretinal fluid (SRF), and pigment epithelial detachment (PED) dimensions. Outcomes were reviewed after the loading phase, at week 24, and at last follow-up. IOI occurrence represented the secondary outcome. BCVA improved significantly in both groups. In switched eyes, IRF and SRF were significantly reduced at every timepoint, with CST reduction from week 24 (p = 0.005). In naïve group, CST decreased from the loading phase (p = 0.006) and all patients showed dry macula from week 24. A significant reduction in PED maximum high was demonstrated in both groups. In seven naïve eyes, PED completely reabsorbed; a slight increase in PED horizontal maximal diameter was also observed from week 24. IOI occurred in 5.4% of cases. In conclusion, brolucizumab showed a strong drying effect, permitting functional improvement together with fluid reabsorption and an encouraging modification of PED dimension, especially on naïve patients. These results together with the extension of treatment intervals make brolucizumab an efficient therapeutic strategy for nAMD.

Brolucizumab for recalcitrant macular neovascularization in age-related macular degeneration with pigment epithelial detachment.

To analyze anatomic and functional response to intravitreal brolucizumab in age-related macular degeneration recalcitrant to previous intravitreal anti-VEGF therapies. In this monocentric, one arm, retrospective study, eyes affected by neovascular age-related macular degeneration (nAMD) resistant to other intravitreally injected anti-vascular endothelial growth factor inhibitors were switched to intravitreal brolucizumab. All patients underwent ophthalmological examinations at baseline and in regular follow-up intervals. Best registered visual acuity (BRVA), Goldmann tonometry, intraocular pressure (IOP), central retinal thickness (CRT) and pigment epithelial detachment (PED) characteristics were analyzed at initiation of anti-VEGF treatment, at treatment switch, and at the end of brolucizumab loading phase. The study included 20 eyes of 18 consecutively treated patients (age: 77 ± 6 years). All eyes had macular neovascularization with PED. Previous treatments included intravitreal aflibercept, bevacizumab, and ranibizumab and had not resulted in a significant improvement in BRVA (0.5 ± 0.5 logMAR vs 0.5 ± 0.6 logMAR) or mean CRT (320 ± 60 µm vs 313 ± 83 µm) up to treatment switch to brolucizumab. At the end of the brolucizumab loading phase, there was significant improvement for both BRVA (0.3 ± 0.2 logMAR, P < 0.05) and CRT (264 ± 55 µm, P < 0.05). Under previous anti-VEGF therapy, there was a significant increase/deterioration in both PED area (2.68 mm2 to 5.18 mm2, P < 0.05) and PED volume (0.39 mm3 to 1.07 mm3, P < 0.05); however, both parameters improved after switching to brolucizumab (3.81 mm2 and 0.37 mm3, P < 0.05). Our results suggest a favourable anatomical and visual response after treatment switch to brolucizumab in patients with nAMD refractory to previous anti-VEGF agents.

LONG-TERM PROGNOSIS OF CHOROIDAL NEOVASCULARIZATION COMPLICATING ANGIOID STREAKS.

To report the very long-term visual prognosis of choroidal neovascularization complicating angioid streaks in the antivascular endothelial growth factor era. Retrospective monocentric study aimed at analyzing patients' demographics, choroidal neovascularization features, angioid streak-associated conditions, and previous and current therapies for choroidal neovascularization. The main outcome measures were the quantitative measurement of central retinal pigment epithelial atrophy enlargement by comparing the ratio of pixels involved on automated infrared images acquired by spectral-domain optical coherence tomography and the changes in best-corrected visual acuity. The secondary outcome measures were the number of intravitreal injections and the changes in central choroidal thickness and central retinal thickness. Subgroup analyzes were performed to compare macular atrophy extent between eyes of patients with or without proven pseudoxanthoma elasticum ("PXE" or "no PXE") and between eyes previously treated or not with photodynamic therapy ("PDT" or "no PDT"). Thirty-three eyes of 23 patients were included. The mean best-corrected visual acuity decreased significantly from 66 ± 19 Early Treatment Diabetic Retinopathy Study letters at the time of the first antivascular endothelial growth factor injection to 52 ± 23 Early Treatment Diabetic Retinopathy Study letters at the end of the follow-up (mean follow-up duration: 109 ± 42 months, range: 47-175 months). The ratio of central retinal pigment epithelial atrophy enlargement was 201%, 110%, 240%, and 111% in the PXE, no PXE, PDT, and no PDT groups, respectively. Despite the use of antivascular endothelial growth factor agents, the very long-term prognosis appeared relatively poor, especially in patients with PXE. This study also suggests that PDT should be used with caution in the management of choroidal neovascularization in eyes with angioid streaks.

Painful facial, oral, and genital ulcers

Painful facial, oral, and genital ulcers

Cutaneous Involvement of Angioimmunoblastic T-cell Lymphoma

A 74-year-old man with chronic lymphocytic leukemia and angioimmunoblastic T-cell lymphoma (AITL) of the right lung was undergoing evaluation for initiation of chemotherapy. Bendamustine and rituximab were previously initiated but stopped after one month due to adverse effects. The patient subsequently completed 7 years of ibrutinib therapy, which was halted 3 weeks prior to presentation due to its ineffectiveness and significant hematologic lab abnormalities. Treatment with CHOP (cyclophosphamide, doxorubicin hydrochloride, vincristine sulfate, prednisone) was proposed, however the patient had a nodule concerning for cellulitis on the left fifth palmar digit requiring treatment prior to chemotherapy initiation. No improvement was seen after courses of cephalexin and doxycycline. Due to a lack of response to these two antibiotics, dermatology was consulted for further evaluation.&#x0D; On physical exam, there was a 1.3-cm red-violaceous crusted nodule on the palmar aspect of the left fifth digit (Figure 1, panel A). Dermoscopy showed central orange-tan pigmentation with loss of normal acral ridge pattern and surrounding irregular vessels (Figure 1, panel B). The differential diagnosis included Sweet syndrome, drug eruption, infection, and malignancy. A punch biopsy was performed and showed an atypical lymphocytic nodular infiltrate with angioinvasive and angiodestructive features, and immunohistochemical stains suggested AITL. The patient’s clinical stage was changed from stage II to stage IV AITL due to skin involvement, and the patient was started on CHOP treatment.&#x0D; AITL is a peripheral CD4+ follicular T-helper cell-based lymphoma that presents with B symptoms and generally has a poor prognosis after conventional chemotherapies [1]. Though rare, AITL has been reported to present with skin manifestations in up to 50% of cases, which typically present as macular or papular eruptions on the trunk, similar to toxic erythema of chemotherapy, drug eruptions, or viral exanthems [2]. However, there are multiple case reports of AITL mimicking a variety of systemic dermatologic or oncologic entities, including dermatomyositis, systemic lupus erythematosus, vasculitis, and urticaria [3].&#x0D; This case of AITL with cutaneous involvement illustrates an uncommon presentation of this peripheral lymphoma that often has skin manifestations. The presence of skin involvement implies an advanced clinical stage, which confers a poorer prognosis [4]. Due to its variable presentations in the skin, it is often misdiagnosed as a vasculitis or exanthem, particularly when its initial presentation is in the skin without prior diagnosis of internal AITL malignancy [3]. As in this case, most patients are treated for their condition with chemotherapy, starting with anthracycline-based chemotherapy, and often require higher-dose or modified therapy due to the short response duration [4]. Here, we highlight the diagnostic challenge of AITL and the clinical importance of its identification for appropriate staging and treatment of this condition.

Dermoscopic Features of Lichenoid Pseudovesicular Papular Eruption of the Nose (LiPEN): A Rare Entity.

Dermoscopic Features of Lichenoid Pseudovesicular Papular Eruption of the Nose (LiPEN): A Rare Entity.

Schwannoma: Another dermoscopic pitfall?

Schwannoma: Another dermoscopic pitfall?

One-Year Outcome of Intravitreal Tissue Plasminogen Activator, Ranibizumab, and Gas Injections for Submacular Hemorrhage in Polypoidal Choroidal Vasculopathy.

This study investigated one-year outcomes of treatment with one session of intravitreal recombinant tissue plasminogen activator, ranibizumab, and gas injections for submacular hemorrhage secondary to polypoidal choroidal vasculopathy (PCV). An extended study of a previous prospective trial of this treatment modality in PCV patients was conducted in 64 patients (64 eyes). Early Treatment Diabetic Retinopathy Study (ETDRS) score, central retinal thickness (CRT), and central pigment epithelial detachment thickness (CPEDT) before and 1, 3, and 12 months after treatment were analyzed. Mean ETDRS score increased from 58 at baseline to 64 letters (p = 0.0122), CRT decreased from 543 to 192 μm (p < 0.0001), and CPEDT decreased from 161 to 103 μm (p = 0.0668) at 3 months and were maintained until 12 months. Complications requiring reoperation occurred within one month in four eyes. Recurrence was observed in 46 eyes (72%), and 1.6 ± 1.5 (0–7) intravitreal aflibercept injections were given pro re nata. Univariate and multivariate analyses identified CPEDT as the pre- and post-treatment factor affecting 12-month ETDRS score (p < 0.0001). Improved visual acuity stabilized 3 months after treatment. Although 72% of patients experienced recurrence, an average of 1.6 aflibercept injections/patient maintained visual acuity up to 12 months. CPEDT was the most important factor associated with visual outcome.

Evolution of chlorophyll degradation is associated with plant transition to land.

Significance StatementChlorophyll, the central pigment of photosynthesis, is highly photo‐active and degraded enzymatically during leaf senescence. Merging comparative genomics and metabolomics, we evaluate the extent to which the chlorophyll detoxification pathway has evolved in Viridiplantae. We argue that cytosolic detoxification of phyllobilins in particular was a critical process to the green lineage’s transition to land.

External limiting membrane disruption predicts long‐term outcome in strict Treat‐and‐Extend Regimen in neovascular age‐related macular degeneration

AbstractPurposeTo determine long‐term outcomes and outcome predicting factors in patients with neovascular age‐related macular degeneration (nAMD) applying a strict treat‐and‐extend regimen (TER).MethodsUp to 8‐year retrospective follow‐up of treatment‐naïve subjects with nAMD starting treatment with either ranibizumab or aflibercept in a TER without loading dose but with predefined exit criteria. Spectral‐domain Optical Coherence Tomography scans were acquired in a follow‐up mode and evaluated following a standardized protocol.ResultsTwo hundred‐eleven (211) eyes of 187 patients with a mean follow‐up of 60.3 ± 20.9 months were included. Real‐life follow‐up adherence was high (e.g. 88% at 3 years, 64% at 5 years) with the major part of discontinuations of TER being due to success. During follow‐up, 30.3% of eyes reached the predefined exit criteria, whereof 79.7% in the first five years. Mean BCVA increased from initially 63.9 ± 15.5 ETDRS letters (20/55) to 70.0 ± 14.7 (20/40) after one year (+6.1 letters, p &lt; 0.001) and to 68.5 ± 18.1 (20/43) (+4.6 letters, p = 0.028) at 5 years. A worse BCVA (p = 0.001) and a better external limiting membrane (ELM) disruption score at baseline predicted (p = 0.019) BCVA gain at 5 years. The probability of reaching the exit criteria was significantly associated with a low central retinal thickness (CRT) (p = 0.025), a better ELM disruption score (p = 0.044) and the absence of a central pigment epithelial detachment (PED) (p = 0.05) at baseline.ConclusionsSignificant visual gains were sustained in a long‐term TER in a real‐world setting. Integrity of ELM at baseline predicted BCVA gain at 5 years and the potential for TER exit due to success.

Vitrectomy for Subretinal and Submacular Hemorrhages

Submacular hemorrhage (SMH) is relatively rare in retinal practice. However, it is an important complication of many choroidal and retinal diseases, particularly neovascular age-related macular degeneration (AMD). When untreated the visual prognosis is poor, especially in patients with AMD, and SMHs cannot be effectively treated with only anti-vascular endothelial growth factor (anti-VEGF) injection. The current therapeutic approach is based upon the displacement of the subretinal hemorrhage away from the central retina as soon as possible. The use of tissue plasminogen activator (tPA) has been an important milestone in the treatment of SMHs. Current vitrectomy techniques for SMH management include subretinal tPA injection and aspiration of the blood, and subretinal tPA, and air/anti-VEGF injection with gas tamponade. Submacular surgery, which involves removal of the SMH and choroidal neovascularization (CNV) through a retinotomy, seems to be a technique reserved for selected cases where central retinal pigment epithelium appears to be undiseased/uninvolved. Among the non-surgical treatment options, pneumatic displacement with intravitreal tPA and gas injection may be preferred especially for small-medium sized and thin SMHs. However, the favored approach in real-life conditions is shaped by the physician's experience and the available treatment options. Regardless of the preferred approach, the continuity of the treatment of the underlying pathology is important. As the underlying pathology is usually a CNV, the continuation of anti-VEGF treatment is important for maintaining the visual gain of the initial treatment and reducing the risk of recurrent SMH. The breakthrough development rate of the drugs and the surgical techniques for the treatment of retinal diseases promises in terms of new and more effective treatment approaches.

External Limiting Membrane Disruption Predicts Long-Term Outcome in Strict Treat-And-Extend Regimen in Neovascular Age-Related Macular Degeneration.

The use of anti-vascular-endothelial growth factor agents for neovascular age-related macular degeneration (nAMD) in different treatment schemes is widely common in clinical practice. However, there is currently limited data on the long-term outcomes of a strict treat-and-extend regimen (TER) and imaging biomarkers to predict both functional outcome and the potential for a TER exit due to success. In this retrospective study we followed treatment-naïve subjects with nAMD starting treatment with either ranibizumab or aflibercept in a TER without loading dose but with predefined exit criteria for up to 8 years. We evaluated both the functional outcome and several spectral-domain optical coherence tomography parameters in a follow-up mode using a standardized protocol. Within the 211 eyes followed for a mean of 60.3 ± 20.9 months, follow-up adherence was high with major part of discontinuations of TER being due to success. Mean best-corrected visual acuity (BCVA) increased from initially 63.9 ± 15.5 ETDRS letters to 70.0 ± 14.7 after 1 year (+6.1 letters, p < 0.001) and to 68.5 ± 18.1 (+4.6 letters, p = 0.028) at 5 years. A worse BCVA (p = 0.001) and a better external limiting membrane (ELM) disruption score at baseline predicted (p = 0.019) BCVA gain at 5 years. The probability of reaching the exit criteria was significantly associated with a better ELM disruption score (p = 0.044) and the absence of a central pigment epithelial detachment (PED) (p = 0.05) at baseline. Significant visual gains were sustained in a long-term TER in a real-world setting. Integrity of ELM at baseline predicted BCVA gain at 5 years and the potential for TER exit due to success.

Clinical Manifestations of Cuticular Drusen: Current Perspectives.

Cuticular drusen are part of the spectrum of age-related macular degeneration (AMD) with particular clinical and multimodal imaging characteristics. This drusen subpopulation shares several high-risk single nucleotide polymorphisms with AMD. Despite this feature, they can manifest at a relatively young age, presenting with a female preponderance. Multimodal imaging is essential for characterizing such lesions, using a combination of color fundus photographs, optical coherence tomography (OCT), fluorescein angiography (FA), and fundus autofluorescence (FAF). The classic starry-sky pattern visible on FA and the typical central hypoautofluorescent lesion with hyperautofluorescent rim on FAF is considered the result of a central retinal pigment epithelium (RPE) erosion from these triangular elevations of the RPE-basal lamina. This finding may also be responsible for the typical choroidal hypertransmission appreciated through OCT. The clinical course of cuticular drusen may be relatively benign at early stages, with small drusen presenting at a young age. However, the presence of clinical phenotypes characterized by diffuse involvement and/or accompanying large drusen in patients older than 60 years may confer a significant risk for either macular neovascularization or geographic atrophy.

Infigratinib (BGJ398) in previously treated patients with advanced or metastatic cholangiocarcinoma with FGFR2 fusions or rearrangements: mature results from a multicentre, open-label, single-arm, phase 2 study

Treatment options are sparse for patients with advanced cholangiocarcinoma after progression on first-line gemcitabine-based therapy. FGFR2 fusions or rearrangements occur in 10-16% of patients with intrahepatic cholangiocarcinoma. Infigratinib is a selective, ATP-competitive inhibitor of fibroblast growth factor receptors. We aimed to evaluate the antitumour activity of infigratinib in patients with locally advanced or metastatic cholangiocarcinoma, FGFR2 alterations, and previous gemcitabine-based treatment. This multicentre, open-label, single-arm, phase 2 study recruited patients from 18 academic centres and hospitals in the USA, Belgium, Spain, Germany, Singapore, Taiwan, and Thailand. Eligible participants were aged 18 years or older, had histologically or cytologically confirmed, locally advanced or metastatic cholangiocarcinoma and FGFR2 fusions or rearrangements, and were previously treated with at least one gemcitabine-containing regimen. Patients received 125 mg of oral infigratinib once daily for 21 days of 28-day cycles until disease progression, intolerance, withdrawal of consent, or death. Radiological tumour evaluation was done at baseline and every 8 weeks until disease progression via CT or MRI of the chest, abdomen, and pelvis. The primary endpoint was objective response rate, defined as the proportion of patients with a best overall response of a confirmed complete or partial response, as assessed by blinded independent central review (BICR) according to Response Evaluation Criteria in Solid Tumors, version 1.1. The primary outcome and safety were analysed in the full analysis set, which comprised all patients who received at least one dose of infigratinib. This trial is registered with ClinicalTrials.gov, NCT02150967, and is ongoing. Between June 23, 2014, and March 31, 2020, 122 patients were enrolled into our study, of whom 108 with FGFR2 fusions or rearrangements received at least one dose of infigratinib and comprised the full analysis set. After a median follow-up of 10·6 months (IQR 6·2-15·6), the BICR-assessed objective response rate was 23·1% (95% CI 15·6-32·2; 25 of 108 patients), with one confirmed complete response in a patient who only had non-target lesions identified at baseline and 24 partial responses. The most common treatment-emergent adverse events of any grade were hyperphosphataemia (n=83), stomatitis (n=59), fatigue (n=43), and alopecia (n=41). The most common ocular toxicity was dry eyes (n=37). Central serous retinopathy-like and retinal pigment epithelial detachment-like events occurred in 18 (17%) patients, of which ten (9%) were grade 1, seven (6%) were grade 2, and one (1%) was grade 3. There were no treatment-related deaths. Infigratinib has promising clinical activity and a manageable adverse event profile in previously treated patients with locally advanced or metastatic cholangiocarcinoma harbouring FGFR2 gene fusions or rearrangements, and so represents a potential new therapeutic option in this setting. QED Therapeutics and Novartis.

Vibration-mediated energy transport in bacterial reaction center: Simulation study.

Exciton energy relaxation in a bacterial Reaction Center (bRC) pigment-protein aggregate presumably involves emission of high energy vibrational quanta to cover wide energy gaps between excitons. Here, we assess this hypothesis utilizing vibronic two-particle theory in modeling of the excitation relaxation process in bRC. Specific high frequency molecular vibrational modes are included explicitly one at a time in order to check which high frequency vibrations are involved in the excitation relaxation process. The low frequency bath modes are treated perturbatively within Redfield relaxation theory. The analysis of the population relaxation rate data indicates energy flow pathways in bRC and suggests that specific vibrations may be responsible for the excitation relaxation process.