Impact of intermediate-dose prophylaxis on progression of haemarthropathy in patients with severe haemophilia A: A 10-year, single-centre experience in Korea.

AIM: To determine the impact of 10-year intermediate-dose prophylaxis on haemarthropathy progression in patients with severe haemophilia A (SHA). METHODS: Prophylactic treatment with intermediate dose was given maximally for 10 years to 42 patients with SHA in a haemophilia treatment centre in Korea. Patients were divided into three groups based on prophylactic treatment started age: 1-10 (group A'), 11-20 (group B'), and ≥21 (group C'). Average annual increase of Pettersson score (P-score) was compared between the treatment groups. RESULTS: Average ages and P-scores at initiation of prophylaxis were 4.65±3.43 years and 2.09±3.25, 16.13±1.73 years and 7.37±4.38, and 28.33±7.25 years and 12.33±6.50 for groups A', B', and C'. Average annual increase of P-score in groups A', B', and C' was 0.039±0.11, 0.063±0.123, and 0.078±0.124. Assuming that intermediate-dose prophylaxis started at the average age, P-score and annual increase of P-score would be the average values of each group; it would thus take 210 and 46.5 years to reach -2SD of the average critical level of haemarthropathy (The level of haemarthropathy (P-score 13.0 ± 2.7) above which there is a significant impact on quality of life in Korean) in groups A' and B'. However, it would take 55 and 15.75 years if the annual P-score increase were +2SD of the average value in groups A' and B'. CONCLUSION: Intermediate-dose prophylaxis for patients with SHA in Korea would maintain arthropathy below the critical level for most of the patients' lifetime when started before adolescence. However, this would not be achieved in some adolescent patients with rapid progression of arthropathy and in most adult patients.

Chronic granulomatous dermatitis induced by talimogene laherparepvec therapy of melanoma metastases.

Talimogene laherparepvec (TVEC) is the first oncolytic viral immunotherapy approved by the FDA, for advanced melanoma consisting of genetically modified herpes simplex type 1 virus which selectively replicates causing tumor lysis, expressing granulocyte macrophage-colony stimulating factor (GM-CSF) and activating dendritic cells. Intratumoral injection of TVEC produces objective response in 41% of stage IIB-IV M1a melanoma. However, clinical response assessment can be problematic due to immune-related inflammation at established tumor sites. Herein, we report 5 cases of granulomatous dermatitis developing at sites of TVEC injection associated with pathologic complete response in 4 of 5 patients. Over 5 months, TVEC injections were administrated in a median of 20 tumors per patient for 9 median doses prior to biopsy of persistent, indurated nodules. Granulomatous dermatitis with melanophages and melanin pigment incontinence was observed in all samples without evidence of melanoma cells in 4 patients. The fifth patient was rendered melanoma-free by resection of the 1 nodule out of 4 with persistent tumor. Repetitive administration of TVEC or other oncolytic viral immunotherapies mimicking unresolved infection can produce granulomatous inflammation confounding assessment of the degree of tumor response and need for additional TVEC therapy. Tumor biopsies are encouraged after 4 to 6 months of TVEC administration to differentiate melanoma from granulomatous inflammation. Patients with confirmed granulomatous dermatitis replace continued with remained in remission after treatment discontinuation. Inflammatory nodules typically regress spontaneously.

Clinical and immunologic correlates of response to PD-1 blockade in a patient with metastatic renal medullary carcinoma.

BACKGROUND: Renal medullary carcinoma (RMC) is a rare kidney tumor that occurs in adolescent and young adults, typically in association with sickle cell trait. RMC exhibits rapid disease progression, frequent metastases at diagnosis, and dismal clinical outcomes. Currently available therapies, including cisplatin-based combination chemotherapy, multi-tyrosine kinase, and mTOR inhibitor strategies demonstrate either transient responses or minimal activity. Therefore, further molecular characterization and additional treatment strategies are urgently needed in this aggressive disease. The role of immune system surveillance and responsiveness to anti-PD-1 therapies in RMC are completely unexplored. CASE PRESENTATION: A 29 year old male with sickle cell trait presented with painless hematuria that ultimately resulted in a diagnosis of RMC. He underwent total nephrectomy and adjuvant cytotoxic chemotherapy with carboplatin, gemcitabine, paclitaxel, and bevacizumab. As is common in this aggressive form of kidney cancer he recurred with biopsy proven lymph node metastasis. He was started on checkpoint inhibitor therapy with nivolumab that inhibits program cell death protein 1 (PD-1), and on his first follow-up imaging he was found to have a partial response that on subsequent scans ultimately resulted in a complete response lasting greater than nine months. In this report, we present a patient with metastatic RMC who exhibited a clinical response to nivolumab, as well as the genetic and immunologic correlates of the pre-treatment tumor. Provocatively, robust immune infiltrate and expression of immune checkpoints were observed, despite the presence of a low mutation burden. CONCLUSIONS: Here, we report the first case of immune microenvironment profiling and response to anti-PD-1 in a patient with RMC to our knowledge. This case suggests that anti-PD-1 based therapies may have clinical activity in RMC.