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.

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.

[Contralateral axillary lymph node metastasis of cancer of the breast]. / Les métastases ganglionnaires axillaires controlatérales du cancer du sein.

Contralateral axillary metastases (CAM) of breast cancer are uncommon, they state some diagnostics and therapeutics problems. From February 1993 until June 1996, 6 cases of CAM were detected in 123 women having a breast's cancer (4.9%). The diagnostic of CAM, was retained after a normal clinical and mammographic examination of ipsilateral breast, and a anatomopathological proof confirming the carcinomatous infiltration of axillary ganglions. These metastases were synchronous for 3 patients and metachronous for the 3 others with an appearance's mean delay of 12 months. The 6 patients were treated for a breast's cancer locally advanced and a tumour with internal or central seat in 5 cases. The CAM were associated to others metastatic areas in 2 patients. Five patients have had a locoregional treatment of CAM (curage and/or axillary radiotherapy), associated to chemotherapy. The 6th patient, is multimetastatic, had refused the treatment. Only 1 patient has developed a tumor of ipsilateral breast after a mean delay of 7 months, others metastatic localizations are appeared in 2 patients after a mean delay of 8 months. The CAM are considered a scare entity with physiopathological mechanism not yet well elucidated. They are perhaps, the prerogative of advanced tumors and the often before metastatic spreading. A problem remains to be raised: is it a question of a real CAM, or an expression of a ipsilateral breast's occult carcinomatous?

[Intraoperative brachytherapy in the management of keloids. Apropos of 114 cases] . / Place de la curiethérapie dans le traitement des chéloïdes. A propos de 114 cas.

PURPOSE: Keloid scars are unsightly, especially when located on the face or bare zones. The purpose of this study was to evaluate the therapeutic results of intraoperative brachytherapy in the management of keloids. MATERIAL AND METHODS: This retrospective study was based on the study of 82 patients with keloids treated in Salah Azaiz Institute (Tunisia) between 1982 and 1994 (65 women and 17 men). The mean age of patients was 23.4 years (+/- 8.4). A total of 114 lesions have been treated with surgical resection and intraoperative brachytherapy using an iridium source placed under the surgical scar. The length of iridium was chosen with the result that the radioactive thread exceeded 5 mm on each side of the surgical scar. The iridium source was loaded less than six hours after resection. Average iridium activity was 1.5 +/- 0.3 mCi/cm. Average iridium length was 56.8 +/- 34 mm. The referred isodose chosen for the target volume included the surgical scar and a margin of 5 mm around the iridium source, which was placed under the surgical scar. The average administered dose was 20.4 Gy (+/- 3.2 Gy). RESULTS: The 2-year local control rate was 87% for the whole group of lesions treated (n = 114). Local control rate of keloids processed by resection and intraoperative brachytherapy as the first treatment (59 cases) was 96% at two years. This rate was better than the local control of lesions that had been previously treated with anterior surgical resection (84% in 55 cases). For the latter group, lesions treated with a dose of more than 20 Gy had better local control, but the difference was not statistically significant (87 vs. 65% at two years, P = 0.41). CONCLUSION: Intraoperative brachytherapy is effective for improving local control of keloids and preventing a recurrence. A rigorous technique and an adequate dose according to previous surgical treatment allows very good results.

[Cutaneous lymphoma in Tunisia: clinical profile and therapeutic results]. / Lymphomes cutanés en Tunisie: profil clinique et résultats thérapeutiques.

PURPOSE: The aim of this retrospective study was to investigate therapeutic result of cutaneous lymphoma in Tunisia. PATIENTS AND METHODS: Between January 1969 and June 1994, 100 patients with cutaneous lymphoma were referred either to Salah Azaiz Institute or the other University Hospitals of Tunisia. Fifty-one patients had epidermotropic lymphoma and 49 non-epidermotropic lesions. Eighty-seven patients received complete treatment. Puvatherapy and other local dermatologic treatments were used for early stage mycosis fungoïdes. Thirty-two patients benefited from radiotherapy, with curative dose in 28 cases. Chemotherapy including anthracyclin agents was used for high grade lymphoma. Thirteen patients had association of radiotherapy and chemotherapy. RESULTS: Five-year survival rates were 50% for patients with epidermotropic lesions and 56% for patients with non-epidermotropic cutaneous lymphoma. Statistical study has not identified any significant prognosis factor. CONCLUSION: Radiotherapy and chemotherapy are both effective. Treatment should depend on stage and histologic type.

[Infected aneurysm of abdominal aorta: early CT finding]. / Anévrisme infectieux de l'aorte abdominale: un aspect TDM précoce.

Infected abdominal aortic aneurysm is an uncommon but life-threatening disease, especially in case of salmonella infection. Early CT findings should be well known in order to allow immediate diagnosis and accurate management. The authors present an early CT finding of a salmonella infected aneurysm of abdominal aorta in an HIV-infected patient. This pattern consists in a slight-enhancing focal densification of periaortic soft-tissue, while aorta remains of normal size. Within two weeks, infection progressed to the constitution of an infected aneurysm. This CT finding seems to be initial to previously described signs.

[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.

[Diabetic fibrous mastopathy]. / La mastopathie fibreuse diabétique.

Diabetic fibrous mastopathy was first described in 1984. This mastopathy usually occurs in patients with autoimmune disorders and often occurs in patients with insulin-dependent diabetes. Little is known about this benign condition. Clinically and radiologically, this entity may simulate malignancy. The presence of an underlying auto-immune disorder or diabetes may suggest the correct diagnosis. The authors report two cases of fibrous mastopathy and suggest that core biopsy could replace surgical biopsy for diagnosis.

[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.

[Exophthalmos and blindness disclosing an ethmoidal-maxillary malignant non-Hodgkin's T-cell lymphoma. Apropos of a case]. / Exophtalmie et cécité révélant un lymphome malin non-hodgkinien ethmoïdo-maxillaire à cellules T. A propos d'une observation.

BACKGROUND: We report a case of non-Hodgkin's malignant lymphoma of the cervicofacial region revealed by unilateral exophthalmos and blindness, an unusual mode of expression. CASE REPORT: A 40-year-old man with a 4-month history of diabetes mellitus had suffered from exophthalmos and blindness of the right eye for 20 years. Physical examination showed a homolateral hemifacial tumefaction and ophthalmoplegia. The right ocular fundus showed papillar edema and non-proliferative diabetic retinopathy. The left eye was normal. The otolaryngology explorations revealed a voluminous tumor in the anterior nasal cavity and in the cavum. Two biopsies were performed. Histology reported non-Hodgkin's T-cell lymphoma. Orbitocerebral and cervicofacial computed tomography visualized the aggressive ethmoidomaxillary extension with intraorbital and intracranial involvement. Chemotherapy (CHOP) combined with radiotherapy led to tumor regression and involution of the exophthalmos. Diagnostic difficulties, management and prognosis are discussed.

[Serious urinary infections and pregnancy]. / Les infections urinaires graves et grossesse.

Retention of infected urine in the upper urinary tract which is due to obstruction is a serious condition during pregnancy. The authors report their experience on five cases and propose attitudes to adopt against such emergency. Ultrasounds allow accurate diagnosis of the obstruction and may be helpful to find its etiology. Plain X ray film could be of interest mainly for stone recognition after the third month of gestation. Surgical treatment, when possible allows either relief of obstruction and cure of the original disease, otherwise performance of percutaneous nephrostomy represents a better way of drainage until the end of pregnancy.

[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.