Causes of death and patterns of metastatic disease at the end of life for patients with advanced melanoma in the immunotherapy era.

Despite remarkable advances in immunotherapy, melanoma remains a significant cause of cancer mortality. Many factors concerning melanoma mortality are poorly understood, posing an obstacle to optimal care. We conducted a retrospective observational cohort study of 183 patients with metastatic melanoma who died following immunotherapy treatment to investigate sites of metastases at death, settings of death, and mechanisms of death. The median time from metastatic diagnosis to death was 16.1 months (range 0.3-135.1 months). Most patients experienced hospitalization within 3 months before death (80.3%), with 31.7% dying while hospitalized, 31.2% while in inpatient hospice, and 29.4% while in home hospice. The most common sites of metastases at death were distant lymph nodes (62.8%), lung (57.9%), liver (50.8%), brain (38.8%), and bone (37.7%). The most common causes of death were progressive failure to thrive (57.5%), respiratory failure (22.4%), and infection (21.8%); the vast majority (87.9%) of patients died from melanoma-specific causes. Overall, 10.9% of patients in our cohort had survival >5 years after metastatic diagnosis, and 76.2% of long-term survivors died due to melanoma. This study describes factors associated with melanoma mortality, highlighting an ongoing need for therapeutic advancements.

Subsets of IFN Signaling Predict Response to Immune Checkpoint Blockade in Patients with Melanoma.

PURPOSE: IFN signaling in the tumor microenvironment is a critical determinant of both response and resistance of cancer to immune checkpoint inhibitors (ICI). We hypothesized that distinct patterns of IFN signaling in melanoma are associated with clinical response or resistance to ICIs. EXPERIMENTAL DESIGN: Two tissue microarrays containing samples from 97 patients with metastatic melanoma who received nivolumab, pembrolizumab, or a combination of ipilimumab and nivolumab at Yale New Haven Hospital between 2011 and 2017 were randomized into discovery and validation cohorts. Samples were stained and visualized using multiplexed immunofluorescence microscopy for STAT1, STAT1 phosphorylated at Y701 (pSTAT1Y701), and PD-L1, and signals were quantified using the automated quantitative analysis method of quantitative immunofluorescence. Treatment response was assessed using RECIST, and overall survival was analyzed. For in vitro studies, human melanoma cell lines were stimulated with IFNγ and IFNß, and Western blotting was performed. RESULTS: Pretreatment STAT1 levels were higher in responders to ICIs [complete response/partial response/stable disease (SD) for > 6 months] than in nonresponders (SD < 6 months/progressive disease). Higher pretreatment STAT1 levels were associated with improved survival after ICIs in both the discovery and validation cohorts. Western blot analysis of human melanoma cell lines stimulated with IFN demonstrated distinct patterns of upregulation of STAT1 compared with pSTAT1Y701 and PD-L1. When combining STAT1 and PD-L1 markers, patients with STAT1highPD-L1low tumors had improved survival compared with those with STAT1lowPD-L1high tumors. CONCLUSIONS: STAT1 may better predict melanoma response to ICIs than current strategies, and combined STAT1 and PD-L1 biomarkers may provide insight into IFN-responsive versus IFN-resistant states.

Salvage radiotherapy for relapsed/refractory non-Hodgkin lymphoma following CD19 chimeric antigen receptor T-cell (CART) therapy.

Background and purpose: CD19-targeting chimeric antigen receptor T-cell (CART) therapy is a promising treatment for relapsed/refractory non-Hodgkin lymphoma, but most patients experience post-CART progression. We describe our institutional experience of salvage radiotherapy (SRT) in this setting. Materials and methods: Of 94 patients who received CART therapy from 2018 to 2020, 21 received SRT for post-CART progression. Patients were divided into two groups: locoregional disease (n = 9 [43 %], all disease encompassable within an RT field) and advanced disease (n = 12 [57 %]). Patterns of failure, progression-free survival (PFS), overall survival (OS), and toxicity were assessed. Results: Median time from CART infusion to SRT was 4.0 months (range, 0.6-11.5 months). In the locoregional disease group, 8/9 patients (89 %) were treated with comprehensive SRT to a median dose of 37.5 Gy in a median of 15 fractions. In the advanced disease group, all patients (n = 12) were treated with focal SRT to a median dose of 20.8 Gy in a median of 5 fractions. Median follow-up post-SRT was 15.2 months. In-field response was observed in 8/9 (89 %) in the locoregional disease and 8/9 (89 %) evaluable patients in the advanced disease groups. 17/18 evaluable patients (94 %) patients experienced post-SRT progression, all with a distant component. Median OS was 7.4 months; 21 months for locoregional disease versus 2.4 months for advanced disease (p = 0.0002). Median PFS was 1.1 month, and similarly poor regardless of group. No grade ≥ 3 toxicities occurred. Conclusions: SRT post-CART therapy appears safe with encouraging in-field response but high rates of out-of-field progression, even for those presenting with locoregional disease, highlighting the need for integration of novel systemic agents.

Dosimetric Results for Adjuvant Proton Radiation Therapy of HPV-Associated Oropharynx Cancer.

Purpose: One significant advantage of proton therapy is its ability to improve normal tissue sparing and toxicity mitigation, which is relevant in the treatment of oropharyngeal squamous cell carcinoma (OPSCC). Here, we report our institutional experience and dosimetric results with adjuvant proton radiation therapy (PRT) versus intensity-modulated radiotherapy (IMRT) for Human Papilloma Virus (HPV)-associated OPSCC. Materials and Methods: This was a retrospective, single institutional study of all patients treated with adjuvant PRT for HPV-associated OPSCC from 2015 to 2019. Each patient had a treatment-approved equivalent IMRT plan to serve as a reference. Endpoints included dosimetric outcomes to the organs at risk (OARs), local regional control (LRC), progression-free survival (PFS), and overall survival (OS). Descriptive statistics, a 2-tailed paired t test for dosimetric comparisons, and the Kaplan-Meier method for disease outcomes were used. Results: Fifty-three patients were identified. Doses delivered to OARs compared favorably for PRT versus IMRT, particularly for the pharyngeal constrictors, esophagus, larynx, oral cavity, and submandibular and parotid glands. The achieved normal tissue sparing did not negatively impact disease outcomes, with 2-year LRC, PFS, and OS of 97.0%, 90.3%, and 97.5%, respectively. Conclusion: Our study suggests that meaningful normal tissue sparing in the postoperative setting is achievable with PRT, without impacting disease outcomes.

Tubarial salivary gland sparing with proton therapy.

The recently identified bilateral macroscopic tubarial salivary glands present a potential opportunity for further toxicity mitigation for patients receiving head and neck radiotherapy. Here, we show superior dosimetric sparing of the tubarial salivary glands with proton radiation therapy (PRT) compared to intensity-modulated radiotherapy (IMRT) for patients treated postoperatively for human papillomavirus (HPV)-associated oropharyngeal squamous cell carcinoma (OPSCC). This was a retrospective, single institutional study of all patients treated with adjuvant PRT for HPV-associated OPSCC from 2015 to 2019. Each patient had a treatment-approved, equivalent IMRT plan to serve as a reference. The main end point was dose delivered to the tubarial salivary glands by modality, assessed via a 2-tailed, paired t-test. We also report disease outcomes for the entire cohort, via the Kaplan-Meier method. Sixty-four patients were identified. The mean RT dose to the tubarial salivary glands was 23.6 Gy (95% confidence interval (CI) 21.7 to 25.5) and 30.4 Gy (28.6 to 32.2) for PRT and IMRT plans (p < 0.0001), respectively. With a median follow-up of 25.2 months, the two-year locoregional control, progression-free survival and overall survival were 97.8% (95% CI 85.6% to 99.7%), 94.1% (82.8% to 98.1%) and 98.1% (87.4% to 99.7%), respectively. Our study suggests that meaningful normal tissue sparing of the recently identified tubarial salivary glands is achievable with PRT. The apparent gains with PRT did not impact disease outcomes, with only 1 observed locoregional recurrence (0 local, 1 regional). Further studies are warranted to explore the impact of the improved dosimetric sparing of the tubarial salivary glands conveyed by PRT on patient toxicity and quality of life.

Central serous chorioretinopathy associated with Adderall (dextroamphetamine-amphetamine) and topical steroid use.

Purpose: To report a case of central serous chorioretinopathy (CSC) associated with Adderall (dextroamphetamine-amphetamine) and topical steroid use. Observations: A 34-year-old man presented for evaluation of a "cloud" in his vision for three months. He was taking Adderall for attention deficit hyperactivity disorder and mometasone 0.1% topical cream for eczema. He was found to have subretinal fluid in the left eye consistent with CSC. The subretinal fluid persisted despite cessation of the steroid cream but resolved after cessation of the Adderall. The subretinal fluid returned when the patient restarted Adderall and again resolved after he stopped it for a second time. Conclusions: Though we cannot prove causality, the course of events was suggestive of a direct relationship between Adderall use and CSC in this patient, with exogenous steroid as a possible modifying factor.

Stricter Postoperative Oropharyngeal Cancer Radiation Therapy Normal Tissue Dose Constraints Are Feasible.

PURPOSE: Although dose de-escalation is one proposed strategy to mitigate long-term toxicity in human papillomavirus associated oropharyngeal cancer, applying more stringent normal tissue constraints may be a complementary approach to further reduce toxicity. Our study demonstrates that in a postoperative setting, improving upon nationally accepted constraints is achievable and leads to reductions in normal tissue complication probabilities (NTCP) without compromising disease control. METHODS AND MATERIALS: We identified 92 patients at our institution between 2015 and 2019 with p16+ oropharyngeal cancer who were treated with adjuvant volumetric modulated arc therapy. We included patients treated to postoperative doses and standard volumes (including bilateral neck). Doses delivered to organs at risk were compared with recommended dose constraints from a recent cooperative group head and neck cancer trial of radiation therapy to 60 Gy. We applied validated and published NTCP models for dysphagia, dysgeusia, esophagitis, oral mucositis, and xerostomia relevant to oropharyngeal cancer. RESULTS: Achievable and delivered mean doses to most normal head and neck tissues were well below national recommended constraints. This translates to notable absolute NTCP reductions for salivary flow (10% improvement in contralateral parotid, 35% improvement in submandibular gland), grade ≥ 2 esophagitis (23% improvement), grade ≥ 3 mucositis (17% improvement), dysgeusia (10% improvement), and dysphagia (8% improvement). Locoregional control at a median follow-up of 26.3 months was 96.7%, with only 3 patients experiencing locoregional recurrence (1 local, 2 regional). CONCLUSIONS: Modern radiation therapy planning techniques allow for improved normal tissue sparing compared with currently established dose constraints without compromising disease control. These improvements may lead to reduced toxicity in a patient population expected to have favorable long-term outcomes. Stricter constraints can be easily achieved and should be used in conjunction with other evolving efforts to mitigate toxicity.

Definitive tumor directed therapy confers a survival advantage for metachronous oligometastatic HPV-associated oropharyngeal cancer following trans-oral robotic surgery.

OBJECTIVES: To assess the prognostic significance of oligometastatic versus polymetastatic disease in human papillomavirus (HPV)-associated oropharyngeal squamous cell carcinoma (OPSCC), and to evaluate the impact of definitive tumor directed therapy on the survival outcomes for patients with oligometastatic disease when compared to systemic therapy. MATERIALS AND METHODS: This was a retrospective observational cohort study of patients with HPV-associated OPSCC who developed distant metachronous metastatic disease after undergoing initial primary surgical management from 2008 to 2017. We classified patients based on the extent of metastatic disease [Oligometastatic (≤5 metastases) and polymetastatic (>5 metastases)], and the initial treatment of metastatic disease [definitive tumor directed therapy (all metastases treated with surgery or radiotherapy) versus upfront systemic therapy]. RESULTS: Among 676 patients undergoing primary surgical management for HPV-associated OPSCC, 39 patients (5.8%) developed metastases after a median follow-up of 29.6 months (range 4.5-127.0). Of the 34 metastatic patients who met study criteria, 26 (76.5%) were oligometastatic and 8 (23.5%) were polymetastatic. Oligometastatic patients had improved median overall survival (OS) compared to polymetastatic patients (47.9 vs. 22.7 months, p = 0.036). For oligometastatic patients, definitive tumor directed therapy was associated with an improved median progression free survival (not reached vs 6.13 months, p = 0.001) and median OS (not reached vs 40.7 months, p = 0.004). CONCLUSION: In a cohort of patients surgically treated for HPV-associated OPSCC, metachronous metastatic disease was uncommon and, in most cases, considered oligometastatic. Oligometastasis portends a favorable prognosis and definitive tumor directed therapy may be associated with improved overall survival in these patients. Future multi-institutional efforts are warranted to further demonstrate the impact of definitive tumor directed therapy on disease outcomes.

Peptide Adjuvant to Invigorate Cytolytic Activity of NK Cells in an Obese Mouse Cancer Model.

Cancer patients who are overweight compared to those with normal body weight have obesity-associated alterations of natural killer (NK) cells, characterized by poor cytotoxicity, slow proliferation, and inadequate anti-cancer activity. Concomitantly, prohibitin overexpressed by cancer cells elevates glucose metabolism, rendering the tumor microenvironment (TME) more tumor-favorable, and leading to malfunction of immune cells present in the TME. These changes cause vicious cycles of tumor growth. Adoptive immunotherapy has emerged as a promising option for cancer patients; however, obesity-related alterations in the TME allow the tumor to bypass immune surveillance and to down-regulate the activity of adoptively transferred NK cells. We hypothesized that inhibiting the prohibitin signaling pathway in an obese model would reduce glucose metabolism of cancer cells, thereby changing the TME to a pro-immune microenvironment and restoring the cytolytic activity of NK cells. Priming tumor cells with an inhibitory the prohibitin-binding peptide (PBP) enhances cytokine secretion and augments the cytolytic activity of adoptively transferred NK cells. NK cells harvested from the PBP-primed tumors exhibit multiple markers associated with the effector function of active NK cells. Our findings suggest that PBP has the potential as an adjuvant to enhance the cytolytic activity of adoptively transferred NK cells in cancer patients with obesity.

The immunostimulatory RNA RN7SL1 enables CAR-T cells to enhance autonomous and endogenous immune function.

Poor tumor infiltration, development of exhaustion, and antigen insufficiency are common mechanisms that limit chimeric antigen receptor (CAR)-T cell efficacy. Delivery of pattern recognition receptor agonists is one strategy to improve immune function; however, targeting these agonists to immune cells is challenging, and off-target signaling in cancer cells can be detrimental. Here, we engineer CAR-T cells to deliver RN7SL1, an endogenous RNA that activates RIG-I/MDA5 signaling. RN7SL1 promotes expansion and effector-memory differentiation of CAR-T cells. Moreover, RN7SL1 is deployed in extracellular vesicles and selectively transferred to immune cells. Unlike other RNA agonists, transferred RN7SL1 restricts myeloid-derived suppressor cell (MDSC) development, decreases TGFB in myeloid cells, and fosters dendritic cell (DC) subsets with costimulatory features. Consequently, endogenous effector-memory and tumor-specific T cells also expand, allowing rejection of solid tumors with CAR antigen loss. Supported by improved endogenous immunity, CAR-T cells can now co-deploy peptide antigens with RN7SL1 to enhance efficacy, even when heterogenous CAR antigen tumors lack adequate neoantigens.

Low-Dose Radiotherapy Versus Moderate-Dose Radiotherapy for the Treatment of Indolent Orbital Adnexal Lymphomas.

PURPOSE: Radiation therapy (RT) with doses ranging from 24 Gray (Gy) to 40 Gy is a proven treatment modality for indolent orbital adnexal lymphoma (IOAL), but recently the use of low dose RT (LDRT, defined as 2 Gy x 2 fractions) has become a notable alternative. However, limited data exists comparing outcomes following LDRT to moderate-dose RT (MDRT, RT dose 4 - 36 Gy). We present a single institution retrospective analysis comparing outcomes of patients with IOALs following LDRT or MDRT. METHODS: A total of 36 patients treated with 38 consecutive courses of RT were identified; LDRT was delivered for 14 courses and MDRT for 24 courses. Overall response rates (ORR) were recorded according to Deauville or RECIST criteria with a response characterized as a complete response (CR) or partial response. Local control (LC), orbital control (OC), and overall survival (OS) rates were estimated with the Kaplan-Meier method. RT toxicity was graded per CTCAEv5 and compared with the Fisher's exact test. RESULTS: Median follow-up time was 29 months (m) (range, 4-129m), and median MDRT dose used was 24 Gy (range 21-36 Gy). Overall response rates (ORR) were 100% (CR 50%) and 87.5% (CR 58.3%) following LDRT and MDRT, respectively. OS at 2 years was 100% and 95% for the LDRT and MDRT groups, respectively (p=0.36). LC rates at 2 years was 100% for both LDRT and MDRT groups and at 4 years was 100% and 89% for the LDRT and MDRT groups, respectively (p=0.56). The 4-year OC rate (including both ipsilateral and contralateral relapses) was 80% and 85% for the LDRT and MDRT groups, respectively (p=0.79). No patient required treatment with RT to a previously irradiated orbit. Acute toxicities were reported following 6 LDRT courses compared to 20 MDRT courses (p=.014). No Grade 3 or higher acute toxicities occurred in either group. Late toxicities were reported following 2 LDRT courses compared to 10 MDRT courses (p=0.147). CONCLUSIONS: LDRT produced similar ORR, LC, OC, and OS rates compared to MDRT with fewer acute and minimal late toxicities reported. Future multi-center studies with larger patient numbers are warranted to show significant associations.

Autologous EBV-specific T cell treatment results in sustained responses in patients with advanced extranodal NK/T lymphoma: results of a multicenter study.

We conducted a phase II clinical trial to develop an autologous EBV-specific T cell product (baltaleucel T) for advanced, relapsed ENKTL. Among 47 patients who provided whole blood starting material for manufacturing the product, 15 patients received a median of 4 doses of baltaleucel T. Thirty-two (68%) patients did not receive baltaleucel-T due to manufacturing failure, rapid disease progression, and death. Of the 15 patients, 10 patients had measurable disease at baseline (salvage cohort), and 5 patients had no disease at baseline assessment (adjuvant cohort). In the 15 patients, the median follow-up duration was 10.2 months (range 2.0-23.5 months), median progression-free survival (PFS) was 3.9 months, and the median overall survival (OS) was not reached. Patients in the salvage cohort achieved a 30% complete response (CR) and a 50% overall response rate (ORR). In the adjuvant cohort, disease progression was reported in three patients and two patients did not relapse during study follow-up. When we compared survival outcomes of seven responders and eight non-responders, the PFS (P = 0.001) and OS (P = 0.014) of responders proved statistically superior to that of non-responders. Baltaleucel-T was well tolerated. We have performed a phase II clinical trial of autologous EBV-specific T cell treatment (baltaleucel-T) in R/R ENKTL. Autologous EBV-specific T cells were well tolerated and demonstrated single-agent activity in R/R ENTKL.

Radiation Therapy for Chemotherapy Refractory Gingival Myeloid Sarcoma.

Gingival myeloid sarcoma (MS) refractory to induction chemotherapy is a rare clinical entity and can be treated with palliative radiation therapy (RT). However, there are few previously published reports of RT approaches for the treatment of gingival MS. We present a single institution retrospective observational study of adult patients treated with palliative RT for chemotherapy refractory gingival MS. A total of six patients diagnosed with gingival MS in the setting of relapsed or refractory acute myeloid leukemia treated with palliative RT were identified, with a median age of 66 (range 52-77). Patients were treated with radiation doses ranging from 5 to 20 Gy in 2-10 fractions. Two patients had adequate follow-up time to assess treatment response. One patient who was simulated with PET/CT experienced a local complete response, while the other patient required retreatment 2 months after initial treatment and experienced an eventual local partial response. Three patients experienced radiation mucositis, with one patient experiencing grade 5 toxicity attributed to concomitant treatment with the radiosensitizer hydroxyurea. We believe that this study can provide a practical reference point for other clinicians given the rarity of gingival MS requiring palliative radiation therapy as a clinical entity.

Targeted delivery of heat shock protein 90 inhibitors prevents growth of HER2-positive tumor.

Heat shock protein 90 (HSP90) plays a crucial role in the survival of cancer cells. When an inhibitor blocks the signaling pathway of HSP90, its client proteins are degraded, destabilized, and inactivated. Although HSP90 inhibitors are in various clinical trials, there are no HSP90 inhibitor-immunoconjugates due to the difficulty in chemical modification of HSP90 inhibitors. Here we show that biological affinity binding enables the incorporation of HSP90 inhibitors to an antibody without the need for chemical conjugation. We constructed a recombinant fusion protein composed of an anti-HER2 scFv and an HSP90 inhibitor-binding domain (HER2 scFv-HBD). The HBD spontaneously captures a HSP90 inhibitor, resulting in the formation of an HER2 scFv-HBD/HSP90 inhibitor complex. In an HER2-positive cancer mouse model, targeted delivery of HSP90 inhibitors was confirmed and improved anti-cancer efficacy was observed. We have proven the promise of tumor-directed HSP90 inhibition as a new form of targeted therapy.

Definitive Local Therapy Is Associated with Improved Survival in Metastatic Soft Tissue Sarcomas.

Background: Definitive local therapy is often utilized in patients with metastatic soft tissue sarcomas (STS) to reduce morbidity associated with local tumor progression. We hypothesize that it is associated with improved overall survival (OS). Methods: Patients with newly diagnosed metastatic STS treated with chemotherapy were identified from the National Cancer Database and dichotomized into cohorts: 1. definitive local therapy (defined as either definitive dose radiotherapy, definitive surgery, or surgery with perioperative radiotherapy) or 2. conservative therapy (defined as systemic therapy with or without palliative therapy). The association between definitive local therapy and OS, and factors associated with the receipt of definitive local therapy were assessed. Results: Total of 4180 patients were identified. Compared with the conservative therapy, receipt of any definitive local therapy was associated with improved OS (median 17.9 vs. 10.1 months). The survival benefit remained on multivariate analyses and propensity-score matched analyses, with a stepwise improvement with surgery and combined modality local therapy, specifically radiotherapy (HR: 0.77; p < 0.001), surgery (HR: 0.67; p < 0.001), and combined surgery and radiotherapy (HR: 0.42; p < 0.001). Conclusions: Analysis of a large national cancer registry of patients with metastatic STS suggests that chemotherapy plus definitive local therapy is associated with a significant survival benefit compared to the standard chemotherapy alone.

A Retrospective Study of Rapid Symptom Response in Bleeding Gynecologic Malignancies With Short Course Palliative Radiation Therapy: Less is More.

CONTEXT: Advanced gynecologic malignancies can cause significant vaginal bleeding. Radiotherapy (RT) is often used to palliate symptoms, but limited data exist concerning the optimal dose and expected time to bleeding hemostasis in this population. OBJECTIVES: 1) To investigate the overall hemostasis response and kinetics of hemostasis in women with gynecologic malignancies receiving palliative RT. 2) To compare the efficacy of short-course RT (SCRT, less than or equal to five fractions, >3.5 Gy per fraction) vs. conventionally fractionated long-course regimens (greater than five fractions). METHODS: We identified women receiving palliative RT for bleeding gynecologic malignancies. Initial and maximal hemostasis responses (IHR and MHR) were recorded and categorized as progressive bleeding (PD), stable disease (SD), partial response (PR), or complete response (CR). Clinical variables were correlated with response or toxicity using binary logistic regression statistical methods. RESULTS: Thirty-three women (median age 63) were identified between 2010 and 2019. Median follow-up and survival after RT were 131 days. About 54.5% (18 of 33) received SCRT. Median time to IHR was five days (two-and-a-half days with SCRT) and 78.8% (26 of 33) responded during treatment. Median time to MHR was 13 days. About 100% achieved PR or CR at MHR. Rates of CR were similar between SCRT (83%) and conventionally fractionated schedules (87%). Average durability of hemostatic control was 5.4 months. Overall rate of rebleeding and Grade 3+ toxicity was 9.1% (3 of 33 each). CONCLUSION: Women receiving SCRT for bleeding gynecologic malignancies achieved rapid symptom control (often during treatment) with minimal rebleeding. In a population whose median survival is four months, SCRT effectively addresses symptomatic disease while minimizing patient burden and toxicity.

Cancer Epigenomics and Beyond: Advancing the Precision Oncology Paradigm.

How cancers are characterized and treated has evolved over the past few decades. Major advances in genomics tools and techniques have revealed interlinked regulatory pathways of cancers with unprecedented detail. Early discoveries led to success with rationally targeted small molecules and more recently with immunomodulatory agents, setting the stage for precision oncology. However, drug resistance to every agent has thus far proven intractable, sending us back to fill the gaps in our rudimentary knowledge of tumor biology. Epigenetics is emerging as a fundamental process in every hallmark of cancer. Large-scale interrogation of the cancer epigenome continues to reveal new mechanisms of astounding complexity. In this review, I present selected experimental and clinical examples that have shaped our understanding of cancer at the molecular level. Translation of our collective erudition into revolutionary diagnostic and treatment strategies will advance the precision oncology paradigm.

Vestibular Schwannoma Tumor Size Is Associated With Acute Vestibular Symptoms After Gamma Knife Therapy.

OBJECTIVE: To assess how pretreatment vestibular schwannoma (VS) tumor characteristics are associated with vestibular symptoms after gamma knife (GK) surgery. STUDY DESIGN: Retrospective chart review of patients undergoing GK treatment for VS at our institution from 2005 to 2018. SETTING: Academic tertiary referral center. PATIENTS: Patients receiving primary GK surgery for vestibular schwannomas with at least 6 months of follow up. Patients with neurofibromatosis 2 or previous surgery were excluded. MAIN OUTCOME MEASURES: The presence of posttreatment vestibular symptoms within 6 months after GK. Clinical records were assessed for pretreatment tumor, patient, and treatment characteristics that impacted posttreatment symptoms. RESULTS: All patients received radiation doses between 12 and 13 Gy. Of 115 patients, the average age was 60. Thirty-seven (32%) patients developed vestibular symptoms within 6 months post-GK, and 18 patients were referred for vestibular rehabilitation. Ten of 13 patients undergoing vestibular rehabilitation reported improvement. Overall, 112 patients had tumor measurements. Pretreatment tumors were significantly smaller for patients with acute vestibular symptoms (mean 1.43 cm versus 1.71 cm, p = 0.007). On multivariate analysis, smaller tumor size (p = 0.009, odds ratio [OR] = 0.29, 95% confidence interval [CI] [0.12-0.73]) was significantly associated with vestibular symptoms within 6 months of GK. Patients with tumors less than 1.6 cm were more likely to receive referrals for vestibular rehabilitation within 6 months posttreatment (25% versus 9.4%, p = 0.026, OR = 3.22, 95% CI [1.00, 11.32]). CONCLUSIONS: Smaller vestibular schwannomas were significantly associated with higher rates of post-GK vestibular symptoms. Pretreatment tumor size may be used to counsel patients on the likelihood of post-GK vestibular symptoms and vestibular rehabilitation.

Phase I and phase II clinical trials in sarcoma: Implications for drug discovery and development.

BACKGROUND: There has been limited progress in the development of novel therapeutics for the treatment of sarcomas. A review of phase I and II clinical trials for sarcomas may give insight into factors influencing sarcoma drug development. METHODS: An exhaustive analysis of phase I and II clinical trials testing drugs for human sarcoma patients between 1 January 2000 and 1 June 2018 was performed using the PubMed search engine, the Thomson Web of Science, and the National Clinical Trials registry. Recorded outcomes included tested drugs, tested histological subtypes, whether the drug was initially developed for sarcoma, reported funding sources, and whether studies led to phase III trials. RESULTS: Out of 238 studies meeting inclusion criteria, 87% (207 studies) reported funding sources. Of these, 59.9% (124/207) reported industry funding, 52.7% (109/207) reported government funding, and 27.5% (57/207) reported private funding. Only 5% (12/238) of phase I and II trials resulted in phase III trials, with 11 of 12 studies funded by industry. Approximately 90% (214/238) of studies tested drugs that were not initially tested in sarcoma, and 60.1% (143/238) of studies grouped different sarcoma histological subtypes together in the same study. CONCLUSION: Industry has funded the majority of phase I and II sarcoma clinical trials that have led to phase III trials. There was a high rate of drugs approved for other cancers and then secondarily tested in sarcoma. Most trials tended to group different sarcoma subtypes rather than studying each subtype separately.

Cell surface engineering and application in cell delivery to heart diseases.

Cell-based therapy has expanded its influence in cancer immunotherapy, regenerative medicine, and tissue engineering. Due to their secretory functions, differentiation capabilities, specific homing effects through chemotaxis, distinctive therapeutic potentials, and ex vivo expandability, cells have become an attractive reagent for advanced therapeutic strategies. Therefore, the ability to modify cells and manipulate their functions according to intended therapeutic designs has been the central scientific interest in the field of biomedical research. Many innovative methods have been developed with genetic modification of cells being the most advanced cell surface engineering technique. Although genetic modification is a powerful tool, it has a limited applicability due to the permanent modifications made on cells. Alternatively, many endeavors have been made to develop surface engineering techniques that can circumvent the limitations of genetic modification. In this review, current methods of non-genetic cell surface modification, including chemical conjugations, polymeric encapsulation, hydrophobic insertion, enzymatic and metabolic addition, will be introduced. Moreover, cell surface engineering plausible for cardiac remodeling and the future prospective will be discussed at the end.