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.

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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

Perineural spread of squamous cell carcinoma: from skin to skin through the brachial plexus.

Expression of Vascular Endothelial Growth Factor Receptors in Benign Vascular Lesions of the Orbit: A Case Series

BACKGROUND

“Small cells” have been described in the cervical-vaginal (Papanicolaou [Pap]) smears of patients receiving tamoxifen. The current study determined the frequency of this finding and its implications for the differential diagnosis.



METHODS

A computer-based search of the cytopathology files from January 1994 to December 1998 was performed for Pap smears from patients with a history of tamoxifen treatment. All smears were reviewed for the presence of “small cells” and endometrial cells. Pap smears from an age-matched control group that was not treated with tamoxifen also were screened for “small cells.”



RESULTS

Five hundred forty-eight Pap smears were identified from 425 patients (mean age, 62 years; average duration of treatment, 43 months). Clusters of these “small cells” were present in 104 Pap smears from 86 patients (19%). The background pattern was proliferative in the majority of the Pap smears (83%). In five Pap smears (5%), these “small cells” were interpreted originally as endometrial cells. In the remaining Pap smears, no reference to the presence of the cells was made in the original report. “Small cells” were identified in 79 Pap smears (18%) in the control group (n = 443 smears).



CONCLUSIONS

The incidence of “small cells” is similar in the Pap smears of patients with or without a history of tamoxifen treatment. These cells are similar to reserve cells noted in atrophic smears. However, as a result of the proliferative effect of tamoxifen in the cervical epithelium, these cells are prominent when admixed with superficial and intermediate cells in patients treated with tamoxifen. These cells need to be differentiated from endometrial cells to avoid unnecessary follow-up procedures. Cancer (Cancer Cytopathol) 2001;93:23–28. © 2001 American Cancer Society.

https://acsjournals.onlinelibrary.wiley.com/doi/pdf/10.1002/1097-0142%2820010225%2993%3A1%3C23%3A%3AAID-CNCR9003%3E3.0.CO%3B2-F

Small cells in cervical-vaginal smears of patients treated with tamoxifen.

Post-transplant lymphoproliferative disorder (PTLD) has rarely been associated with ocular manifestations. We report a case of bilateral ocular involvement by PTLD with histopathologic features of extranodal marginal zone (MALT) lymphoma in an 8-year-old boy following orthotopic heart transplantation. The anterior segment disease was treated successfully using a combination of intraocular and systemic injections of humanized anti-CD20 antibody (rituximab).

Combined intraocular and systemic rituximab for ocular lymphoproliferative disorder with extranodal marginal zone lymphoma-type morphology after heart transplant.

1. Yang Z, Camp NJ, Sun H, et al. A variant of the HTRA1 gene increases susceptibility to age-related macular degeneration. Science. 2006;314(5801):992-993. 2. Dewan A, Liu M, Hartman S, et al. HTRA1 promoter polymorphism in wet age-related macular degeneration. Science. 2006;314(5801):989-992. 3. Kanda A, Chen W, Othman M, et al. A variant of mitochondrial protein LOC387715/ARMS2, not HTRA1, is strongly associated with age-related macular degeneration. Proc Natl Acad Sci U S A. 2007;104(41):16227-16232. 4. Chowers I, Meir T, Lederman M, et al. Sequence variants in HTRA1 and LOC387715/ARMS2 and phenotype and response to photodynamic therapy in neovascular age-related macular degeneration in populations from Israel. Mol Vis. 2008;14:2263-2271. 5. Chan CC, Shen D, Zhou M, et al. Human HtrA1 in the archived eyes with age-related macular degeneration. Trans Am Ophthalmol Soc. 2007;105:9297, discussion 97-98. 6. Tuo J, Ross RJ, Reed GF, et al. The HtrA1 promoter polymorphism, smoking, and age-related macular degeneration in multiple case-control samples. Ophthalmology. 2008;115(11):1891-1898.

https://jamanetwork.com/journals/jamaophthalmology/articlepdf/426487/elt1110_1493_1494.pdf

Diva R. Salomao

Papers

Perineural spread of squamous cell carcinoma: from skin to skin through the brachial plexus.

Expression of Vascular Endothelial Growth Factor Receptors in Benign Vascular Lesions of the Orbit: A Case Series

Small cells in cervical-vaginal smears of patients treated with tamoxifen.

Combined intraocular and systemic rituximab for ocular lymphoproliferative disorder with extranodal marginal zone lymphoma-type morphology after heart transplant.

Periorbital and Ocular Necrobiotic Xanthogranuloma Leading to Perforation