Background Blockade of programmed death 1 (PD-1), an inhibitory receptor expressed by T cells, can overcome immune resistance. We assessed the antitumor activity and safety of BMS-936558, an antibody that specifically blocks PD-1. Methods We enrolled patients with advanced melanoma, non–small-cell lung cancer, castrationresistant prostate cancer, or renal-cell or colorectal cancer to receive anti–PD-1 antibody at a dose of 0.1 to 10.0 mg per kilogram of body weight every 2 weeks. Response was assessed after each 8-week treatment cycle. Patients received up to 12 cycles until disease progression or a complete response occurred. Results A total of 296 patients received treatment through February 24, 2012. Grade 3 or 4 drugrelated adverse events occurred in 14% of patients; there were three deaths from pulmonary toxicity. No maximum tolerated dose was defined. Adverse events consistent with immune-related causes were observed. Among 236 patients in whom response could be evaluated, objective responses (complete or partial responses) were observed in those with non–small-cell lung cancer, melanoma, or renal-cell cancer. Cumulative response rates (all doses) were 18% among patients with non–small-cell lung cancer (14 of 76 patients), 28% among patients with melanoma (26 of 94 patients), and 27% among patients with renal-cell cancer (9 of 33 patients). Responses were durable; 20 of 31 responses lasted 1 year or more in patients with 1 year or more of follow-up. To assess the role of intratumoral PD-1 ligand (PD-L1) expression in the modulation of the PD-1–PD-L1 pathway, immunohistochemical analysis was performed on pretreatment tumor specimens obtained from 42 patients. Of 17 patients with PD-L1–negative tumors, none had an objective response; 9 of 25 patients (36%) with PD-L1–positive tumors had an objective response (P = 0.006). Conclusions Anti–PD-1 antibody produced objective responses in approximately one in four to one in five patients with non–small-cell lung cancer, melanoma, or renal-cell cancer; the adverse-event profile does not appear to preclude its use. Preliminary data suggest a relationship between PD-L1 expression on tumor cells and objective response. (Funded by Bristol-Myers Squibb and others; ClinicalTrials.gov number, NCT00730639.)

https://www.nejm.org/doi/pdf/10.1056/NEJMoa1200690

Safety, activity, and immune correlates of anti-PD-1 antibody in cancer.

Immune checkpoints refer to the plethora of inhibitory pathways that are crucial to maintaining self-tolerance. Tumour cells induce immune checkpoints to evade immunosurveillance. This Review discusses the progress in targeting immune checkpoints, the considerations for combinatorial therapy and the potential for additional immune-checkpoint targets.

/pdf/the-blockade-of-immune-checkpoints-in-cancer-immunotherapy-j2cp4ba5s9.pdf

The blockade of immune checkpoints in cancer immunotherapy

Background: Thyroid nodules are a common clinical problem, and differentiated thyroid cancer is becoming increasingly prevalent. Since the American Thyroid Association's (ATA's) guidelines for the management of these disorders were revised in 2009, significant scientific advances have occurred in the field. The aim of these guidelines is to inform clinicians, patients, researchers, and health policy makers on published evidence relating to the diagnosis and management of thyroid nodules and differentiated thyroid cancer. Methods: The specific clinical questions addressed in these guidelines were based on prior versions of the guidelines, stakeholder input, and input of task force members. Task force panel members were educated on knowledge synthesis methods, including electronic database searching, review and selection of relevant citations, and critical appraisal of selected studies. Published English language articles on adults were eligible for inclusion. The American College of Physicians Guideline Gr...

/pdf/2015-american-thyroid-association-management-guidelines-for-32kri8vrhd.pdf

2015 American Thyroid Association Management Guidelines for Adult Patients with Thyroid Nodules and Differentiated Thyroid Cancer: The American Thyroid Association Guidelines Task Force on Thyroid Nodules and Differentiated Thyroid Cancer.

Background: Thyroid nodules are a common clinical problem, and differentiated thyroid cancer is becoming increasingly prevalent. Since the publication of the American Thyroid Association's guidelines for the management of these disorders was published in 2006, a large amount of new information has become available, prompting a revision of the guidelines. Methods: Relevant articles through December 2008 were reviewed by the task force and categorized by topic and level of evidence according to a modified schema used by the United States Preventative Services Task Force. Results: The revised guidelines for the management of thyroid nodules include recommendations regarding initial evaluation, clinical and ultrasound criteria for fine-needle aspiration biopsy, interpretation of fine-needle aspiration biopsy results, and management of benign thyroid nodules. Recommendations regarding the initial management of thyroid cancer include those relating to optimal surgical management, radioiodine remnant ablation, a...

/pdf/revised-american-thyroid-association-management-guidelines-3i6bt8nj9c.pdf

Revised American Thyroid Association Management Guidelines for Patients with Thyroid Nodules and Differentiated Thyroid Cancer

Background Programmed death 1 (PD-1) protein, a T-cell coinhibitory receptor, and one of its ligands, PD-L1, play a pivotal role in the ability of tumor cells to evade the host's immune system. Blockade of interactions between PD-1 and PD-L1 enhances immune function in vitro and mediates antitumor activity in preclinical models. Methods In this multicenter phase 1 trial, we administered intravenous anti–PD-L1 antibody (at escalating doses ranging from 0.3 to 10 mg per kilogram of body weight) to patients with selected advanced cancers. Anti–PD-L1 antibody was administered every 14 days in 6-week cycles for up to 16 cycles or until the patient had a complete response or confirmed disease progression. Results As of February 24, 2012, a total of 207 patients — 75 with non–small-cell lung cancer, 55 with melanoma, 18 with colorectal cancer, 17 with renal-cell cancer, 17 with ovarian cancer, 14 with pancreatic cancer, 7 with gastric cancer, and 4 with breast cancer — had received anti–PD-L1 antibody. The media...

/pdf/safety-and-activity-of-anti-pd-l1-antibody-in-patients-with-2g1sbl9vc4.pdf

Safety and Activity of Anti–PD-L1 Antibody in Patients with Advanced Cancer

Merkel cell carcinoma is a rare primary cutaneous neuroendocrine tumor that is locally aggressive and frequently accompanied by distant metastases. Neurologic complications of Merkel cell carcinoma are rare. We describe a 69-year-old man who presented with Lambert-Eaton myasthenic syndrome and was found to have Merkel cell carcinoma. The paraneoplastic syndrome improved with initial treatment of the malignancy. He subsequently developed a solitary brain metastasis and died of leptomeningeal carcinomatosis.

Paraneoplastic and metastatic neurologic complications of Merkel cell carcinoma.

Inflammatory orbital pseudotumor with extension beyond the orbit

To describe the histological findings of birdshot chorioretinopathy. This is a case study of a single patient who has both birdshot chorioretinopathy and ciliochoroidal melanoma. A 55-year-old woman who was HLA-A29 positive and had birdshot chorioretinopathy had a large ciliochoroidal melanoma (T4b N0 M0) and underwent enucleation. Using histopathology, we hope to further define the pathological findings in an eye with both birdshot chorioretinopathy and coexistant ciliochoroidal melanomas. The eye showed a ciliochoroidal melanoma. In addition, elsewhere, there were multiple choroidal nodules of lymphocytes that showed the presence of CD3-positive cells, which also stained for CD4 or CD8. There were only a few CD20-positive B cells and rare CD68-positive histiocytes. No granulomas were present. To our knowledge, there are only two previous reports describing the histological findings in birdshot chorioretinopathy: one that was HLA-A29 negative showing choroidal granulomas and another that was HLA-A29 positive exhibiting histological findings similar to our case. Incidentally, the latter case had a history of cutaneous melanoma. Birdshot chorioretinopathy is a nongranulomatous nodular infiltration of the choroid.

/pdf/histological-findings-of-birdshot-chorioretinopathy-in-an-2bb7kpjt6c.pdf

Histological findings of birdshot chorioretinopathy in an eye with ciliochoroidal melanoma

Background To describe the technique of intravitreal chemotherapy preceded by subconjunctival chemotherapy for the treatment of vitreous seeds in advanced stage retinoblastoma. Methods This non-comparative interventional case series retrospectively reviewed the medical records and postenucleation histopathological findings of two patients who presented within weeks of each other with bilateral retinoblastoma, Reese–Ellsworth (R-E) stage Vb in the worse eye. Both patients had failed systemic chemotherapy prior to receiving a single treatment of 0.5 ml (5 mg per 0.5 ml) of subconjunctival carboplatin, through which 0.05 ml (3 mcg per 0.05 ml) of carboplatin was injected into the vitreous (Case 2 received 0.1 ml of intravitreal carboplatin). The subconjunctival chemotherapy was given to reduce the risk of orbital tumour seeding following intravitreal injection. Following enucleation, ocular toxicity and the presence or absence of viable tumour cells at the intravitreal injection site were recorded. Results Histopathological examination did not reveal patency of the pars plana intravitreal penetration site in either case at 6 weeks post-treatment nor was malignant seeding detected in the area of injection. Examination of the two enucleated eyes did not demonstrate structural toxicity to the cornea, anterior segment, iris or retina. Additionally, both cases were followed for over 37 months post-treatment, without the occurrence of orbital malignancy. Conclusions Injecting a bleb of subconjunctival chemotherapy prior to intravitreal drug delivery appeared to mitigate the risk of orbital tumour seeding in two patients with advanced stage retinoblastoma. Incorporating this technique may allow further investigation of intravitreal chemotherapy for the treatment of vitreous seeds in retinoblastoma.

https://bjo.bmj.com/content/bjophthalmol/early/2012/02/23/bjophthalmol-2011-300829.full.pdf

Combined intravitreal and subconjunctival carboplatin for retinoblastoma with vitreous seeds

We report the absence of photic retinal injury after exposing the retina to light from class 3A laser pointers for durations of up to 15 minutes. Three patients with uveal melanomas were scheduled to have an enucleation. Each agreed to have his or her retina exposed to laser light from a class 3A laser pointer prior to enucleation. Continuous exposure was directed to the fovea for 1 minute, to the retina 5° below fixation for 5 minutes, and to the retina 5° above fixation for 15 minutes. Ophthalmoscopic evaluation of the cornea, lens, and retina and fluorescein angiographic studies of the retina were conducted before, 24 hours after, and 11 days after laser exposure in the first case; before and 86 hours after exposure in the second case; and before, 96 hours after, and 15 days after exposure in the third case. Other than transient afterimages that lasted only a few minutes, we were unable to document any functional, ophthalmoscopic, fluorescein angiographic, or histologic evidence of damage to any structures of the eyes. Transmission electron microscopic studies of retinal sites targeted by the laser pointers in the second and third cases revealed ultrastructural abnormalities in the outer retina and the pigment epithelium that were similar to abnormalities seen in the retina approximately 8 mm away from the targeted sites. The risk to the human eye from transient exposure to light from commercially available class 3A laser pointers having powers of 1, 2, and 5 mW seems negligible.

https://jamanetwork.com/journals/jamaophthalmology/articlepdf/413875/ecp90048.pdf

Diva R. Salomao

Papers

Paraneoplastic and metastatic neurologic complications of Merkel cell carcinoma.

Inflammatory orbital pseudotumor with extension beyond the orbit

Histological findings of birdshot chorioretinopathy in an eye with ciliochoroidal melanoma

Combined intravitreal and subconjunctival carboplatin for retinoblastoma with vitreous seeds

Laser pointers and the human eye: a clinicopathologic study