A phase Ib study of BGJ398, a pan-FGFR kinase inhibitor in combination with imatinib in patients with advanced gastrointestinal stromal tumor.

Background Preclinical studies suggest that imatinib resistance in gastrointestinal stromal tumor (GIST) can be mediated by MAP-kinase activation via fibroblast growth factor (FGF) signaling. In FGF stimulated GIST cell lines, BGJ398, a pan-FGFR kinase inhibitor in combination with imatinib, was cytotoxic and superior to imatinib therapy alone. In FGF-dependent GIST, the combination of BGJ398 and imatinib may provide a mechanism to overcome imatinib resistance. Methods This phase Ib study of BGJ398 and imatinib was performed in patients with imatinib refractory advanced GIST. A standard 3 + 3 dosing schema was utilized to determine the recommended phase II dose (RP2D). Two treatment schedules were evaluated incorporating imatinib 400 mg daily in combination with (A) BGJ398 daily 3 weeks on, 1 week off or (B) BGJ398 daily 1 week on, 3 weeks off. Results 16 patients enrolled. The median age was 54 years (range: 44-77), 81% were male, and the median number of lines of prior therapy was 4 [range: 2-6, 13 patients had ≥3 prior therapies]. 12 patients received treatment on schedule A [BGJ398 dose range: 25 - 75 mg]: 2 patients experienced dose limiting toxicities (DLT) (n = 1, myocardial infarction & grade (G)4 CPK elevation; n = 1, G3 ALT elevation) on schedule A (BGJ398 75 mg), significant hyperphosphatemia, an on-target effect, was not observed, implying the maximum tolerated dose was below the therapeutic dose. Following protocol amendment, 4 patients enrolled on schedule B [BGJ398 dose range: 75 - 100 mg]: no DLTs were observed. The most common treatment related adverse events occurring in >15% of patients included CPK elevation (50%), lipase elevation (44%), hyperphosphatemia (24%), anemia (19%), and peripheral edema (19%). Among the 12 evaluable patients, stable disease (SD) was the best response observed in 7 patients by RECIST v1.1 and 9 patients by CHOI. Stable disease ≥ 32 weeks was observed in 3 patients (25%). Median progression free survival was 12.1 weeks (95% CI 4.7-19.5 weeks). Conclusions Toxicity was encountered with the combination therapy of BGJ398 and imatinib. Due to withdrawal of sponsor support the study closed before the RP2D or dosing schedule of the combination therapy was identified. In heavily pre-treated patients, stable disease ≥ 32 weeks was observed in 3 of 12 evaluable patients. Trial Registration: NCT02257541 .

Therapeutic algorithm for treatment of cytomegalovirus retinitis in persons with AIDS. A roundtable summary.

Foscarnet and ganciclovir appear to be of similar effectiveness in halting active infection when given as induction therapy and in forestalling progression of disease when given as maintenance therapy in persons with AIDS who have cytomegalovirus (CMV) retinitis. The primary dose-limiting toxicity of foscarnet is nephrotoxicity, whereas that of ganciclovir is neutropenia. The availability of two effective agents with different toxicities permits selection of initial treatment for CMV retinitis based on individual patient characteristics and provides an alternative for therapy if drug intolerance or viral resistance develops. An approach to treatment of first-episode and recurrent CMV retinitis based on patient and drug characteristics is presented. Case reports detailing the use of foscarnet and ganciclovir and problems encountered in patient management are discussed.

Horner's syndrome after coronary artery bypass surgery.

We established the frequency of Horner's syndrome (HS) in 248 elective patients after coronary artery bypass surgery. Patients were evaluated neurologically pre- and post-operatively and 6 months after surgery. Nineteen patients (7.7%) developed unilateral HS postoperatively, 12 involving the left eye. The finding persisted in 10 patients (4%) at 6 months. When assessed 2 to 6 days, or 6 months, postoperatively, HS tended to be isolated and not associated with C8/T1 plexopathy. Among nondiabetic subjects, hypertensive patients had a higher frequency of HS than normotensive patients (10.6% versus 2.9%, p = 0.05). Among normotensive subjects, diabetic patients had a higher frequency than nondiabetic patients (15% versus 2.9%, p = 0.08). There was no association between HS, age, sex, internal mammary artery grafting, or length of cardiopulmonary bypass time. In summary, HS is a common and sometimes persistent complication of coronary artery bypass surgery. Hypertensive, and possibly diabetic, patients appear to be at greatest risk for developing HS.

Primary CNS lymphoma: combined treatment with chemotherapy and radiotherapy.

Primary central nervous system lymphoma (PCNSL), an uncommon tumor, is occurring with increasing frequency. Conventional therapy with corticosteroids and cranial radiotherapy (RT) usually gives a dramatic initial response, but median survival is only 10 to 18 months. Chemotherapy is more successful in comparable systemic lymphoma and has been employed for PCNSL at relapse, causing remission but not cure. Between June 1985 and June 1988, we prospectively staged 32 patients with PCNSL at Memorial Sloan-Kettering Cancer Center and treated 28 on a new protocol that combined chemotherapy and radiotherapy at diagnosis. None had occult systemic lymphoma, but 19% had ocular and 69% had definite or probable leptomeningeal lymphoma. There were no complications in 19 stereotactic biopsies, but 4/10 patients who had a complete resection suffered a severe postoperative deficit. Four patients received RT alone, and 28 received chemotherapy and cranial RT, 17 of whom (group A) received a combination regimen using pre-RT systemic (1 g/m2) and intra-Ommaya methotrexate (MTX), 4,000 cGy whole-brain RT with a 1,440 cGy boost, and 2 courses of post-RT high-dose cytosine arabinoside; 5 other patients received an identical regimen but with a decreased dose of MTX (200 mg/m2). Sixty-three percent of assessable patients had a response to MTX independent of corticosteroid and prior to RT. Eighteen of 26 (69%) assessable patients who received combined therapy are alive with a median follow-up of 25.4 months. Twelve of 16 (75%) assessable group A patients are alive in the same period. Chemotherapy-related toxicity was minimal, and no late toxicities have occurred to date.(ABSTRACT TRUNCATED AT 250 WORDS)

Characteristics of cytomegalovirus retinitis in patients with acquired immunodeficiency syndrome.

Cytomegalovirus (CMV) retinitis is the most common ocular opportunistic infection in patients with acquired immunodeficiency syndrome (AIDS). The disease is inexorably progressive when untreated, making early detection and prompt treatment essential for preservation of functional vision. The retinitis tends to be unilateral at presentation but often becomes bilateral as it progresses. Lesions may be unifocal or multifocal and may appear in the posterior retina or peripheral retina. Primary ophthalmoscopic features of CMV retinitis include white granular zones of retinal necrosis, variable degrees of associated hemorrhage, and low-grade iritis and vitritis. Differential diagnosis is aided by characteristic features of CMV retinitis and other AIDS-related retinopathies. Initial treatment with ganciclovir or foscarnet has been found to stabilize retinitis, and maintenance therapy with either has been shown to prolong the time to retinitis progression. Further studies should help to determine the optimal approach to treatment of the disease.

Hyperpigmented lesions of the retinal pigment epithelium in familial adenomatous polyposis.

Ophthalmic examinations were performed on 56 patients with validated familial adenomatous polyposis (FAP) for hyperpigmented defects of the retinal pigment epithelium. Such lesions were seen bilaterally in 29 patients (52%) and unilaterally in 8 patients (14%). Of the 56 patients, 33 had one or more of the extracolonic expressions associated with Gardner syndrome. We found retinal lesions in 8 patients without any of the expressions of Gardner syndrome. No association was found between Gardner syndrome and the retinal lesions when these patients were compared to patients without any stigmata of Gardner syndrome, nor was any significant association found when each of the expressions was compared individually with the presence of the pigmented retinal lesions. The presence or absence of eye findings were seen to cluster within families. There was no association with sex. Fundus lesions are apparently a variable expression of the FAP gene and are not specifically associated with Gardner syndrome.

Long-term intravitreal ganciclovir therapy for cytomegalovirus retinopathy.

The safety and efficacy of intravitreously administered ganciclovir sodium as sole treatment for cytomegalovirus retinitis complicating the acquired immunodeficiency syndrome was studied prospectively in seven patients. All but one of the patients had bilateral cytomegalovirus retinitis and none were able to tolerate therapy with systemically administered ganciclovir because of myelosuppression in six patients and hepatotoxicity in one patient. Intravitreal ganciclovir therapy was discontinued in two patients within the initial 2-week induction phase because of severe intractable thrombocytopenia in one patient and retinal detachment in the other. The retinal detachment could not be conclusively attributed to the injections and was probably a secondary complication of cytomegalovirus retinitis. The remaining five patients were treated weekly, with the course of therapy ranging from a minimum of 14 weeks (18 injections) to a maximum of 56 weeks (58 injections). The patients were followed up for an average of 23.5 weeks. All eyes responded to intravitreal therapy initially, while the six untreated control eyes with cytomegalovirus retinitis all demonstrated progression of disease. Two eyes relapsed while receiving intravitreal doses of 200 micrograms of ganciclovir sodium and were subsequently treated with 300 micrograms of ganciclovir sodium per injection. One eye responded to this regimen, while in the other one the disease progressed. In the long-term treatment group, one eye developed Staphylococcus epidermidis endophthalmitis, which was treated with vitrectomy and intravitreal and systemic antibiotics.

Treatment of bilateral cytomegalovirus retinitis with sustained-release ganciclovir implants in a child.

PURPOSE: To report treatment of bilateral cytomegalovirus (CMV) retinitis in an 11-year-old girl with acquired immunodeficiency syndrome (AIDS). METHOD: Case report describing the use of intravitreal ganciclovir sustained-release devices to treat CMV retinitis, involving zones 1 through 3, which progressed despite single and combination intravenous therapy with ganciclovir and foscarnet. RESULTS: Stabilization with no active CMV retinitis was achieved after bilateral implantation of intravitreal sustained-release ganciclovir devices. There was no reactivation of the retinitis during the 5 months of follow-up. CONCLUSION: Sustained-release ganciclovir implants can be used to achieve local control of CMV retinitis in the pediatric patient.

Response of human immunodeficiency virus-associated uveitis to zidovudine.

A patient with human immunodeficiency virus (HIV) type 1 infection developed chronic iridocyclitis and anterior vitritis that were poorly responsive to topical and systemic corticosteroid therapy. Anterior chamber paracentesis was performed and HIV was isolated from culture of aqueous humor. Subsequent treatment with oral zidovudine resulted in resolution of the iridocyclitis and vitritis and full functional recovery of the eye. This case suggests that HIV may be a cause of uveitis responsive to systemic zidovudine therapy.

Uveitis associated with human immunodeficiency virus infection.

PURPOSE: To report uveitis associated with human immunodeficiency virus (HIV) infection and to suggest guidelines for treatment. METHODS: Six HIV-seropositive patients (10 eyes) with anterior or posterior uveitis or both were evaluated. After ineffective prolonged treatment with systemic and topical corticosteroids, specific systemic antiretroviral therapy with zidovudine was initiated in all patients. Aqueous humor was cultured in three eyes of three patients, and vitreous humor was cultured in one eye of one patient. RESULTS: In all 10 eyes of six patients, there was resolution of inflammation in 10 to 42 days after commencement of treatment with zidovudine (600 to 800 mg/day), despite no or minimal response to corticosteroids. Cultures of aqueous humor from three eyes of three patients and culture of vitreous humor from one eye of one patient were positive for HIV; no other organism was isolated. Systemic evaluation disclosed no other identifiable cause for the uveitis in any patient. CONCLUSIONS: Infection with HIV appears to be a cause of uveitis. A trial of zidovudine may be warranted in HIV-seropositive patients with uveitis that is poorly responsive to corticosteroid treatment when no other cause is identified. The efficacy of other retroviral agents was not determined.

Use of the ganciclovir implant for treating cytomegalovirus retinitis secondary to immunosuppression after bone marrow transplantation.

PURPOSE: To report a case in which we treated cytomegalovirus retinitis using an intravitreal ganciclovir sustained-release device in a patient negative for the human immunodeficiency virus, with a history of myeloproliferative syndrome with myelofibrosis and profound immunosuppression after allogeneic bone marrow transplantation. METHODS: Case report. Review of medical records and fundus photographs. RESULTS: After the ganciclovir device was implanted, the cytomegalovirus retinitis did not progress, and visual acuity improved. We removed the device 9 months after implantation. CONCLUSIONS: The ganciclovir sustained-release device may be useful for treating cytomegalovirus retinitis in patients without the acquired immunodeficiency syndrome who are profoundly immunosuppressed and fail conventional intravenous therapy. If immune suppression is of limited duration, the device can be removed.

Medical management of AIDS patients. Ophthalmic problems.

The majority of AIDS patients will develop ocular complications at some point during the course of their illness. The most common complications involve the retina. Accurate diagnosis of noninfectious and infectious (especially CMV) retinopathy is extremely important as most forms of infectious retinitis can be treated, albeit not without significant complications in many cases. Close cooperation between the ophthalmologist and internist is essentially to ensure that timely therapeutic intervention, which can dramatically reduce the risk of visual impairment and blindness, can be initiated. AIDS-related diseases of the central nervous system, especially nonviral infections, are often associated with abnormalities of ocular function. Assessment of visual acuity, visual fields, extraocular movements, pupillary reflexes, color perception, and the condition of optic nerve and retina is important for accurate diagnosis.

Rieger's syndrome with pericentric inversion of chromosome 6.

Pericentric inversion of chromosome 6 (6p+q-) was found in a girl with Rieger's syndrome and in her father. The only ocular signs in the father were prominent iris mounds and Schwalbe's line. The association of chromosomal anomalies with Rieger's syndrome indicates the need for a chromosome banding test in familial or sporadic patients with the syndrome and in patients with mild anomalies of the anterior chamber angle.

The use of pneumatic retinopexy to delay surgical repair of a retinal detachment associated with the ganciclovir intraocular device.

Rhegmatogenous retinal detachments are associated with cytomegalovirus (CMV) retinitis and the use of the ganciclovir intraocular device. Pars plana vitrectomy with silicone oil tamponade is the preferred technique to repair such detachments. The authors describe the use of pneumatic retinopexy as part of a treatment strategy in the management of multiple retinal detachments in a patient with CMV retinitis treated with ganciclovir implants. Pneumatic retinopexy may benefit patients when the causative retinal break is superior and is located in an area of retina uninvolved with CMV infection, because it can be used to delay surgical intervention.

Bilateral toxoplasma retinochoroiditis in a patient with acquired immune deficiency syndrome.

A 32-year-old patient with acquired immune deficiency syndrome (AIDS) was evaluated for bilateral visual loss accompanied by uveitis, vitritis and retinochoroiditis. Diagnostic vitrectomy was performed on the right eye, and the diagnosis of ocular toxoplasmosis made. Central nervous system involvement was suggested by ring enhancing lesions on CT scan. The patient improved on a pyrimethamine, sulfadiazine and clindamycin, but succumbed to disseminated toxoplasmosis when treatment was discontinued.