BRAF inhibitor-associated cutaneous squamous cell carcinoma: new mechanistic insight, emerging evidence for viral involvement and perspectives on clinical management.

Mutations in the BRAF proto-oncogene occur in the majority of cutaneous melanomas. The commonly detected valine (V) to glutamate (E) mutation (V600E) is known to drive melanomagenesis and has thus been the target of two highly selective chemotherapeutic agents: vemurafenib and dabrafenib. While BRAF inhibitor therapy has revolutionized the treatment of metastatic melanoma, unanticipated cutaneous toxicities, including the development of cutaneous squamous cell carcinomas (cSCCs), are frequently reported and hinder therapeutic durability. However, the mechanisms by which BRAF inhibitors induce cutaneous neoplasms are poorly understood, thus posing a challenge for specific therapies. In this review, we summarize the clinical and molecular profiles of BRAF inhibitor-associated cSCCs, with a focus on factors that may contribute to disease pathogenesis. In particular, we discuss the emerging evidence pointing towards viral involvement in BRAF inhibitor-induced cutaneous neoplasms and offer new perspectives on future therapeutic interventions. Continued clinical and mechanistic studies along this line will not only allow for better understanding of the pathogenic progression of BRAF inhibitor-induced cSCCs, but will also lead to development of new therapeutic and preventative options for patients receiving targeted cancer therapy.

Fatal Scopulariopsis infection in a lung transplant recipient: lessons of organ procurement.

Seventeen days after double lung transplantation, a 56-year-old patient with idiopathic pulmonary fibrosis developed respiratory distress. Imaging revealed bilateral pulmonary infiltrates with pleural effusions and physical examination demonstrated sternal instability. Broad-spectrum antibacterial and antifungal therapy was initiated and bilateral thoracotomy tubes were placed. Both right and left pleural cultures grew a mold subsequently identified as Scopulariopsis brumptii. The patient underwent pleural irrigation and sternal debridement three times but pleural and wound cultures continued to grow S. brumptii. Despite treatment with five antifungal agents, the patient succumbed to his illness 67 days after transplantation. Autopsy confirmed the presence of markedly invasive fungal disease and pleural rind formation. The patient's organ donor had received bilateral thoracostomy tubes during resuscitation in a wilderness location. There were no visible pleural abnormalities at the time of transplantation. However, the patient's clinical course and the location of the infection, in addition to the lack of similar infection in other organ recipients, strongly suggest that Scopulariopsis was introduced into the pleural space during prehospital placement of thoracostomy tubes. This case of lethal infection transmitted through transplantation highlights the unique risk of using organs from donors who are resuscitated in an outdoor location.

Blurred vision: problems of auditing elective surgery, as seen in an audit of lens extraction for cataract.

Failure to limit the topic can complicate the audit process by producing too many variations and data not relevant to all patients in the study. Because assessment of the need for lens extraction is subjective, formulating justification criteria is difficult; objective evidence that the patient actually needed the surgery may be lacking. Outpatient records showing the results of surgery, ie, whether a patient's vision has been improved, are usually not available to the audit committee. Consequently, the patient's true outcome after surgery cannot be properly evaluated unless specific follow-up criteria are developed and outpatient records are available to the audit committee. An ideal audit of lens extraction for cataract might combine outpatient records noting results of preoperative workup, the hospital chart, and the clinic record of postoperative care and results. Only with all pertinent information can a complete assessment of the quality of care be made. Because audits rely heavily on the use of data from inpatient records, other methodologies may be more appropriate for review of elective procedures. Audit committees should consider this possibility and beware.

A comparison of the sensitivity of carotid compression tonography with ophthalmodynamometry in the diagnosis of internal carotid artery occlusive disease.

The cases of 100 consecutive patients with arteriographic evidence of carotid occlusive disease were reviewed. All 100 patients had undergone ODMY and CCT prior to carotid arteriography. A comparison of the sensitivity of ODM testing with CCT testing revealed the ODMY pressure differences were reliable in detecting carotid occlusive disease in only 70 of these 100 patients, whereas CCT testing detected decreased blood flow on the involved side in 95 of the 100 patients. The advantages of CCT testing are discussed, comparing certain limitations and contraindications often encountered with ODMY testing. The CCT test is more sensitive than ODMY testing and is easier to perform. In addition, the results of CCT are more objective and provide a permanent record which can be analyzed at any time to check for reproducibility. Overall, the CCT test appears to be a more suitable screening test than ODMY to study carotid occlusive disease.

Ocular manifestations of subacute sclerosing panencephalitis.

We report a case of subacute sclerosing panencephalitis (SSPE) with severe peripheral chorioretinal pigment changes in addition to the more typical pigment clumping in the macula. The differential diagnosis of peripheral inactive chorioretinitis, the typical ocular findings, and clinical course of SSPE are discussed.

Alexia without agraphia.

This typical case of alexia without agraphia, caused by an astrocytoma, is the first recorded case in the literature of alexia without agraphia with a right homonymous hemianopia caused by a tumor. This case differs from previously reported cases of the syndrome by its fluctuating clinical course and its slow progression. All but one of previously reported cases had been of vascular or surgical etiology. This course and the associated radiographic findings should differentiate the neoplastic from the vascular etiology of this most fascinating syndrome.

Ophthalmic injuries: handbook of initial evaluation and management.

Initial management of ophthalmic injury in the combat zone of guerrilla warfare has been discussed primarily from the vantage points of paramedical personnel and the physician nonophthalmologist. Details of surgical management have been greatly abbreviated and many areas not discussed at all, since they lie beyond the scope of this report. Continuing improvement and innovations in this report. Continuing improvement and innovations in this sphere require constant familiarity with current ophthalamic literature. Most, if not all, of the methods of examination and treatment described in this paper are as applicable to civilian trauma as to wartime injuries. The improved salvage rate of traumatized eyes and the conspicuous absence of sympathetic ophthalmia among US battle casualties since World War II are encouraging. If similar methods are used to evaluate, treat, and evacuate civilians inflicted with traumatic eye disease, the results should be similar.

Temporal arteritis: a spectrum of ophthalmic complications.

Seven patients of temporal arteritis with eye involvement have been presented. These cases represent a spectrum of disease from intermittent diplopia with minimal 6th nerve weakness through mild retinal ischemia with recovery to permanent bilateral blindness. Temporal arteritis should be suspected when any form of ocular ischemia is suspected by history or found on examination of an elderly person. An early diagnosis may protect the vision in both eyes if vision is normal at the time of diagnosis. If vision in one eye is decreased because of ischemia, the vision in the other eye can usually be retained if proper therapy is instituted. Furthermore, adequate therapy may even result in improvement in vision in the involved eye. Patients with biopsy proven temporal arteritis should be continued on steroid therapy until the active disease is quiescent. Inactivity should be determined by carefully monitoring the ESR while steroids are being tapered. If the ESR rises, it is indicative of continued inflammation and if steroids are not continued, the eyes remain at risk as seen in Case 5. If the ESR remains elevated for a year or more despite continuation of high steroid levels, consideration should be given to repeating the temporal artery biopsy. Temporal arteritis should be considered in the differential diagnosis of any multisystem disease in older patients. Even central nervous system involvement may occur concomitantly, since the intracranial vessels are not immune from the disease process. Tuberculosis, systemic syphilis and more recently the collagen vascular diseases have been dubbed the "great imitators" and "the protean diseases." We suggest that the same terminology can be applied to temporal arteritis. Temporal arteritis can affect any organ. Moreover, there is a wide spectrum of variation in the degree of involvement of any particular tissue as illustrated by these 7 cases of ocular involvement.

Granulomatous arteritis.

Granulomatous, or temporal, arteritis is a disease of older people and should be considered when any patient over 55 years old has complaints consistent with a multi-system disease and/or visual loss, especially if combined with a history of diplopia, amaurosis fugax, loss of vision, or with the findings of ischemic optic neuritis or central retinal artery occlusion. Treatment should be instituted immediately with high doses of corticosteroids. The sine qua non for the diagnosis is a positive temporal artery biopsy when ocular involvement is a feature of the disease. Treatment includes administration of systemic and retrobulbar steroids. The ESR is used as a guide in determining the level of maintenance steroid dosage.

The diagnosis of Adie's pupil using 0.0625% pilocarpine solution.

In five patients a 0.0625% concentration of pilocarpine provided the marked difference in miosis between Adie's and normal pupils. Other concentrations did not produce as much as a difference.

Carotid compression tonography. Correlation with bilateral carotid arteriography in the diagnosis of extracranial carotid occlusive disease.

One hundred twenty two patients ahd carotid compression tonography (CCT) followed by bilateral carotid arteriogaraphy. Inthe group (82 patients) which was felt to have significant occlusive disease of internal carotid at the level of carotid bifurcation (smaller than 50 percent stenosis), the CCT showed a 92 per cent correlation with arteriography. Of the group (48 patients) that underwent endarterectomy, there was a 94 per cent correlation with CCT testing. In 40 patients, with normal arteriogram or with less than 50 percent stenotic lesions on arteriography, there was a larger number (25% of patients with a CCT test which appeared to indicate decreased flow. Various reasons for this are discussed. The high correlation of the CCT test and carotid arteriography in the patients with surgically amenable lesions would suggest that the CCT test is a good noninvasive screening technique for the detection of significant occlusive disease of the extracranialcarotid vascular system.