Multidimensional biomarker predicts disease control in response to immunotherapy in recurrent or metastatic head and neck squamous-cell carcinoma.

PURPOSE: Anti-PD-1 therapy provides clinical benefit in 40-50% of patients with relapsed and/or metastatic head and neck squamous cell carcinoma (RM-HNSCC). Selection of anti- PD-1 therapy is typically based on patient PD-L1 immunohistochemistry (IHC) which has low specificity for predicting disease control. Therefore, there is a critical need for a clinical biomarker that will predict clinical benefit to anti-PD-1 treatment with high specificity. METHODS: Clinical treatment and outcomes data for 103 RM-HNSCC patients were paired with RNA-sequencing data from formalin-fixed patient samples. Using logistic regression methods, we developed a novel biomarker classifier based on expression patterns in the tumor immune microenvironment to predict disease control with monotherapy PD-1 inhibitors (pembrolizumab and nivolumab). The performance of the biomarker was internally validated using out-of-bag methods. RESULTS: The biomarker significantly predicted disease control (65% in predicted non-progressors vs. 17% in predicted progressors, p < 0.001) and was significantly correlated with overall survival (OS; p = 0.004). In addition, the biomarker outperformed PD-L1 IHC across numerous metrics including sensitivity (0.79 vs 0.64, respectively; p = 0.005) and specificity (0.70 vs 0.61, respectively; p = 0.009). CONCLUSION: This novel assay uses tumor immune microenvironment expression data to predict disease control and OS with high sensitivity and specificity in patients with RM-HNSCC treated with anti-PD-1 monotherapy.

The Treatment of a Novel Epidermal Growth Factor Receptor (EGFR)-GRB2 Genetic Mutation Using Osimertinib in Metastatic Non-Small Cell Lung Cancer.

Mutations in the epidermal growth factor receptor (EGFR) have been implicated in nearly one-third of non-small-cell lung cancers. For patients harboring non-traditional mutations, genomic and transcriptomic sequencing can help direct treatment. As cancer genomics evolves, novel driver mutations continue to be uncovered. We report on a unique EGFR-GRB2 fusion in a 48-year-old female never-smoker. This patient presented with stage IV lung adenocarcinoma (T2aN3M1) with metastatic disease in the iliac wing and liver. Despite systemic treatment, this patient continued to progress. On whole transcriptome sequencing, this patient was found to have a novel EGFR-GRB2 RNA fusion transcript similar to other EGFR fusions described in the literature. After treatment with osimertinib, this patient experienced remarkable clinical and radiological improvements. We believe that, especially for patients with metastatic lung cancer, the presence of novel driver mutations should be investigated. Potentially, patients harboring similar mutations may demonstrate analogous improvements with targeted treatment using the most recent generation of tyrosine kinase inhibitors.

Positive Impact of Implementing a Comprehensive Genetic Testing Protocol for Prostate Cancer Patients in a Multi-disciplinary Uro-oncology Practice.

INTRODUCTION: Prior to the 2017 Philadelphia Consensus Conference guidelines, genetic testing for prostate cancer was conducted based on personal and family history of malignancy pursuant to National Comprehensive Cancer Network recommendations. The updated 2019 guidelines addressed the subject of genetic testing by endorsing point-of-care genetic testing and referral to genetic counseling. However, limited literature is available regarding successful implementation of a streamlined method for genetic testing. This paper explores the benefits of implementing an on-site guideline-based genetic testing process for prostate cancer patients. METHODS: Data were retrospectively reviewed for 552 prostate cancer patients seen in a uro-oncology clinic since January 2017. Prior to September 2018 genetic testing was recommended based on National Comprehensive Cancer Network guidelines, and swabs for testing were procured off-site 1 mile from the clinic (n = 78). After September 2018 genetic testing was recommended based on the Philadelphia Consensus Conference guidelines, and swabs for testing were procured at the clinic itself (n = 474). RESULTS: A statistically significant increase in testing compliance was observed after the implementation of on-site, guideline-based testing. Genetic testing compliance increased from 33.3% to 98.7%. The time to receive the genetic test results was also reduced from 38 days to 21 days. CONCLUSIONS: The implementation of an on-site, guideline-based genetic testing model for prostate cancer patients significantly improved compliance with genetic testing to 98.7% and decreased the time to receive genetic test results by 17 days. Adopting a guideline-based model with on-site genetic testing can significantly improve the detection rate for pathogenic and actionable mutations and increase the utilization of targeted therapies.

Pembrolizumab-Induced Giant Cell Arteritis in the Setting of Urothelial Carcinoma.

A 65-year-old male presented to the Ophthalmology clinic with painless loss of vision in his right eye. Over the previous week the right eye's vision had progressed from being blurry to complete loss. Three weeks prior to presentation he had begun treatment with pembrolizumab for urothelial carcinoma. Ophthalmological assessment and subsequent imaging prompted further investigation, and a temporal artery biopsy confirmed a diagnosis of giant cell arteritis. This case demonstrates a rare, yet serious, condition of biopsy-confirmed giant cell arteritis in the setting of pembrolizumab treatment for urothelial carcinoma. In addition to reporting a vision threatening side effect of pembrolizumab we emphasise the need for vigilant care of patients on this drug as symptomatology and laboratory results may be inconspicuous.

MULTIMODAL IMAGING AND HISTOLOGIC CORRELATION OF ISOLATED METASTASIS OF PROSTATE ADENOCARCINOMA TO THE CHOROID.

PURPOSE: To provide correlative clinical-multimodal imaging-histopathologic findings of isolated prostatic choroidal metastasis. METHODS: Ophthalmologic examination, fluorescein angiogram, spectral-domain optical coherence tomography, fundus autofluorescence, computerized tomography, magnetic resonance imaging, positive emission tomography, CSF analysis, serologies, tissue pathology with immunohistochemistry, and examination of relevant literature. RESULTS: A 76-year-old man with a history of prostate adenocarcinoma was referred for 2 months of unilateral blurry vision. Fundus examination revealed elevated deep orange choroidal lesions in the macula with overlying retinal pigment epithelium mottling and subretinal fluid. Fluorescein angiogram demonstrated alternating areas of hypofluorescence and hyperfluorescence (staining) without leakage. Optical coherence tomography revealed dome-shaped and lumpy choroidal lesions with surrounding undulating "lumpy bumpy" and "rippled/seasick" patterns. Workup for a primary or additional metastatic lesion including computerized tomography of head/chest/abdomen/pelvis, lumbar puncture, magnetic resonance imaging brain, and whole-body positive emission tomography scan was negative. Full-thickness excisional chorioretinal biopsy was obtained through pars plana vitrectomy with diathermy and vertical scissors. Histologic examination revealed adenocarcinoma with weak positive staining for prostate specific antigen, moderate positive staining for P501S (prostein), and strong positive staining for prostatic acid phosphatase, consistent with metastasis from a prostate primary. Treatment consisted of local radiation with regression of the metastatic tumor. The patient is also on concomitant androgen deprivation treatment because there is a very high incidence of systemic recurrence due to hematogenous involvement. The patient's vision has continued to improve 6 months past treatment. CONCLUSION: The authors present a unique case to highlight the multimodal imaging and histology of a rare presentation of biopsy-proven, isolated metastasis of prostate adenocarcinoma to the choroid. Systemic workup is required, and if unrevealing of a primary or metastatic lesion, full-thickness chorioretinal biopsy and histopathology can provide a definitive diagnosis, allowing optimal treatment. Chorioretinal biopsy is a useful technique and may allow for visual preservation while also giving superior histologic quality.

Impact of a prostate multidisciplinary clinic program on patient treatment decisions and on adherence to NCCN guidelines: the William Beaumont Hospital experience.

OBJECTIVES: In order to demonstrate the impact of multidisciplinary care in the community oncology setting, we evaluated treatment decisions after the initiation of a dedicated prostate and genitourinary (GU) multidisciplinary clinic (MDC). METHODS: In March 2010, a GU MDC was created at William Beaumont Hospital with the goal of providing patients with a comprehensive multidisciplinary evaluation and consensus treatment recommendations in a single visit. Urologists, radiation, and medical oncologists along with ancillary support staff participated in this comprehensive initial evaluation. The impact of this experience on patient treatment decisions was analyzed. RESULTS: During the first year, a total of 182 patients were seen. Compared with previous years, low-risk MDC patients more frequently chose external beam radiation therapy (41.1% vs. 26.6%, P=0.02), and active surveillance (14.3% vs. 6.1%, P=0.02) and less frequently prostatectomy (30.4% vs. 44.0%, P=0.03). Similar increases in external beam were seen in intermediate and high-risk patients. Increased use of hormonal therapy was found in high-risk patients compared with the years before the initiation of the MDC (76.2% vs. 51.1%, P=0.03). Increased adherence to National Comprehensive Cancer Network (NCCN) guidelines was seen with intermediate-risk patients (89.8% vs. 75.9%, P=0.01), whereas nonsignificant increases were seen in low-risk (100% vs. 98.9%, P=0.43) and high-risk patients (100% vs. 94.2%, P=0.26). CONCLUSIONS: The establishment of a GU MDC improved the quality of care for cancer patients as demonstrated by improved adherence to National Comprehensive Cancer Network guidelines, and a broadening of treatment choices made available.

Phase I study of conformal radiotherapy and concurrent full-dose gemcitabine with erlotinib for unresected pancreatic cancer.

PURPOSE: To determine the recommended dose of radiotherapy when combined with full-dose gemcitabine and erlotinib for unresected pancreas cancer. METHODS AND MATERIALS: Patients with unresected pancreatic cancer (Zubrod performance status 0-2) were eligible for the present study. Gemcitabine was given weekly for 7 weeks (1,000 mg/m(2)) with erlotinib daily for 8 weeks (100 mg). A final toxicity assessment was performed in Week 9. Radiotherapy (starting at 30 Gy in 2-Gy fractions, 5 d/wk) was given to the gross tumor plus a 1-cm margin starting with the first dose of gemcitabine. A standard 3 plus 3 dose escalation (an additional 4 Gy within 2 days for each dose level) was used, except for the starting dose level, which was scheduled to contain 6 patients. In general, Grade 3 or greater gastrointestinal toxicity was considered a dose-limiting toxicity, except for Grade 3 anorexia or Grade 3 fatigue alone. RESULTS: A total of 20 patients were treated (10 men and 10 women). Nausea, vomiting, and infection were significantly associated with the radiation dose (p = .01, p = .03, and p = .03, respectively). Of the 20 patients, 5 did not complete treatment and were not evaluable for dose-escalation purposes (3 who developed progressive disease during treatment and 2 who electively discontinued it). Dose-limiting toxicity occurred in none of 6 patients at 30 Gy, 2 of 6 at 34 Gy, and 1 of 3 patients at 38 Gy. CONCLUSION: The results of the present study have indicated that the recommended Phase II dose is 30 Gy in 15 fractions.

Factors associated with the development of breast cancer-related lymphedema after whole-breast irradiation.

PURPOSE: To determine the rates of breast cancer-related lymphedema (BCRL) in patients undergoing whole-breast irradiation as part of breast-conserving therapy (BCT) and to identify clinical, pathologic, and treatment factors associated with its development. METHODS AND MATERIALS: A total of 1,861 patients with breast cancer were treated at William Beaumont Hospital with whole-breast irradiation as part of their BCT from January 1980 to February 2006, with 1,497 patients available for analysis. Determination of BCRL was based on clinical assessment. Differences in clinical, pathologic, and treatment characteristics between patients with BCRL and those without BCRL were evaluated, and the actuarial rates of BCRL by regional irradiation technique were determined. RESULTS: The actuarial rate of any BCRL was 7.4% for the entire cohort and 9.9%, 14.7%, and 8.3% for patients receiving a supraclavicular field, posterior axillary boost, and internal mammary irradiation, respectively. BCRL was more likely to develop in patients with advanced nodal status (11.4% vs. 6.3%, p = 0.001), those who had a greater number of lymph nodes removed (14 nodes) (9.5% vs. 6.0%, p = 0.01), those who had extracapsular extension (13.4% vs. 6.9%, p = 0.009), those with Grade II/III disease (10.8% vs. 2.9%, p < 0.001), and those who received adjuvant chemotherapy (10.5% vs. 6.7%, p = 0.02). Regional irradiation showed small increases in the rates of BCRL (p = not significant). CONCLUSIONS: These results suggest that clinically detectable BCRL will develop after traditional BCT in up to 10% of patients. High-risk subgroups include patients with advanced nodal status, those with more nodes removed, and those who receive chemotherapy, with patients receiving regional irradiation showing a trend toward increased rates.

Long-term results of full-dose gemcitabine with radiation therapy compared to 5-fluorouracil with radiation therapy for locally advanced pancreas cancer.

PURPOSE: To retrospectively compare the efficacy and toxicity of full-dose gemcitabine based chemoradiotherapy (GemRT) versus 5-fluorouracil (5-FU) based chemoradiotherapy (5FURT) for locally advanced pancreas cancer (LAPC). METHODS: From January 1998 to December 2008, 93 patients with LAPC were treated either with 5FURT (n=38) or GemRT (n=55). 5FURT consisted of standard-field radiotherapy given concurrently with infusional 5-FU or capecitabine. GemRT consisted of involved-field radiotherapy given concurrently with full-dose gemcitabine (1000mg/m(2) weekly) with or without erlotinib. The follow-up time was calculated from the time of diagnosis to the date of death or last contact. RESULTS: Patient characteristics were not significantly different between treatment groups. The overall survival (OS) was significantly better for GemRT compared to 5FURT (median 12.5months versus 10.2months; 51% versus 34% at 1year; 12% versus 0% at 3years; 7% versus 0% at 5years, respectively; all P=0.04). The OS benefit of GemRT was maintained on subset analysis without concurrent erlotinib or with sequential gemcitabine (all P<0.05). The rates of distant metastasis, subsequent hospitalization, acute and late grade 3-5 gastrointestinal toxicities were not significantly different between the GemRT and 5FURT groups. CONCLUSIONS: GemRT was associated with an improved OS compared to standard 5FURT. This approach yielded long-term survivors and was not associated with increased hospitalization or severe gastrointestinal toxicity.

Case report: mantle cell lymphoma, prolymphocytoid variant, with leukostasis syndrome.

A 76-year-old man presented with leukostasis syndrome, including oculodynia, blurred vision, and visual field defects, due to mantle cell lymphoma, prolymphocytoid variant, with marked leukocytosis, 1227 x 10(9)/l. He had splenomegaly but no lymphadenopathy or hepatomegaly. The tumor cells were CD5+, CD19+, CD20+, FMC-7+, and kappa light chain restricted. Immunohistochemistry showed expression of p53 and of cyclin D1. Fluorescent in situ hybridization demonstrated t(11;14) with translocation between CYCLIN D1 and the immunoglobulin heavy-chain genes. The patient received leukapheresis and aggressive chemotherapy, but the leukocyte count remained above 100 x 10(9)/l. The patient's condition rapidly deteriorated with lymphomatous infiltration of his lungs and soft tissues, and he expired 6 months after diagnosis. While it is known that mantle cell lymphoma may have a leukemic phase, the degree of leukocytosis in this case exceeds that previously reported in the literature and resulted in a clinical syndrome of leukostasis.