Translational insights and overall survival in the U31402-A-U102 study of patritumab deruxtecan (HER3-DXd) in EGFR-mutated NSCLC.

BACKGROUND: Human epidermal growth factor receptor 3 (HER3) is broadly expressed in non-small-cell lung cancer (NSCLC) and is the target of patritumab deruxtecan (HER3-DXd), an antibody-drug conjugate consisting of a HER3 antibody attached to a topoisomerase I inhibitor payload via a tetrapeptide-based cleavable linker. U31402-A-U102 is an ongoing phase I study of HER3-DXd in patients with advanced NSCLC. Patients with epidermal growth factor receptor (EGFR)-mutated NSCLC that progressed after EGFR tyrosine kinase inhibitor (TKI) and platinum-based chemotherapy (PBC) who received HER3-DXd 5.6 mg/kg intravenously once every 3 weeks had a confirmed objective response rate (cORR) of 39%. We present median overall survival (OS) with extended follow-up in a larger population of patients with EGFR-mutated NSCLC and an exploratory analysis in those with acquired genomic alterations potentially associated with resistance to HER3-DXd. PATIENTS AND METHODS: Safety was assessed in patients with EGFR-mutated NSCLC previously treated with EGFR TKI who received HER3-DXd 5.6 mg/kg; efficacy was assessed in those who also had prior PBC. RESULTS: In the safety population (N = 102), median treatment duration was 5.5 (range 0.7-27.5) months. Grade ≥3 adverse events occurred in 76.5% of patients; the overall safety profile was consistent with previous reports. In 78/102 patients who had prior third-generation EGFR TKI and PBC, cORR by blinded independent central review (as per RECIST v1.1) was 41.0% [95% confidence interval (CI) 30.0% to 52.7%], median progression-free survival was 6.4 (95% CI 4.4-10.8) months, and median OS was 16.2 (95% CI 11.2-21.9) months. Patients had diverse mechanisms of EGFR TKI resistance at baseline. At tumor progression, acquired mutations in ERBB3 and TOP1 that might confer resistance to HER3-DXd were identified. CONCLUSIONS: In patients with EGFR-mutated NSCLC after EGFR TKI and PBC, HER3-DXd treatment was associated with a clinically meaningful OS. The tumor biomarker characterization comprised the first description of potential mechanisms of resistance to HER3-DXd therapy.

Patritumab deruxtecan in untreated hormone receptor-positive/HER2-negative early breast cancer: final results from part A of the window-of-opportunity SOLTI TOT-HER3 pre-operative study.

BACKGROUND: Patritumab deruxtecan (HER3-DXd) is a human epidermal growth factor receptor 3 (HER3)-directed antibody-drug conjugate composed of a fully human anti-HER3 monoclonal antibody (patritumab) covalently linked to a topoisomerase I inhibitor payload via a stable, tumor-selective, tetrapeptide-based cleavable linker. TOT-HER3 is a window-of-opportunity study designed to assess the biological activity, measured by CelTIL score [= -0.8 × tumor cellularity (in %)  + 1.3  × tumor-infiltrating lymphocytes (TILs) (in %)], and clinical activity of HER3-DXd during short-term (21 days) pre-operative treatment in patients with primary operable HER2-negative early breast cancer. PATIENTS AND METHODS: Patients with previously untreated hormone receptor-positive/HER2-negative tumors were allocated to one of four cohorts according to baseline ERBB3 messenger RNA expression. All patients received one dose of HER3-DXd 6.4 mg/kg. The primary objective was to evaluate change from baseline in CelTIL score. RESULTS: Seventy-seven patients were evaluated for efficacy. A significant change in CelTIL score was observed, with a median increase from baseline of 3.5 (interquartile range, -3.8 to 12.7; P = 0.003). Among patients assessable for clinical response (n = 62), an overall response rate of 45% was observed (tumor measurement by caliper), with a trend toward an increase in CelTIL score among responders compared with non-responders (mean difference, +11.9 versus +1.9). Change in CelTIL score was independent of baseline ERBB3 messenger RNA and HER3 protein levels. Genomic changes occurred, including switching toward a less proliferative tumor phenotype based on PAM50 subtypes, suppression of cell proliferation genes, and induction of genes associated with immunity. Treatment-emergent adverse events were observed in 96% of patients (14% grade ≥3); most common were nausea, fatigue, alopecia, diarrhea, vomiting, abdominal pain, and neutrophil count decrease. CONCLUSIONS: A single dose of HER3-DXd was associated with clinical response, increased immune infiltration, suppression of proliferation in hormone receptor-positive/HER2-negative early breast cancer, and a tolerable safety profile consistent with previously reported results. These findings support further study of HER3-DXd in early breast cancer.

Long-term efficacy and safety of sonidegib in patients with locally advanced and metastatic basal cell carcinoma: 30-month analysis of the randomized phase 2 BOLT study.

BACKGROUND: Patients with locally advanced basal cell carcinoma (laBCC) or metastatic BCC (mBCC), two difficult-to-treat populations, have had limited treatment options. Sonidegib, a hedgehog pathway inhibitor (HPI), was approved in laBCC based on results from the BOLT trial. OBJECTIVE: To evaluate long-term efficacy and safety of sonidegib in laBCC and mBCC in the BOLT 18- and 30-month analyses. METHODS: BOLT (NCT01327053, ClinicalTrials.gov), a double-blind phase 2 study, enrolled patients from July 2011 until January 2013. Eligible HPI-treatment-naïve patients with laBCC not amenable to curative surgery/radiotherapy or mBCC were randomized 1 : 2 to sonidegib 200 mg (laBCC, n = 66; mBCC, n = 13) or 800 mg (laBCC, n = 128; mBCC, n = 23). Tumour response was assessed per central and investigator review. RESULTS: With 30 months of follow-up, among patients treated with sonidegib 200 mg (approved dose), objective response rates were 56.1% (central) and 71.2% (investigator) in laBCC and 7.7% (central) and 23.1% (investigator) in mBCC. Tumour responses were durable as follows: median duration of response was 26.1 months (central) and 15.7 months (investigator) in laBCC and 24.0 months (central) and 18.1 months (investigator) in mBCC. Five patients with laBCC and three with mBCC in the 200-mg arm died. Median overall survival was not reached in either population; 2-year overall survival rates were 93.2% (laBCC) and 69.3% (mBCC). In laBCC, efficacy was similar regardless of aggressive or non-aggressive histology. Sonidegib 200 mg continued to have a better safety profile than 800 mg, with lower rates of grade 3/4 adverse events (43.0% vs. 64.0%) and adverse events leading to discontinuation (30.4% vs. 40.0%). CONCLUSION: Sonidegib continued to demonstrate long-term efficacy and safety in these populations. These data support the use of sonidegib 200 mg per local treatment guidelines.

[Use of silicone oil in vitreal hemorrhage complicating proliferated diabetic retinopathy]. / Intérêt de l'huile de silicone dans la rétinopathie diabétique proliférante compliquée d'hémorragie intravitréenne.

INTRODUCTION: Vitreous hemorrhage is a frequent complication of proliferated diabetic retinopathy. Vitrectomy has vastly improved its prognosis. The purpose of this study was to evaluate the use of silicone oil in vitreal surgery in this indication. METHODS: We present a retrospective study of 15 eyes that underwent vitrectomy and silicone oil injection for vitreal hemorrhage complicating proliferative diabetic retinopathy. For each patient, we noted the clinical and echographic features, the surgical procedure, and the postoperative outcome after a mean period of 20 months. RESULTS: The indications for silicone injection were recurrent vitreal hemorrhage (seven eyes), aggressive fibrovascular proliferations (five eyes), and iatrogenic retinal breaks (three eyes). Anatomic success was noted in ten cases. Four patients had a hemorrhage reoccurrence after silicone oil removal and one patient developed neovascular glaucoma. Silicone cataract (seven eyes) and emulsification of silicone (one eye) were noted. DISCUSSION: The use of silicone oil in vitreal surgery for complicated proliferated diabetic retinopathy contributes a hemostatic and plugging effect, but it still has a number of disadvantages such as the need to remove it and its own side effects. It can be beneficial in cases of rubeosis or recurrent hemorrhage. However, it is essentially indicated in recurrent hemorrhage in monophthalmos patients.

[Ocular findings in Alport syndrome: 32 case studies]. / Atteinte oculaire au cours du syndrome d'Alport. A propos de 32 cas.

BACKGROUND: Alport syndrome is an inherited disease resulting in kidney failure, hearing loss, and ocular abnormalities. The purpose of this study was to describe the incidence and type of ocular abnormalities and to determine inheritance of this syndrome in our population. PATIENTS AND METHODS: A total of 32 patients, from ten different families in South Tunisia, underwent a complete ocular examination. Inheritance was determined using pedigrees and genotyping. RESULTS: The best corrected visual acuity was 7.6/10. Biomicroscopy showed polymorphous dystrophy in 3%, anterior lenticonus in 28%, lens opacities in 3%, cataract in 19%, and retinal flecks in 37%. The genetic survey found five families with X-linked Alport syndrome, four families with recessive autosomal disease, and one family with dominant autosomal disease. DISCUSSION: Ocular abnormalities have been reported in 9%-82% of Alport syndrome patients. They are rare in childhood and increase in frequency and severity with age. The types of ocular defects described mostly involve the lens, the retina and more rarely the cornea. The most common changes are anterior lenticonus and perimacular retinal flecks. In approximately 85%, Alport syndrome is X-linked. In the remaining 15%, the transmission is autosomal recessive and exceptionally autosomal dominant. CONCLUSION: Ocular examination is a precious help for Alport syndrome diagnosis. It can also determine the prognosis of nephropathy.

[Retinal neovascularization with myelinated nerve fibers]. / Néovaisseaux rétiniens compliquant des fibres à myéline.

INTRODUCTION: The prevalence of myelinated retinal nerve fibers is 0.3%-0.6% of eyes. Although they often constitute benign lesions, they are rarely associated with retinal vascular abnormalities including preretinal neovascularization. CASE REPORT: A 31-year-old patient, with no previous pathological antecedents, consulted us for myodesopsia in her left eye. The exam found a visual acuity of 10/10 and a normal anterior segment in the two eyes. At the ophthalmoscopic examination of the left eye, we noted myelinated nerve fibers in the inferotemporal quadrant that were associated with a temporal neovascular bouquet covering area of 1.5 optic disks. A small amount of intravitreal hemorrhage was found. The ophthalmoscopic examination of the right eye was normal. The treatment consisted in sector-based photocoagulation with argon laser and cryotherapy. DISCUSSION: The source of neovascularization in the myelinated retinal nerve fibers was discussed. Underlying retinal ischemia is the most probable mechanism. The treatment was based on sector-based or panretinal photocoagulation. CONCLUSION: Preretinal neovascularization is a rare complication of myelinated nerve fibers. The earlier the care is given, the more complications can be avoided.

Epidemiology and risk factors for corneal graft rejection.

OBJECTIVE: The aim of this study was to evaluate the frequency and main risk factors for corneal graft rejection. PATIENTS AND METHODS: This retrospective study included 285 eyes in 256 patients who underwent a penetrating keratoplasty (KPT) from January 1995 to December 2004. The minimum follow-up was 12 months to evaluate graft evolution. Except for complications, the follow-up was weekly, then monthly for 6 months, and ultimately quarterly during the first year. Thereafter the follow-up was performed semi-annually. Patients were informed about the functional signs for which they have to urgently consult. RESULTS: Immunologic rejection of the corneal graft occurred in 128 KPT in 112 patients (rejection frequency = 41%). The identified main risk factors were new vascularization of the recipient cornea over 2 or more quadrants, corneal opacity due to an infectious origin, posttraumatic corneal opacity or congenital glaucoma, graft diameter >8 mm, and therapeutic KPT. CONCLUSIONS: Rejection of the corneal graft is the primary cause of KPT failure. One out of 2 graft failures was due to rejection. Two criteria are unanimously recognized as risk factors for rejection: neovascularization of recipient cornea and antecedents of corneal rejection. The rejection must be treated early to not endanger graft success, which imposes a close follow-up for grafted patients.

[Discoid lupus erythematosus with eyelid involvement. A series of nine patients]. / Lupus érythémateux discoïde et paupière. Une série de 9 patients.

INTRODUCTION: Discoid lupus erythematosus (DLE) is a chronic autoimmune skin disease that usually affects the sun-exposed skin. Palpebral involvement occurs uncommonly. MATERIAL AND METHOD: The goal of our study was to present the clinical and therapeutic features of a series of nine patients with discoid lupus erythematosus with eyelid involvement. RESULTS: Lesions of discoid lupus were more frequent in the lower eyelids (seven cases). The palpebral location was the only manifestation of the disease in a 34-year-old woman. In the other cases, cutaneous lesions of typical discoid lupus were noted. Seven patients responded to therapy with antimalarial drugs associated with local corticosteroids and photoprotection. DISCUSSION: Eyelid lesions of discoid lupus erythematosus are rare. Involvement of the lower eyelids is more common. It is important to diagnose discoid lupus of the eyelids because misdiagnosis (isolated form) can delay treatment and cause deformities. The treatment is systemic antimalarial drugs, which have an excellent clinical response.

[Ocular manifestations associated with nephronophthisis and genetic study in three Tunisian families]. / Analyse des manifestations oculaires associées à la néphronophtise et étude génétique chez trois familles tunisiennes.

PURPOSE: Nephronophthisis is a familial interstitial nephropathy with an autosome recessive mode of transmission. In some cases, it is associated with ocular manifestations such as retinitis pigmentosa in Senior-Løken syndrome. We report ocular abnormalities and genetic results in three affected Tunisian families. PATIENTS AND METHODS: Twenty-two members of these three families underwent a complete ophthalmologic examination (visual acuity, slit lamp biomicroscopy, ophthalmoscopy, and retinal electrophysiology). For genetic study, all individuals were genotyped and underwent a genomic sequence. RESULTS: Twenty-two subjects, nine of whom presented nephronophthisis, were included in this study. Retinitis pigmentosa was found in three cases. Our genetic study demonstrated that patients belonging to family 1 had homozygous deletions in NPHP1, all affected individuals from family 3 were linked to NPHP4 and presented a deletion in exons 2 and 3. Results are pending for patients in family 2. CONCLUSION: Senior-Løken syndrome is a rare hereditary disease that combines familial juvenile nephronophthisis and retinitis pigmentosa. This association was described in the literature in 39%-43% of cases. In our study, it was approximately 33% of cases. The genetic study can sometimes obviate the need for renal puncture, especially when the homozygous deletion of NPHP1 gene is confirmed.

[Allgrove syndrome. Report on a family]. / Syndrome d'Allgrove: à propos d'une famille.

Triple A or Allgrove syndrome is a rare autosomal recessive disease with alacrima, achalasia, and ACTH-resistant adrenal insufficiency. It is usually associated with neurological disorders. Recently, mutations in the AAAS, a candidate gene mapped to chromosome 12q13, were identified. We report a family with seven affected siblings. All of them have signs of alacrima, four were operated on for achalasia, five have neurological abnormalities including cranial nerve abnormalities, amyotrophic lateral sclerosis, pyramidal syndrome, distal motor neuropathy, and amyotrophy, and two have adrenal insufficiency. Triple A syndrome should be considered in any young patient with alacrima.

[Two cases of subretinal neovascular membrane in Vogt-Koyanagi-Harada syndrome]. / Néovaisseaux choroïdiens compliquant une maladie de Vogt-Koyanagi-Harada.

AIM: To report two cases of Vogt-Koyanagi-Harada syndrome (VKH) complicated by subretinal neovascularization. CASE REPORTS: The first patient was a 12-year-old girl in whom choroidal neovascularization occurred after VKH had evolved for 9 months. Fundus examination of the left eye revealed a macular extrafoveolar superior serous retinal detachment (SRD) centered by a grey-white pseudo-tumoral zone. A crown of exudates lined the SRD. Pigment epithelium impairment was substantial. Fluorescein angiography showed an early intensive and diffuse staining in the left eye corresponding to a neovascular membrane associated with a late impregnation of the SRD. Green monochromatic laser photocoagulation was considered but refused by the parents. The second patient was an 18-year-old girl followed up for VKH for 2 years. Ophthalmoscopy showed a serous retinal detachment with hemorrhage and hard exudates in the right eye. Fluorescein angiography showed early staining in the juxtapapillary region corresponding to a juxtapapillary neovascular membrane. High-dose systemic corticotherapy was instituted. Photocoagulation was not indicated because of the juxtapapillary topography of the neovascular membrane. CONCLUSION: VKH is a bilateral panuveitis that can be complicated by subretinal neovascularization in 2.5%-10% of cases. This complication must be diagnosed early. We discuss angiogenic factors and therapeutic modalities.

[Phthiriasis pubis palpebrarum in children. Diagnosis and treatment]. / Phtiriase ciliaire de l'enfant. Diagnostic et traitement.

INTRODUCTION: Phtiriasis palperarum is an unusual cause of blepharitis. This ectoparasitic infestation of the lashes is more frequent in adult; a pubic attack is usually associated. It is however rare in children. The goal of our study is to bring back four observations of infantile phtiriasis palpebrarum. PATIENTS AND METHODS: Four children presented themselves for palpebral itching and ocular redness. Slit lamp examination revealed evidence of small parasites attached to the proximal extreme of the eyelashes. A survey within the family was carried out and parasitological examination was realized. RESULTS: Parasitological examination had identified adult forms and nits of phtirus pubis. The bed linen was the way of contamination. Mechanical extraction of the parasite was tried but was very painful. Two patients were treated with a regimen of 1% yellow oxide of mercury ointment four times daily for 14 days, the two others was treated by Vaseline pomade because of a very important palpebral irritation. Evolution was favorable among all patients. DISCUSSION: We discuss in this work the ways of contamination of phtiriasis palpebrarum in children. In fact, eyelashes contamination in children is secondary to a contact with an adult carrier of a pubic phtiriasis. The transmission can be done following sexual maltreatments or by the means of infected clothing or bed linen. The diagnosis of phtiriasis palpebrarum is clinical confirmed by parasitological examination. Different therapeutic were proposed, the mechanical treatment must be carried out but it is seldom sufficient and it is often necessary to associate a chemical treatment (malathion to 1%, mercury oxide with 1%, fluorescein with 20%...) or physical treatment (cryotherapy, laser argon). CONCLUSION: Diagnosis of phtiriasis palpebrarum is easy and requires the detection of the source of contamination in order to prevent reinfestations.

[Palpebral seborrheic keratosis: a case study]. / Kératose séborrhéique palpébrale.

INTRODUCTION: Seborrheic keratosis is the most frequent palpebral tumor, observed for the most part in the second half of life. It may be confused clinically with a basal cell carcinoma or a melanoma. The histopathological study confirms the diagnosis. OBSERVATION: A 69-year-old man presented with a giant superior palpebral tumor leading to ptosis of the eyelid, which had evolved over 5 years. Examination found a pigmented cerebriform multilobed granulated mass, with a smooth surface and a more or less seborrheic aspect, pedicled in places, covering the entire eyelid but sparing the internal angle. This aspect suggested melanoma, basal cell carcinoma or seborrheic keratosis. Histological biopsy revealed basal cell carcinoma. Excision with palpebral reconstitution using palpebral flaps was performed. The histopathological analysis of the tumor concluded in seborrheic keratosis. DISCUSSION: Seborrheic keratosis is a frequent tumor of the face and eyelids. Its highly pigmented clinical aspect can be confounded with a nevus or a melanoma, whereas the histological aspect can suggest basal cell carcinoma or squamous cell carcinoma, but the basal membrane is always intact. Several treatments have been proposed, including electrocoagulation, cryotherapy, dermabrasion, as well as CO2 laser treatment. However, when there is doubt with regard to the histological nature, surgery is preferred. CONCLUSION: This was a case of seborrheic keratosis, atypical in that it covered the entire upper eyelid and produced a highly disfiguring aspect and functional problems, requiring surgical treatment with eyelid reconstruction.

[Purtscher-like retinopathy in systemic lupus erythematosus. Two cases]. / Pseudorétinopathie de Purtscher révélant un lupus érythémateux disséminé

Purtscher-like retinopathy is a retinopathy with vascular manifestations resembling Purtscher's retinopathy associated with autoimmune disorders such as lupus erythematosus. We report two cases of blurred vision associated with multiple whitish patches scattered over the macular and peripapillary areas. In the absence of trauma, these symptoms led us to systemic lupus erythematosus. The diagnosis was confirmed by the immunological and biological examinations. A steroid treatment was given with poor visual response. Purtscher-like retinopathy is a rare complication of systemic lupus erythematosus and there is some controversy about its pathogenesis and its treatment.

Acute rejection following lung transplantation: limitations in accuracy of thin-section CT for diagnosis.

PURPOSE: To evaluate the sensitivity, specificity, predictive values, and accuracy of thin-section computed tomography (CT) for the diagnosis of acute rejection following lung transplantation and to determine whether any individual CT abnormalities are associated with histopathologically proved acute rejection. MATERIALS AND METHODS: Thin-section CT studies from 64 lung transplant recipients were retrospectively reviewed. CT studies were temporally correlated with various grades of biopsy-proved acute rejection (n = 34); 30 other CT studies were from a control group with no histopathologic evidence of acute rejection. Acute rejection was diagnosed as present or absent, and the diagnostic was calculated. RESULTS: The sensitivity, specificity, positive predictive value, negative predictive value, and accuracy of CT for the diagnosis of acute rejection were as follows: 35%, 73%, 60%, 50%, 53%, respectively. No individual CT finding was significantly associated with acute rejection. The sensitivity of CT for the detection of various grades of acute rejection was 17% for grade A1, 50% for grade A2, and 20% for grade A3. The combination of volume loss and septal thickening, with or without pleural effusion, was never seen in the absence of acute rejection. CONCLUSION: Thin-section CT has limited accuracy for the diagnosis of acute rejection following lung transplantation, and no individual CT finding is significantly associated with this diagnosis.

Minute pulmonary meningothelial-like nodules: thin-section CT appearance.

Minute pulmonary meningothelial-like nodules are often incidentally discovered during pathologic evaluation of pulmonary parenchymal specimens. These lesions were once thought to represent pulmonary chemodectomas, but pathological studies have shown that they are not of neuroendocrine origin. Minute pulmonary meningothelial-like nodules are benign, perhaps reactive in nature, but are occasionally found in association with lung carcinoma. They may appear as randomly distributed well-defined micronodules on thin-section chest CT, and thus may simulate metastatic disease when associated with lung carcinoma.

Hypersensitivity pneumonitis: patterns on high-resolution CT.

Hypersensitivity pneumonitis, also known as extrinsic allergic alveolitis, is caused by inhalation of specific environmental organic antigens. This disease may have typical high-resolution CT findings that, in the appropriate clinical setting, can be sufficiently characteristic to allow a confident diagnosis without the need for a lung biopsy. In this pictorial essay, the high-resolution CT patterns of hypersensitivity pneumonitis are illustrated. The authors emphasize the correlation among the radiologic presentation, functional abnormalities, and pathologic findings.