Pembrolizumab Induced Ocular Hypotony With Near Complete Vision Loss, Interstitial Pulmonary Fibrosis and Arthritis.

Clinical outcomes for patients with advanced melanoma have improved significantly with the introduction of immune checkpoint inhibitors. These agents have distinct adverse effects with the potential for heightened host immune responses manifesting as an autoimmune reaction in any organ. We report a unique case who developed pembrolizumab induced arthritis, ocular hypotony with vision loss and pulmonary interstitial fibrosis. A 57-year old gentleman with advanced melanoma was treated with pembrolizumab and attained complete response with no evidence of disease on functional imaging. Treatment was well-tolerated with the only side effect being arthritis controlled with low dose steroids. Following a work related blunt trauma to the right eye, the patient developed bilateral visual impairment secondary to ocular hypotony. The ocular hypotony failed to respond to high-dose glucocorticoid and multiple surgeries. Intraoperatively, ciliary body atrophy was found. Pembrolizumab was ceased after the eye trauma and he remained in complete remission from melanoma. After a further 10 months, the patient developed symptomatic pulmonary fibrosis. There was moderate symptomatic improvement with nintedanib, an antifibrotic agent. This case describes two rare and unique adverse effects. Ocular adverse effects are extremely uncommon and this is the first case to report immune checkpoint inhibitor related ocular hypotony without uveitis to the best of our knowledge. Similarly, the incidence of severe pneumonitis is reported to be low, however limited data is available regarding pulmonary interstitial fibrosis. The occurrence of multiple adverse effects in this case including one occurring several months after cessation of treatment highlights the need for vigilance by clinicians who manage patients treated with immune checkpoint inhibitors. Further research is necessary with regards to rare adverse effects of immune checkpoint inhibitors and the relation of these to treatment administration.

Early worsening of diabetic retinopathy due to intensive glycaemic control.

The prevalence of diabetes and diabetic retinopathy is increasing around the world. Glycaemic control is important in reducing the long-term risk of complications of diabetes, however intensive glycaemic control, particularly in patients with longstanding and poorly controlled diabetes, is associated with the risk of early worsening of diabetic retinopathy and vision loss. We present two clinical cases to illustrate the presentation of early worsening and to highlight a role for intravitreal anti-vascular endothelial growth factor therapies in ameliorating this phenomenon, as well as a review of the current understanding of this phenomenon. We emphasise the importance of identifying individuals at risk of early worsening of diabetic retinopathy and recommend regular ophthalmological review during the period of intensive glycaemic control to ensure optimal visual outcomes.

The Influence of Intravitreal Ranibizumab on Inflammation-associated Cytokine Concentrations in Eyes With Diabetic Macular Edema.

Purpose: To evaluate the effect of intravitreal ranibizumab injections on aqueous concentrations of angiogenic or inflammatory cytokines in patients with diabetic macular edema (DME). Methods: Thirty eyes of 25 patients with center-involved DME were recruited to the study. All had a central macular thickness (CMT) of >300 µm and best-corrected visual acuity (BCVA) between 28 and 70 logMAR letters (Snellen equivalent 20/320-20/40). At baseline, all eyes had 0.1 mL of aqueous collected before ranibizumab treatment. At week 4, a second ranibizumab injection was administered and at week 8, aqueous sampling was repeated before a third ranibizumab injection. From week 12, all eyes were followed at 4-weekly intervals and the need for ranibizumab treatment was determined by BCVA and CMT measurements. Levels of 32 cytokines were assessed at baseline and at week 8 using a multiplex array assay. Results: Following two consecutive ranibizumab injections, there was a statistically significant reduction in VEGF (P < 0.00001), as well as IL-1ß (P = 0.00006), IL-7 (P = 0.00002), IL-8 (P = 0.00023), IL-10 (P < 0.00001), IL-12 (P < 0.00001), IL-17 (P = 0.00024), MCP-1 (P = 0.00023), and TNF-α (P < 0.00001). There was also an upregulation of soluble VEGF receptor-2 (P = 0.00004). A P < 0.0015 was considered significant in this study. Conclusions: Ranibizumab treatment influences various inflammatory cytokine concentrations in addition to reducing aqueous VEGF concentrations in patients with DME. This may contribute to its therapeutic effect in patients with DME.

Inpatient management of pyoderma gangrenosum: treatments, outcomes, and clinical implications.

BACKGROUND: Pyoderma gangrenosum (PG) is a rare, ulcerative neutrophilic skin condition of unknown etiology. The disease continues to pose therapeutic challenges, with ongoing controversy regarding the role of surgery. METHODS: A retrospective medical records review was conducted for 29 patients who were diagnosed and treated for PG at an Australian tertiary center over 10 years, from 1 January 2000 to 31 December 2010. RESULTS: A total of 29 patients had a diagnosis of PG, with a total of 35 admissions. Nearly all patients had immunosuppressant therapy and 10 (35%) patients underwent surgery. Eight (28%) received hyperbaric oxygen therapy. Complications secondary to medical therapy occurred in 23 (66%) of admissions, with the commonest being poor blood sugar control in patients with diabetes (n = 6, 17%) and steroid-induced diabetes (n = 5, 14%). At discharge, 21 (72%) patients' ulcers had improved and there were 4 (14%) inpatient deaths. At 6 months, 3 of 10 cases with available follow-up showed complete ulcer healing. Most of the patients (n = 8, 80%) who underwent combined medical and surgical therapy had ulcers that had either completely healed or improved at 6 months after discharge. All 3 patients who underwent split skin grafting under immunosuppressive cover (with 2 having hyperbaric oxygen therapy) had no postoperative graft failure or pathergy. CONCLUSIONS: Pyoderma gangrenosum remains a therapeutic challenge, with significant complications and morbidity from long-term medical treatment. Surgery should be considered in conjunction with combined hyperbaric and immunosuppressive therapy once the disease is quiescent, to reduce disease-related comorbidity as well as the consequent adverse effects of long-term immunosuppressant therapy.

Emergence of chemoresistance in a metastatic basal cell carcinoma patient after complete response to hedgehog pathway inhibitor vismodegib (GDC-0449).

Vismodegib (GDC-0449, Genentech, USA), a small molecule inhibitor of the Hedgehog signalling pathway, has potent anti-tumour activity in advanced basal cell carcinoma (BCC). We report a case of a 67-year-old Australian man with metastatic BCC including pulmonary disease with malignant effusion who showed a dramatic complete response to vismodegib but subsequently experienced a recurrence of pulmonary disease, indicative of chemoresistance to vismodegib. This case is the first to illustrate chemoresistance in a patient with metastatic BCC, and demonstrates the need for closely monitoring metastatic BCC patients even after an apparently complete response.