Selective RET kinase inhibition for patients with RET-altered cancers.

Background: Alterations involving the RET kinase are implicated in the pathogenesis of lung, thyroid and other cancers. However, the clinical activity of multikinase inhibitors (MKIs) with anti-RET activity in RET-altered patients appears limited, calling into question the therapeutic potential of targeting RET. LOXO-292 is a selective RET inhibitor designed to inhibit diverse RET fusions, activating mutations and acquired resistance mutations. Patients and methods: Potent anti-RET activity, high selectivity, and central nervous system coverage were confirmed preclinically using a variety of in vitro and in vivo RET-dependent tumor models. Due to clinical urgency, two patients with RET-altered, MKI-resistant cancers were treated with LOXO-292, utilizing rapid dose-titration guided by real-time pharmacokinetic assessments to achieve meaningful clinical exposures safely and rapidly. Results: LOXO-292 demonstrated potent and selective anti-RET activity preclinically against human cancer cell lines harboring endogenous RET gene alterations; cells engineered to express a KIF5B-RET fusion protein -/+ the RET V804M gatekeeper resistance mutation or the common RET activating mutation M918T; and RET-altered human cancer cell line and patient-derived xenografts, including a patient-derived RET fusion-positive xenograft injected orthotopically into the brain. A patient with RET M918T-mutant medullary thyroid cancer metastatic to the liver and an acquired RET V804M gatekeeper resistance mutation, previously treated with six MKI regimens, experienced rapid reductions in tumor calcitonin, CEA and cell-free DNA, resolution of painful hepatomegaly and tumor-related diarrhea and a confirmed tumor response. A second patient with KIF5B-RET fusion-positive lung cancer, acquired resistance to alectinib and symptomatic brain metastases experienced a dramatic response in the brain, and her symptoms resolved. Conclusions: These results provide proof-of-concept of the clinical actionability of RET alterations, and identify selective RET inhibition by LOXO-292 as a promising treatment in heavily pretreated, multikinase inhibitor-experienced patients with diverse RET-altered tumors.

Nasal Reconstruction: A Simplified Approach Based on 419 Operated Cases.

BACKGROUND: The purpose of this review is to examine a single surgeon's 10-year experience with nose defects and offer a simplified approach for nasal reconstruction to close most nasal defects following Mohs micrographic surgery (MMS). PATIENTS AND METHODS: A retrospective chart review was performed on patients undergoing repair of MMS defects of the nose over a 10-year period. Data collected included patients' age and sex, anatomic location of the defect, type of reconstruction, and number of operations required. RESULTS: A total of 419 patients were included in this study. The most common location for nasal reconstruction was the nasal dorsum and sidewalls (66.35 %). Complications mainly related to reconstruction of defects of the tip ± ala (n = 31), followed by the ala (n = 15) and the dorsum and sidewalls (n = 13). Bulkiness of the flap used (n = 32) and hypertrophic scar (n = 13) were the most common complications. The bilobed flap was the most commonly used flap (n = 145), followed by nasolabial flap (n = 69), FTSGs (n = 63), forehead flap (n = 62), and dorsal glabellar flap (n = 44). CONCLUSIONS: In this article, a simplified approach for nasal defects reconstruction is presented, which is based on commonly performed local flaps and skin grafting. This algorithm can be useful for the novice plastic surgeons in planning a reconstructive strategy that will be efficient, easy to perform, and produces an acceptable esthetic and functional outcome.

Microcystic adnexal carcinoma.

Microcystic adnexal carcinoma is an unusual, locally aggressive tumor that recently has been recognized as a distinct clinicopathologic entity. It typically occurs on the face of young or middle-aged women and often requires extensive surgical excision to gain local control. A case involving the upper lip and columella of a young woman is described and the available literature reviewed. The difficult reconstructive challenge this lesion usually presents is illustrated in this patient who required upper lip and complete columellar reconstruction.

Identical twins discordant for presenile dementia of the Alzheimer type.

In genetically proven identical female twins, discordant for presenile dementia of the Alzheimer type, the affected twin began to dement at the age of 49, and died 15 years later; the diagnosis was confirmed at post-mortem. The surviving twin remains clinically unaffected 20 years after the onset of dementia in her sister. Environmental aetiological factors are postulated to account for this discordance.

State of adenovirus 2 deoxyribonucleic acid in the nucleus and its mode of transcription: studies with isolated viral deoxyribonucleic acid-protein complexes and isolated nuclei.

Newly replicated adenovirus 2 deoxyribonucleic acid (DNA) can be isolated from the nucleus of HeLa cells by a gentle lysis procedure as a fairly homogeneous complex with a sedimentation of 73S. The viral DNA complex can be prepared completely free from host cell DNA. The viral complex is slightly active in ribonucleic acid (RNA) synthesis in vitro. Treatment of the complex with Pronase and sodium dodecyl sulfate converts the DNA to a form which sediments at 43S. Nuclei isolated from adeno-infected cells synthesize high-molecular-weight virus-specific RNA in vitro. Optimal RNA synthesis requires a divalent cation, preferentially manganese, and relatively high salt concentrations. The synthesis of virus-specific RNA by the isolated nuclei is strongly inhibited by low doses of alpha-amanitine. The latter experimental result is discussed in terms of the polymerase used to transcribe the adenovirus DNA in vivo.