R that keratoacanthomas can be produced in the rabbit,l5 rat,1* hamster,lG mouse,16 hedgehog:' and chicken80 by the application of chemical carcinogens and that these tumors arise from the hair follicles.1* The keratoacanthoma is a common cutaneous tumor in man, but little is known about the etiological factors involved in its production, Familial, viral, and actinic factors have been incriminated as operative in certain cases: while the Occurrence of these tumors in pitch and tar workers and the results of work with experimental animals indicate that chemical carcinogens may play a part in the production of this lesion in man.16We have studied 238 cases of keratoacanthomas treated at the Sheffield Royal Infirmary, Sheffield, England, over a period of 6 years. T h e purpose of this paper is to report the results of this study and tu present our assessment of the extent to which our observations correspond with the concept that chemical carcinogens may be involved in the production of this tumor in man. Also, whether the mechanisms involved are similar to those known to operate in experimental animals is discussed. MATERIALS AND METHODSThis histology files of the Pathology Department and case notes of the Skin Department were used in this survey. All available hist* logical material from skin tumors diagnosed as keratoacanthoma, papilloma, and squamous carcinoma over a period of 6 years (1 954-1 959) was re-examined. The case notes furnished the ages and addresses of the patients and the sites at which the tumor occurred. Question-TABLE 1 ANNUAL INCIDENCE OF KERATO-ACANTHOMAS DURING THE PERIOD 1954-1959 Year No. cases 1954 47 1955 ~. .. 1956 1957 1958 1959 25 29 44 34 59 -TOTAL 238naires asking details of past and present occupations; contact with pitch, tar, coal, and machine oils; smoking habits; and family history of the same condition were sent to patients who had presented with keratoacanthoma.The main aim of the questionnaire was to determine whether the patients had been in contact with known carcinogenic agents. With this in view, they were asked to give details of their past and present occupations. They were also asked whether they had been in contact with tar, pitch, coal, or machine oil. Although coal does not contain a known carcinogenic agent, it was included as a control to test the reliability of answers obtained for known carcinogenic substances such as pitch and tar. Details of smoking history were asked because it seemed likely that the skin of the face and hands of the smoker might be affected by the carcinogenic agents from cigarette smoke. In the questionnaire we also tried to determine if hereditary factors might be involved in the production of the tumor. With this in view we enquired whether any member of the family had developed similar lumps. The effect of environmental factors was further investigated by asking whether friends or neighbors had developed similar tumors.tending the Skin Department of the Infirmary, was selected over a period of several months. The method of selection was ...

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Tay-Sachs Disease (TSD) is an inherited neurological disorder caused by deficiency of hexosaminidase A (HexA). Preclinical work demonstrated safety and efficacy of CNS gene therapy using AAVrh8-HEXA/HEXB. Here we describe an expanded access trial in two patients with infantile TSD (IND 18225). Case TSD-001 demonstrated neurodevelopmental regression by 8 months of age and severe seizures by 1 year was treated at 30 months. An equimolar mix of AAVrh8-HEXA and AAVrh8-HEXB (now AXO-AAV-GM2) was administered intrathecally (IT), with 75% of the dose (1x1014vg) delivered to the cisterna magna and 25% at the thoraco-lumbar junction. The second patient (TSD-002) was treated at 7 months of age with 4.2x1013 vg by a combination of bilateral thalamic (0.18 mL; 1.5x1012vg per thalamus), and IT infusion (3.9x1013vg). Both patients underwent immunosuppression with sirolimus, corticosteroids, and rituximab. Injection procedures were well tolerated and have shown no vector-related adverse events to date. CSF HexA activity nearly doubled from baseline and remained stable. In TSD-002 (now 16 months of age), MRI showed stabilization of disease by 3 months post-injection and appeared to temporarily deviate from the natural history of infantile TSD but declined again 6 months post-treatment. TSD-001 (now 4.5 years of age remains seizure-free on the same anti-convulsant therapy as pre-therapy, but TSD-002 developed seizures between 13 and 17 months posttreatment (by 2 years of age). Administration of AXO-AAV-GM2 by IT and thalamic injections was safe, HexA activity increased in CSF and ongoing myelination was apparent in the younger patient treated at an early symptomatic stage. This study provides early safety and proof-of-concept in humans for treatment of TSD patients by AAV gene therapy.