Comparative analysis of the tumor microbiome, molecular profiles, and immune cell abundances by HPV status in mucosal head and neck cancers and their impact on survival.

Head and Neck Squamous Cell Carcinoma (HNSCC) comprises a diverse group of tumors with variable treatment response and prognosis. The tumor microenvironment (TME), which includes microbiome and immune cells, can impact outcomes. Here, we sought to relate the presence of specific microbes, gene expression, and tumor immune infiltration using tumor transcriptomics from The Cancer Genome Atlas (TCGA) and associate these with overall survival (OS). RNA sequencing (RNAseq) from HNSCC tumors in TCGA was processed through the exogenous sequences in tumors and immune cells (exotic) pipeline to identify and quantify low-abundance microbes. The detection of the Papillomaviridae family of viruses assessed HPV status. All statistical analyses were performed using R. A total of 499 RNAseq samples from TCGA were analyzed. HPV was detected in 111 samples (22%), most commonly Alphapapillomavirus 9 (90.1%). The presence of Alphapapillomavirus 9 was associated with improved OS [HR = 0.60 (95%CI: 0.40-0.89, p = .01)]. Among other microbes, Yersinia pseudotuberculosis was associated with the worst survival (HR = 3.88; p = .008), while Pseudomonas viridiflava had the best survival (HR = 0.05; p = .036). Microbial species found more abundant in HPV- tumors included several gram-negative anaerobes. HPV- tumors had a significantly higher abundance of M0 (p < .001) and M2 macrophages (p = .035), while HPV+ tumors had more T regulatory cells (p < .001) and CD8+ T-cells (p < .001). We identified microbes in HNSCC tumor samples significantly associated with survival. A greater abundance of certain anaerobic microbes was seen in HPV tumors and pro-tumorigenic macrophages. These findings suggest that TME can be used to predict patient outcomes and may help identify mechanisms of resistance to systemic therapies.

Association between Tumor Microbiome and Hypoxia across Anatomic Subsites of Head and Neck Cancers.

Purpose/Objective(s): Microbiome has been shown to affect tumorigenesis by promoting inflammation. However, the association between the upper aerodigestive microbiome and head and neck squamous cell carcinoma (HNSCC) is not well established. Hypoxia is a modifiable factor associated with poor radiation response. Our study analyzed the HNSCC tumor samples from The Cancer Genome Atlas (TCGA) to investigate the relationship between different HNSCC tumor subsites, hypoxia, and local tumor microbiome composition. Results: A total of 357 patients were included [Oral cavity (OC) = 226, Oropharynx (OPx) = 53, and Larynx/Hypopharynx (LHPx) = 78], of which 12.8%, 71.7%, and 10.3%, respectively, were HPV positive. The mean (SD) hypoxia scores were 30.18 (11.10), 24.31 (14.13), and 29.53 (12.61) in OC, OPx, and LHPx tumors, respectively, with higher values indicating greater hypoxia. The hypoxia score was significantly higher for OC tumors compared to OPx (p = 0.044) and LHPx (p = 0.002). There was no significant correlation between hypoxia and HPV status. Pseudomonas sp. in OC, Actinomyces sp. and Sulfurimonas sp. in OPx, and Filifactor, Pseudomonas and Actinomyces sp. in LHPx had the strongest association with the hypoxia score. Materials/Methods: Tumor RNAseq samples from TCGA were processed, and the R package "tmesig" was used to calculate gene expression signature, including the Buffa hypoxia (BH) score, a validated hypoxia signature using 52 hypoxia-regulated genes. Microbe relative abundances were modeled with primary tumor location and a high vs. low tertile BH score applying a gamma-distributed generalized linear regression using the "stats" package in R, with adjusted p-value < 0.05 considered significant. Conclusions: In our study, oral cavity tumors were found to be more hypoxic compared to other head and neck subsites, which could potentially contribute to their radiation resistance. For each subsite, distinct microbial populations were over-represented in hypoxic tumors in a subsite-specific manner. Further studies focusing on an association between microbiome, hypoxia, and patient outcomes are warranted.

Metformin increases natural killer cell functions in head and neck squamous cell carcinoma through CXCL1 inhibition.

BACKGROUND: Metformin slows tumor growth and progression in vitro, and in combination with chemoradiotherapy, resulted in high overall survival in patients with head and neck cancer squamous cell carcinoma (HNSCC) in our phase 1 clinical trial (NCT02325401). Metformin is also postulated to activate an antitumor immune response. Here, we investigate immunologic effects of metformin on natural killer (NK) and natural killer T cells, including results from two phase I open-label studies in patients with HNSCC treated with metformin (NCT02325401, NCT02083692). METHODS: Peripheral blood was collected before and after metformin treatment or from newly diagnosed patients with HNSCC. Peripheral immune cell phenotypes were evaluated using flow cytometry, cytokine expression by ELISA and/or IsoLight, and NK cell-mediated cytotoxicity was determined with a flow-based NK cell cytotoxicity assay (NKCA). Patient tumor immune infiltration before and after metformin treatment was analyzed with immunofluorescence. NK cells were treated with either vehicle or metformin and analyzed by RNA sequencing (RNA-seq). NK cells were then treated with inhibitors of significant pathways determined by RNA-seq and analyzed by NKCA, ELISA, and western blot analyses. RESULTS: Increased peripheral NK cell activated populations were observed in patients treated with metformin. NK cell tumor infiltration was enhanced in patients with HNSCC treated with metformin preoperatively. Metformin increased antitumorigenic cytokines ex vivo, including significant increases in perforin. Metformin increased HNSCC NK cell cytotoxicity and inhibited the CXCL1 pathway while stimulating the STAT1 pathway within HNSCC NK cells. Exogenous CXCL1 prevented metformin-enhanced NK cell-mediated cytotoxicity. Metformin-mediated NK cell cytotoxicity was found to be AMP-activated protein kinase independent, but dependent on both mechanistic target of rapamycin and pSTAT1. CONCLUSIONS: Our data identifies a new role for metformin-mediated immune antitumorigenic function through NK cell-mediated cytotoxicity and downregulation of CXCL1 in HNSCC. These findings will inform future immunomodulating therapies in HNSCC.

Update of a prognostic survival model in head and neck squamous cell carcinoma patients treated with immune checkpoint inhibitors using an expansion cohort.

BACKGROUND: Immune checkpoint inhibitors (ICI) treatment in recurrent/metastatic (R/M) head and neck squamous cell carcinoma (HNSCC) offers new therapeutic venues. We have previously developed a predictive survival model in this patient population based on clinical parameters, and the purpose of this study was to expand the study cohort and internally validate the model. METHODS: A single institutional retrospective analysis of R/M HNSCC patients treated with ICI. Clinical parameters collected included p-16 status, hemoglobin (Hb), albumin (Alb), lactate dehydrogenase (LDH), neutrophil, lymphocyte and platelet counts. Cox proportional hazard regression was used to assess the impact of patient characteristics and clinical variables on survival. A nomogram was created using the rms package to generate individualized survival prediction. RESULTS: 201 patients were included, 47 females (23%), 154 males (77%). Median age was 61 years (IQR: 55-68). P-16 negative (66%). Median OS was 12 months (95% CI: 9.4, 14.9). Updated OS model included age, sex, absolute neutrophil count, absolute lymphocyte count, albumin, hemoglobin, LDH, and p-16 status. We stratified patients into three risk groups based on this model at the 0.33 and 0.66 quantiles. Median OS in the optimal risk group reached 23.7 months (CI: 18.5, NR), 13.8 months (CI: 11.1, 20.3) in the average risk group, and 2.3 months (CI: 1.7, 4.4) in the high-risk group. Following internal validation, the discriminatory power of the model reached a c-index of 0.72 and calibration slope of 0.79. CONCLUSIONS: Our updated nomogram could assist in the precise selection of patients for which ICI could be beneficial and cost-effective.

Current Therapy for Metastatic Head and Neck Cancer: Evidence, Opportunities, and Challenges.

Management of metastatic head and neck squamous cell carcinoma is evolving as new systemic therapies have led to improvements in survival, and as advances in locoregional therapy and the increased numbers of patients with HPV-associated cancers who develop oligometastases raise the possibility of ablation of limited numbers of metastases. We review the data regarding first-line immunotherapy in PD-L1-expressing metastatic head and neck squamous cell carcinoma, the experience with aggressive local management of oligometastases, and promising novel immunotherapies, targeted therapies, and HPV-specific treatments. For patients with metastatic head and neck squamous cell carcinoma that is PD-L1 expressing, first-line systemic therapy is pembrolizumab or pembrolizumab with chemotherapy. Inclusion of chemotherapy is associated with higher objective response proportion in all biomarker subgroups and may have a greater impact on survival in HPV-associated cancers. For patients with oligometastatic disease, particularly when metastases are metachronous, current evidence supporting the role of local ablation is limited to a small number of retrospective studies. Based on retrospective data, patients with a smaller number of metastases, lung metastases, and/or virally associated head and neck squamous cell carcinoma are most likely to benefit from an aggressive ablative approach. Additionally, we review emerging evidence for targeted therapy in metastatic head and neck squamous cell carcinoma, including with agents that inhibit mutant HRAS or NOTCH1, or overexpressed EGFR. Studies of antiangiogenic agents in combination with immune checkpoint blockade, and combination immunotherapy, are also under study.

Multi-Institutional Study Validates Safety of Intraoperative Cesium-131 Brachytherapy for Treatment of Recurrent Head and Neck Cancer.

INTRODUCTION: Surgery is the primary treatment for resectable, non-metastatic recurrent head and neck squamous cell carcinoma (HNSCC). We explore the safety and oncologic benefit of intraoperative Cesium-131 (Cs-131) brachytherapy combined with salvage local and/or regional surgical resection. METHODS AND MATERIALS: Findings were reported from a single arm multi-institutional prospective phase 1/2 trial involving surgery plus Cs-131 (surgery + Cs-131) treatment. The results of two retrospective cohorts-surgery alone and surgery plus intensity modulated radiation therapy (surgery + ReIMRT)-were also described. Included patients had recurrent HNSCC and radiation history. Safety, tumor re-occurrence, and survival were evaluated. RESULTS: Forty-nine patients were enrolled in the surgery + Cs-131 prospective study. Grade 1 to 3 adverse events (AEs) occurred in 18 patients (37%), and grade 4 AEs occurred in 2 patients. Postoperative percutaneous endoscopic gastrostomy (PEG) tubes were needed in 10 surgery + Cs-131 patients (20%), and wound and vascular complications were observed in 12 patients (24%). No cases of osteoradionecrosis were reported in the surgery + Cs-131 cohort. We found a 49% 2-year disease-free survival at the site of treatment with a substantial number of patients (31%) developing metastatic disease, which led to a 31% overall survival at 5 years. CONCLUSIONS: Among patients with local/regional recurrent HNSCC status-post radiation, surgery + Cs-131 demonstrated acceptable safety with compelling oncologic outcomes, as compared to historic control cohorts. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, identifiers NCT02794675 and NCT02467738.

Weekly vs. 3-weekly paclitaxel, carboplatin, and cetuximab (PCC) in recurrent/metastatic head and neck cancer.

The combination of paclitaxel, carboplatin and cetuximab (PCC) is efficacious in patients with recurrent/metastatic (R/M) squamous cell carcinoma of the head and neck (SCCHN). The current study assessed the incidence of grade 3/4 (G3/4) toxicity for patients receiving weekly or 3-weekly PCC for R/M SCCHN. The present single-institution, retrospective analysis included 74 patients who received weekly [paclitaxel 45 mg/m2 and carboplatin area under the curve (AUC), 1.5] or 3-weekly (paclitaxel 175 mg/m2 and carboplatin AUC, 5) PCC. For each regimen, cetuximab was administered at 400 mg/m2 for the first week, after which the dosage was reduced to 250 mg/m2 weekly until disease progression occurred. Toxicity was assessed according to the Common Terminology Criteria for Adverse Events v4.03, and response to therapy was determined using computed tomography every 12 weeks. The results revealed that 26 patients (35%) received weekly PCC and 48 patients (65%) received PCC every 3 weeks. A total of 6 (25%) patients receiving weekly PCC experienced G3/4 toxicity compared with 30 (66%) patients that received PCC every 3 weeks (odds ratio, 0.18; 95% confidence interval, 0.05-0.64; P=0.01). The most common G3/4 side effects were neutropenia (8 vs. 53%), anemia (15 vs. 32%) and fatigue (3 vs. 10%). The incidence of G3/4 toxicity or any grade toxicity requiring dose modification or discontinuation was 74 vs. 77%, respectively. The overall response rate was 39% with weekly PCC compared with 27% in those receiving PCC every 3 weeks. The 1-year progression-free and overall survival rates were 27 and 46% for patients receiving weekly PCC, and 13 and 44% for patients receiving PCC every 3 weeks. Weekly PCC had a reduced risk of G3/4 toxicity when compared with PCC administered every 3 weeks. Considering the improved tolerance of weekly PCC, this regimen should be considered for older patients and patients being treated with second-line chemotherapy.

Treatment Outcomes of Head and Neck Cancer Patients in the Elderly Receiving Different Chemoradiation Combinations: A Single-Center Experience.

OBJECTIVES: This study aimed to assess the effect of definitive or adjuvant concurrent chemoradiation (CRT) among elderly patients with locally advanced head and neck squamous cell carcinoma (LA HNSCC). MATERIALS AND METHODS: We retrospectively analyzed 150 elderly LA HNSCC patients (age ≥70) at a single institution. Demographics, disease control outcomes, and toxicities with different chemotherapy regimens were reviewed. The Kaplan-Meier method was used to estimate progression-free survival (PFS) and overall survival (OS) estimates. RESULTS: Median age at diagnosis was 74 years (range 70-88). Of the cohort, 98 (65.3%) patients received definitive and 52 (34.7%) received adjuvant CRT; 44 (29.3%) patients received weekly carboplatin and paclitaxel, 43 (28.7%) weekly cetuximab, 33 (22%) weekly carboplatin, and 30 (20%) weekly cisplatin. The OS at 2 years was 70% (95% confidence interval [CI]: 63-79%), and PFS at 2 years was 61% (95% CI: 53-70%). There was no significant difference in OS or PFS between definitive and adjuvant CRT (p = 0.867 and p = 0.475, respectively). Type of chemotherapy regimen (single-agent carboplatin vs. others) (95% CI: 1.1-3.9; p = 0.009) was a key prognostic factor in predicting OS in multivariable analysis. Concurrent use of cetuximab was associated with increased risk of PEG tube dependence at 6 months (p < 0.001). CONCLUSIONS: Management of LA HNSCC in the elderly is a challenging scenario. Our study shows that CRT is a feasible treatment modality for elderly patients with LA HNSCC. We recommend CRT with weekly cisplatin or weekly carboplatin and paclitaxel. A chemotherapy regimen should be carefully selected in this difficult to treat population.

Managing Recurrent Metastatic Head and Neck Cancer.

Head and neck squamous cell carcinoma (HNSCC) treatment is often associated with high morbidity especially in the recurrent and/or metastatic (R/M) setting, limiting effective treatment options. Local disease control is important. Therefore, local therapies including reirradiation and salvage surgery, either alone or in combination with systemic treatment, may be used for selected patients with R/M HNSCC. Although chemotherapy and targeted agents have modest efficacy in HNSCC, the advent of immunotherapy has revolutionized the treatment paradigm of R/M HNSCC. Multiple trials have resulted in the past 5 years advocating for its use alone or in combination with chemotherapy.

Identification of Clinical and Socioeconomic Predictors of Adjuvant Therapy after Trans-Oral Robotic Surgery in Patients with Oropharyngeal Squamous Cell Carcinoma.

Trans-oral robotic surgery (TORS) has emerged as an important surgical treatment option in the management of human papillomavirus (HPV)-positive and -negative oropharynx cancer. However, treatment selection is paramount to ensure that patients will not require multimodality adjuvant therapy. In this study, we determined predictors of adjuvant therapy in TORS-treated patients. The National Cancer Database (NCDB) was used to identify patients with newly diagnosed clinical T1-T4, N0-N3 oropharyngeal squamous cell carcinoma who underwent TORS between 2010-2016. Kaplan-Meier survival analysis was used to estimate overall survival (OS). A total of 2999 patients were studied, and the five-year OS for the entire cohort was 82.5%, and for HPV-positive and -negative cohorts it was 88.3% and 67.9%, respectively (p < 0.001). Among all patients treated with TORS, 35.1% of patients received no additional treatment, 33.5% received adjuvant radiation alone (RT), and 31.3% received adjuvant chemoradiation. The N stage was pathologically upstaged in 629 (20.9%) patients after TORS. Patients treated at higher-volume centers were more likely to have negative surgical margins (OR: 0.96, 95% CI: 0.94, 0.98, p < 0.001), but this did not influence the receipt of adjuvant therapy. The high rate of adjuvant multimodality treatment after TORS suggests a need for improved patient selection. Limitations of this study, including lack of data on loco-regional control, progression free survival, acute and late toxicities, and utilization of pretreatment PET/CT imaging, should be addressed in future studies.

Corrigendum to "Nivolumab and Ipilimumab in the Treatment of Metastatic Uveal Melanoma: A Single-Center Experience".

[This corrects the article DOI: 10.1155/2019/3560640.].

A review of optimal prostate biopsy: indications and techniques.

Prostate biopsy is the gold standard diagnostic technique for the detection of prostate cancer. Patient selection for prostate biopsy is complex and is influenced by emerging use of prebiopsy imaging. The introduction of the magnetic resonance imaging (MRI)-transrectal ultrasound (TRUS) fusion prostate biopsy has clear advantages over the historical standard of care. There are several biopsy techniques currently utilized with unique advantages and disadvantages. We review and summarize the current body of literature pertaining to when and how a prostate biopsy should be performed. We discuss current recommendations regarding patient selection for biopsy and discuss future directions regarding prebiopsy imaging. We offer a description of the MRI-TRUS fusion biopsy technique and a comparison of many of the currently available fusion software platforms. Articles pertaining to the title were obtained via PubMed index search with relevant keywords supplemented with personal collection of related publications. Prostate biopsy should be considered for patients with gross digital rectal exam (DRE) abnormality, patients with a prostate-specific antigen (PSA) greater than 4 ng/ml, and concomitant risk factors for prostate cancer or patients with lesions identified on multiparametric MRI (mpMRI) with Prostate Imaging Reporting and Data System 2 (PI-RADS2) score of 4 or 5. MRI-TRUS fusion biopsy has demonstrated advantages in cancer detection when compared with TRUS-guided biopsy. There are currently several fusion software platforms available with a variety of biopsy approaches. Future efforts should detail the role of prebiopsy imaging as a triage tool for prostate biopsy. Consensus should be sought regarding the preferred modality of fusion biopsy. Additional data describing each fusion software platform would enable a more rigorous comparison of platform sensitivities.

Role of Positron Emission Tomography Imaging in Metabolically Active Renal Cell Carcinoma.

PURPOSE OF REVIEW: The clinical role of fluorine-18 fluoro-2-deoxyglucose (FDG)-positron emission tomography (PET) in renal cell carcinoma (RCC) is still evolving. Use of FDG PET in RCC is currently not a standard investigation in the diagnosis and staging of RCC due to its renal excretion. This review focuses on the clinical role and current status of FDG PET and PET/CT in RCC. RECENT FINDINGS: Studies investigating the role of FDG PET in localized RCC were largely disappointing. Several studies have demonstrated that the use of hybrid imaging PET/CT is feasible in evaluating the extra-renal disease. A current review of the literature determines PET/CT to be a valuable tool both in treatment decision-making and monitoring and in predicting the survival in recurrent and metastatic RCC. PET/CT might be a viable option in the evaluation of RCC, especially recurrent and metastatic disease. PET/CT has also shown to play a role in predicting survival and monitoring therapy response.

Nivolumab and Ipilimumab in the Treatment of Metastatic Uveal Melanoma: A Single-Center Experience.

BACKGROUND: Metastatic uveal melanoma (MUM) is associated with a poor prognosis, with a median overall survival (OS) of 4-15 months. Despite new insights into the genetic and molecular background of MUM, satisfactory systemic treatment approaches are currently lacking. The study results of innovative treatment strategies are urgently needed. PATIENTS AND METHODS: This was a retrospective case series of 8 patients with MUM managed at the University of Cincinnati between January 2015 and January 2018. The immune-related Response Evaluation Criteria in Solid Tumors (irRECIST) 1.1 criteria were used for patient evaluation, and magnetic resonance imaging was used for evaluation at treatment checkpoints. OBJECTIVE: To assess the clinical outcome of patients with MUM treated with a combination of checkpoint inhibitors. RESULTS: The series included eight patients, six men and two women, with MUM. Their median age at MUM diagnosis was 69 (range, 55-77) years. All patients were treated with ipilimumab and nivolumab combination along with transarterial chemoembolization (TACE), followed by nivolumab maintenance and monthly TACE procedures. The majority of patients had a partial response or stable disease. Two of the patients had partial response, while four others had stable disease. Two other patients experienced disease progression. CONCLUSION: We report the outcomes of eight patients with MUM treated with the combination of ipilimumab and nivolumab. We report the clinical outcome and toxicity associated with this treatment approach. Further studies are warranted to explore immunotherapy in MUM. These findings support the consideration of immunotherapy in MUM.

Salvage treatment for radio-recurrent prostate cancer: a review of literature with focus on recent advancements in image-guided focal salvage therapies.

Biochemical recurrence of prostate cancer occurs in 25-33% of patients who undergo radiation therapy (RT). Unfortunately, greater than 90% of patients with radiation recurrence undergo androgen deprivation therapy (ADT), despite the detrimental side effect profile and the lack of supporting evidence for ADT use in local recurrence. In patients who experience recurrence after treatment with RT, options for treatment include salvage radical prostatectomy (SRP), salvage cryotherapy (SCT), salvage brachytherapy (SBT), and high-intensity focused ultrasound (HIFU). These salvage treatments provide recurrence-free survival in almost half of the patients with an acceptable safety profile. However, it is important to note that approximately 20-40% of radio-recurrent prostate cancers are isolated and local. Recent studies have shown salvage focal treatments to have encouraging outcomes with significantly less side effects. This article summarizes the outcomes of currently used salvage treatment options for radio-recurrent prostate cancer and focuses on recent advancements in image-guided focal salvage therapies.

High-risk pathological features at the time of salvage surgery predict poor survival after definitive therapy in patients with head and neck squamous cell carcinoma.

OBJECTIVES: Salvage surgical resection is the preferred treatment for head and neck squamous cell carcinoma (HNSCC) patients who develop locally recurrent disease after failing primary therapy. However, salvage surgical resection is not always feasible, and survival outcomes for those that do undergo salvage remain poor. It is well known that patients with adverse pathological features (extracapsular extension (ECE) of lymph nodes (LN), positive margins, perineural invasion (PNI), lymphovascular invasion (LVI), and multiple LN metastases) at the time of primary surgical resection are likely to have relatively poor outcomes. However, the impact of adverse pathological features on outcomes in the salvage setting remains controversial. MATERIALS AND METHODS: We retrospectively analyzed 73 patients at a single institution from 2008 to 2017 who developed recurrence and subsequently underwent salvage surgery (SS) after definitive curative-intent therapy including radiation. Demographic and disease control outcomes were reviewed. Kaplan-Meier curves were used to estimate relapse free survival (RFS) and overall survival (OS). RESULTS: Median age at diagnosis was 61 years (range 40-86), 49/73 (67%) were male, and 55/73 (75%) had smoked. Patients with any adverse pathological features at SS had worse RFS (HR 3.15 p = 0.0008) and worse OS (3.97 p = 0.0008). Patients who relapsed <6 months after initial therapy had worse OS (HR 2.96 p = 0.004). CONCLUSIONS: Patients with adverse pathological features at time of salvage surgery as well as those who have an early recurrence after definitive treatment and salvage surgery have worse outcomes. Prospective studies are necessary to clarify which patients should receive more intense treatment at salvage.

Systemic therapy for brain metastases.

Central nervous system metastases cause grave morbidity in patients with advanced malignancies. Lung cancer, breast cancer, and melanoma are the three most common causes of brain metastases. Although the exact incidence of brain metastases is unclear, there appears to be an increasing incidence which has been attributed to longer survival, better control of systemic disease, and better imaging modalities. Until recently surgical resection of solitary or symptomatic brain metastases, and radiation therapy (either whole-brain radiation therapy or stereotactic radiation) were the mainstay of treatment for patients with brain metastases. The majority of traditional chemotherapies have shown limited activity in the central nervous system, which has been attributed to the blood-brain barrier and the molecular structure of the used agents. The discovery of driver mutations and drugs targeting these mutations has changed the treatment landscape. Several of these targeted small-molecule tyrosine kinase inhibitors do cross the blood-brain barrier and/or have shown activity in the central nervous system. Another major advance in the care of brain metastases has been the advent of new immunotherapeutic agents, for which initial studies have shown intracranial activity. In this chapter, we will review the unique challenges in the treatment of brain metastases. The pertinent clinical studies of chemotherapy in brain metastases will be discussed. The currently reported clinical trials and evidence for use of targeted therapies and immunotherapeutic agents will be emphasized.

Longitudinal experience with WHO Grade III (anaplastic) meningiomas at a single institution.

To retrospectively analyze and assess the outcomes and prognostic factors in patients with anaplastic meningioma (AM) (WHO Grade III). Clinical data and outcome [overall (OS) and progression-free (PFS) survival] from 18 patients with Grade III meningioma (AM, based on World Health Organization 2016 definition) initially treated between March 2000 and June 2015 were analyzed. Eleven patients (61%) were male, median age at diagnosis was 63 (range 48-86), and 55% (10/18 patients) had good performance status (KPS ≥ 80). Eight patients (45%) had lower grade disease (Grade I-n = 2; Grade II-n = 6) prior to being upgraded to AM. Ten patients had fractionated radiation after primary surgery, eight patients had salvage fractionated RT, stereotactic radiosurgery (SRS) boost along with primary RT in 1 patient, and salvage SRS to 18 separate areas in 14 patients. Salvage chemotherapy was mainly considered in third or fourth recurrences. 13 (72%) patients recurred and 10 (56%) have died. Median PFS was 14.5 months (95% CI 6.9-22.2). The 5-year survival rate was 40 ± 15% and median OS was 55.8 months (95% CI 27.7-80.3). Of all factors examined, only Karnofsky performance status (KPS) affected outcome (PFS p = 0.0003; OS p = 0.0003). With median OS of 55 months (4.6 years) our results are consistent with existing reports of the poor outcomes for AM patients. From the available data, surgical resection followed by RT and salvage radiosurgery and/or chemotherapy can lead to extended survival; however the benefit may decrease with successive treatments.

A case of typhoid Fever with hepatic granulomas and enteritis.

The common histopathologic hepatic manifestations in patients infected with Salmonella include cloudy swelling and balloon degeneration with vacuolation of the hepatocytes and steatosis. Hepatic granulomas are a very rare finding, so far reported in very few cases. We report a 64-year-old patient with Salmonella enteritis who was found to have multiple 1.4 to 1.6 cm hypoechoic liver masses on ultrasound of the abdomen which on biopsy revealed hepatic granulomas. This case highlights the importance of keeping the differential diagnosis of Salmonella typhi (S. typhi) in mind in a patient with hepatic granulomas.