Velopharyngeal Insufficiency Following Furlow Versus Straight Line Repair With Intravelar Veloplasty: A Single-institution Experience.

BACKGROUND: Measurements of postoperative velopharyngeal dysfunction (VPD) can be used to determine the efficacy of a palatoplasty operation. Hypernasality and audible nasal air emission are typical manifestations of VPD during speech. We aimed to longitudinally compare VPD outcomes in postpalatoplasty patients who underwent Furlow repair versus straight line repair with intravelar veloplasty (IVVP). Additionally, we examined the relationship between VPD outcomes and select pre-existing patient characteristics. METHODS: Retrospective chart review was performed to identify primary palatoplasty patients treated from April 2012 to March 2021. Variables collected included gender, syndromic status, primary language, Veau cleft type, type of speech assessment, age at time of surgery, degree of hypernasality, presence of audible nasal air emission, and overall adequacy of velopharyngeal function. Pearson χ2 test and multivariable t tests were used to analyze variables. Logistic regression was used to control for statistically significant variables. RESULTS: Of the 118 patients included, 38 received a Furlow procedure and 80 received a straight line with IVVP procedure. Audible nasal air emission was present in 57.3% of straight line with IVVP patients and 42.9% of Furlow patients, with no statistically significant difference between groups. Clinically significant hypernasality was present in 42.1% of straight line with IVVP patients and 22.9% of Furlow patients (P=0.05). Velopharyngeal function was classified as adequate in 63.5% of straight line with IVVP patients and 83.3% of Furlow patients (P=0.03). However, after stratifying by syndromic versus nonsyndromic status, there was no statistically significant difference between straight line with IVVP and Furlow patients for postoperative hypernasality and velopharyngeal function. CONCLUSIONS: This study suggests that there are no statistically significant differences between straight line with IVVP and Furlow palatoplasty techniques regarding speech outcomes including hypernasality, audible nasal air emission, and overall VP function. Furthermore, select patient characteristics such as gender, primary language, syndromic status, age at repair, and Veau cleft type do not significantly impact postoperative speech outcomes.

Vaginal Corrosion Due to Insertion of a 9-Volt Battery.

BACKGROUND: Batteries are known to cause damage to mucosal surfaces. Unfortunately, the timing of serious sequelae and recommendations for removal of a vaginally inserted battery in a premenopausal patient are not well characterized. This case report aims to detail the timeline of events and complications after vaginal insertion of a 9-volt alkaline battery and to further clarify the recommendation for urgent removal. CASE: A 24-year-old nulliparous woman with significant psychiatric and trauma history was admitted for ingestion and insertion of multiple foreign objects, including a 9-volt battery that she inserted into her vagina during her hospital admission. Examination under anesthesia was required for removal of the battery, with cervical and vaginal necrosis and partial-thickness burns noted. Removal occurred approximately 5.5 hours after insertion. Management included vaginal irrigation and topical estrogen. CONCLUSION: Given our findings of rapid and severe damage to the vaginal mucosa, urgent removal of a vaginally inserted battery is indicated.

When silence feels safer: Challenges and successes of delivering a school-based cognitive behavioral intervention to Central American unaccompanied immigrant youth.

OBJECTIVE: To explore cultural and immigration-related factors, among Central American unaccompanied immigrant youth (UIY), affecting the safety and acceptability of Cognitive Behavioral Intervention for Trauma in Schools (CBITS), a group intervention designed to treat trauma symptoms. METHOD: Thematic analysis of data from grounded theory study of group interventions to support resilience in UIY, consisting of interviews with 10 key stakeholders (5 CBITS facilitators) and 16 UIY (6 CBITS participants) from El Salvador, Guatemala, or Honduras, interviews conducted in Spanish, English, or Mam. RESULTS: Five themes emerged from interviews with CBITS facilitators and UIY: (a) Todo está bién: self-protective silence about trauma and symptom denial, (b) Chisme goes around: personal risks of disclosure, (c) marginalizing the language and world view of indigenous youth, (d) "CBITS didn't really quite land for them": adapting the curriculum and delivery, and (e) "I learn to appreciate things": benefits of the CBITS group. CBITS facilitators endorsed skill-building aspects of the groups and expressed concerns about a curriculum relying on written homework and parental support for youth with limited home country schooling, currently living with distant relatives. CBITS participants endorsed hearing about other youths' stories and learning coping skills. CONCLUSIONS: Models for group intervention that emphasize coping skill development and group support, while de-emphasizing the trauma narrative, should be explored and tested. Group intervention leaders should consider the impact of differences in gender, country of origin, and native language on group dynamics. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

Association between continued cannabis use during pregnancy and symptoms of anxiety and depression.

Cannabis use in pregnancy is common, as are mental health disorders, but the association between the two is not well established. This study is a single-site retrospective cohort. Urine testing for cannabis was evaluated at two-time points to categorize women as having never used, quit or continued to use. Edinburgh Postnatal Depression Scale (EPDS) and Generalized Anxiety Disorder (GAD) screen results were compared across groups using multinomial logistic regression. In addition, EPDS and GAD change scores between initiation of care and delivery were analyzed. 604 women were included, 221 (36.3%) with positive toxicology testing for cannabis at the initiation of care. Women who continued cannabis use were significantly more likely to have elevated GAD and EPDS scores (2.55 [1.31, 4.99]) and EPDS score (2.75 [1.43, 5.28]), respectively as compared to those with no use. No significant differences were found between groups in GAD or EPDS change scores t women with higher depression scores on the EPDS had 2.70 times the odds of being in the continuous use group compared to the quit using group (aOR = 2.70, 95% CI = [1.30, 5.88]). Both anxiety and depression symptoms were found to be associated with cannabis use and continued use during pregnancy.

Neoadjuvant PD-1 Immune Checkpoint Blockade Reverses Functional Immunodominance among Tumor Antigen-Specific T Cells.

PURPOSE: Surgical resection of primary tumor with regional lymphadenectomy remains the treatment of choice for patients with advanced human papillomavirus-negative head and neck squamous cell carcinoma. However, even when pathologic disease-free margins can be achieved, locoregional and/or distant disease relapse remains high. Perioperative immunotherapy may improve outcomes, but mechanistic data supporting the use of neoadjuvant or adjuvant treatment clinically are sparse. EXPERIMENTAL DESIGN: Two syngeneic models of oral cavity carcinoma with defined T-cell antigens were treated with programmed death receptor 1 (PD-1) mAb before or after surgical resection of primary tumors, and antigen-specific T-cell responses were explored with functional and in vivo challenge assays. RESULTS: We demonstrated that functional immunodominance developed among T cells targeting multiple independent tumor antigens. T cells specific for subdominant antigens expressed greater levels of PD-1. Neoadjuvant, but not adjuvant, PD-1 immune checkpoint blockade broke immunodominance and induced T-cell responses to dominant and subdominant antigens. Using tumors lacking the immunodominant antigen as a model of antigen escape, neoadjuvant PD-1 immune checkpoint blockade induced effector T-cell immunity against tumor cells lacking immunodominant but retaining subdominant antigen. When combined with complete surgical excision, neoadjuvant PD-1 immune checkpoint blockade led to formation of immunologic memory capable of preventing engraftment of tumors lacking the immunodominant but retaining subdominant antigen. CONCLUSIONS: Together, these results implicate PD-1 expression by T cells in the mechanism of functional immunodominance among independent T-cell clones within a progressing tumor and support the use of neoadjuvant PD-1 immune checkpoint blockade in patients with surgically resectable carcinomas.

Semaphorin4D Inhibition Improves Response to Immune-Checkpoint Blockade via Attenuation of MDSC Recruitment and Function.

Tumor infiltration by immunosuppressive myeloid cells, such as myeloid-derived suppressor cells (MDSCs), causes resistance to immunotherapy. Semaphorin4D, originally characterized for its axonal guidance properties, also contributes to endothelial cell migration and survival and modulates global immune cytokine profiles and myeloid cell polarization within the tumor microenvironment. Here, we show how a therapeutic murine Sema4D mAb improves responses to immune-checkpoint blockade (ICB) in two murine carcinoma models. Treatment of tumor-bearing mice with Sema4D mAb abrogated Ly6Ghi PMN-MDSC recruitment through reducing MAPK-dependent chemokine production by tumor cells in Murine oral cancer-1 (MOC1) tumors. PMN-MDSC suppressive capacity was reduced through inhibition of Sema4D-driven arginase expression. These changes led to enhanced tumor infiltration by CD8+ TIL and activation of tumor-draining lymph node T lymphocytes in response to tumor antigen. Sema4D mAb in combination with either CTLA-4 or PD-1 blockade enhanced rejection of tumors or tumor growth delay, resulting in prolonged survival with either treatment. This function of Sema4D mAb provides a rationale for its evaluation in combination with ICB to treat tumors with immunosuppressive myeloid infiltration.

Speech Outcomes After LeFort I Advancement Among Cleft Lip and Palate Patients.

BACKGROUND: Velopharyngeal insufficiency (VPI) results from incomplete closure of the velopharyngeal (VP) sphincter with oral pressure consonants during speech. Maxillary hypoplasia is common among cleft children and often requires LeFort I advancement. This results in anterior movement of the soft palate with the bony maxillary segment. Consequently, the size of the VP sphincter is increased and may result postoperative VPI or worsening of prior VPI. To better counsel our patients and their families of the risk of VPI after LeFort I advancement, we chose to evaluate our own cohort. METHODS: We conducted an institutional review board-approved prospective review of all cleft children presenting to Texas Children's Hospital who underwent LeFort I advancement after previous palatoplasty between 2013 and 2016 in a three-surgeon, consecutive patient series. Data collected included age, sex, ethnicity, cleft type, prior secondary speech surgery, presence of preoperative fistula, planned distance of advancement, orthognathic surgery performed, and any concurrent procedures performed. Primary outcomes measured included preoperative and postoperative VP function and hypernasality as measured by a certified speech pathologist. RESULTS: Velopharyngeal function was unchanged in 67% of our cohort after LeFort I advancement. Of those patients, 83% had evidence of VPI preoperatively, and 17% had normal speech preoperatively. Twenty-two percent of the patients displayed worsening VP function after surgery, and 6% displayed evidence of improvement. Velopharyngeal function was unable to be assessed in 6% of patients. Nasality ratings worsened in 39% of patients, were unchanged in 39%, and improved in 22%. Of the patients with incompetent VP function after surgery, 50% already received or are currently scheduled for secondary speech surgery, 25% declined secondary surgery, and 25% are pending scheduling. CONCLUSIONS: Although VP function remains unchanged in a majority of patients after LeFort I advancement, VPI should be carefully screened for after surgery. If detected, secondary operations to correct speech should be strongly considered.

WEE1 kinase inhibition reverses G2/M cell cycle checkpoint activation to sensitize cancer cells to immunotherapy.

Intrinsic resistance to cytotoxic T-lymphocyte (CTL) killing limits responses to immune activating anti-cancer therapies. Here, we established that activation of the G2/M cell cycle checkpoint results in tumor cell cycle pause and protection from granzyme B-induced cell death. This was reversed with WEE1 kinase inhibition, leading to enhanced CTL killing of antigen-positive tumor cells. Similarly, but at a later time point, cell cycle pause following TNFα exposure was reversed with WEE1 kinase inhibition, leading to CTL transmembrane TNFα-dependent induction of apoptosis and necroptosis in bystander antigen-negative tumor cells. Results were reproducible in models of oral cavity carcinoma, melanoma and colon adenocarcinoma harboring variable Tp53 genomic alterations. WEE1 kinase inhibition sensitized tumors to PD-1 mAb immune checkpoint blockade in vivo, resulting in CD8+-dependent rejection of established tumors harboring antigen-positive or mixed antigen-positive and negative tumor cells. Together, these data describe activation of the G2/M cell cycle checkpoint in response to early and late CTL products as a mechanism of resistance to CTL killing, and provide pre-clinical rationale for the clinical combination of agents that inhibit cell cycle checkpoints and activate anti-tumor immunity.

Inhibition of WEE1 kinase and cell cycle checkpoint activation sensitizes head and neck cancers to natural killer cell therapies.

BACKGROUND: Natural killer (NK) cells recognize and lyse target tumor cells in an MHC-unrestricted fashion and complement antigen- and MHC-restricted killing by T-lymphocytes. NK cells and T-lymphocytes mediate early killing of targets through a common granzyme B-dependent mechanism. Tumor cell resistance to granzyme B and how this alters NK cell killing is not clearly defined. METHODS: Tumor cell sensitivity to cultured murine KIL and human high affinity NK (haNK) cells in the presence or absence of AZD1775, a small molecule inhibitor of WEE1 kinase, was assessed via real time impedance analysis. Mechanisms of enhanced sensitivity to NK lysis were determined and in vivo validation via adoptive transfer of KIL cells into syngeneic mice was performed. RESULTS: Cultured murine KIL cells lyse murine oral cancer 2 (MOC2) cell targets more efficiently than freshly isolated peripheral murine NK cells. MOC2 sensitivity to granzyme B-dependent KIL cell lysis was enhanced by inhibition of WEE1 kinase, reversing G2/M cell cycle checkpoint activation and resulting in enhanced DNA damage and apoptosis. Treatment of MOC2 tumor-bearing wild-type C57BL/6 mice with AZD1775 and adoptively transferred KIL cells resulted in enhanced tumor growth control and survival over controls or either treatment alone. Validating these findings in human models, WEE1 kinase inhibition sensitized two human head and neck cancer cell lines to direct lysis by haNK cells. Further, WEE1 kinase inhibition sensitized these cell lines to antibody-dependent cell-mediated cytotoxicity when combined with the anti-PD-L1 IgG1 mAb Avelumab. CONCLUSIONS: Tumor cell resistance to granzyme B-induced cell death can be reversed through inhibition of WEE1 kinase as AZD1775 sensitized both murine and human head and neck cancer cells to NK lysis. These data provide the pre-clinical rationale for the combination of small molecules that reverse cell cycle checkpoint activation and NK cellular therapies.

Nanocomplex-based TP53 gene therapy promotes anti-tumor immunity through TP53- and STING-dependent mechanisms.

Loss or mutation of TP53 has been linked to alterations in anti-tumor immunity as well as dysregulation of cell cycle and apoptosis. We explored immunologic effects and mechanisms following restoration of wild-type human TP53 cDNA in murine oral cancer cells using the therapeutic nanocomplex scL-53. We demonstrated scL-53 induces dose-dependent expression of TP53 and induction of apoptosis and immunogenic cell death. We further demonstrated both TP53-dependent and independent induction of tumor cell immunogenicity through the use of blocking mAbs, nanocomplex loaded with DNA plasmid with or without TP53 cDNA, empty nanocomplex and siRNA knockdown techniques. TP53-independent immune modulation was observed following treatment with nanocomplex loaded with DNA plasmid lacking TP53 cDNA and abrogated in STING-deficient tumor cells, supporting the presence of a cytoplasmic DNA sensing, STING-dependent type-I IFN response. Cooperatively, TP53- and STING-dependent alterations sensitized tumor cells to CTL-mediated lysis, which was further enhanced following reversal of adaptive immune resistance with PD-1 mAb. In vivo, combination scL-53 and PD-1 mAb resulted in growth control or rejection of established tumors that was abrogated in mice depleted of CD8+ cells or in STING deficient mice. Cumulatively, this work demonstrates 1) a direct anti-tumor effects of functional TP53; 2) non-redundant TP53- and STING-dependent induction of tumor cell immunogenicity following scL-53 treatment; and 3) that adaptive immune resistance following scL-53 treatment can be reversed with PD-based immune checkpoint blockade, resulting in the rejection or control of syngeneic murine tumors. These data strongly support the clinical combination of scL-53 and immune checkpoint blockade.

PD-1 blockade reverses adaptive immune resistance induced by high-dose hypofractionated but not low-dose daily fractionated radiation.

Preclinical evidence suggests that high-dose hypofractionated ionizing radiation (IR) can enhance anti-tumor immunity and result in significant tumor control when combined with immune checkpoint blockade (ICB). However, low-dose daily fractioned IR used for many tumor types including head and neck squamous cell carcinoma results in lymphopenia and may be immunosuppressive. We compared immune correlates, primary tumor and abscopal tumor control rates following the addition of PD-1 mAb to either high-dose hypofractioned (8Gyx2) or low-dose daily fractionated (2Gyx10) IR in syngeneic models of cancer. When compared to 2Gyx10 IR, 8Gyx2 IR preserved peripheral and tumor-infiltrating CD8+ T-lymphocyte accumulation and activation and reduced peripheral and tumor gMDSC accumulation. Regulatory T-lymphocytes were largely unaltered. Type I and I IFN levels and expression of IFN-responsive MHC class I and PD-L1 was enhanced in tumors treated with 8Gyx2 compared to 2Gyx10 IR. Functionally, tumor-specific CD8+ T-lymphocyte IFN responses within tumor draining lymph nodes were enhanced following 8Gyx2 IR but suppressed following 2Gyx10 IR. When combined with PD-1 mAb, reversal of adaptive immune resistance and subsequent enhancement of CD8+ cell dependent primary and abscopal tumor control was observed following 8Gyx2 but not 2Gyx10 IR. These data strongly support that compared to daily fractionated low-dose IR, high-dose hypofractionated IR preserves or enhances anti-tumor immunity and, when combined with PD-1 mAb to reverse adaptive immune resistance, promotes anti-tumor immunity to control primary and distant tumors. These data critically inform the rational design of trials combining IR and ICB.

Cisplatin Alters Antitumor Immunity and Synergizes with PD-1/PD-L1 Inhibition in Head and Neck Squamous Cell Carcinoma.

Head and neck squamous cell carcinoma (HNSCC) has been treated for decades with cisplatin chemotherapy, and anti-PD-1 immunotherapy has recently been approved for the treatment of this disease. However, preclinical studies of how antitumor immunity in HNSCC is affected by cisplatin alone or in combination with immunotherapies are lacking. Here, we show that sublethal doses of cisplatin may enhance antigen presentation and T-cell killing in vitro, though cisplatin also upregulates tumor cell expression of PD-L1 and may impair T-cell function at higher doses. In a syngeneic mouse model of HNSCC, concurrent use of cisplatin and anti-PD-L1/PD-1 delayed tumor growth and enhanced survival without significantly reducing the number or function of tumor-infiltrating immune cells or increasing cisplatin-induced toxicities. These results suggest that moderate doses of cisplatin may enhance antitumor immunity by mechanisms other than direct tumor cell killing, which may be further enhanced by anti-PD-L1/PD-1 therapy. Cancer Immunol Res; 5(12); 1141-51. ©2017 AACR.

Resistance to CTLA-4 checkpoint inhibition reversed through selective elimination of granulocytic myeloid cells.

PURPOSE: Local immunosuppression remains a critical problem that limits clinically meaningful response to checkpoint inhibition in patients with head and neck cancer. Here, we assessed the impact of MDSC elimination on responses to CTLA-4 checkpoint inhibition. EXPERIMENTAL DESIGN: Murine syngeneic carcinoma immune infiltrates were characterized by flow cytometry. Granulocytic MDSCs (gMDSCs) were depleted and T-lymphocyte antigen-specific responses were measured. Tumor-bearing mice were treated with MDSC depletion and CTLA-4 checkpoint blockade. Immune signatures within the human HNSCC datasets from The Cancer Genome Atlas (TCGA) were analyzed and differentially expressed genes from sorted human peripheral MDSCs were examined. RESULTS: gMDSCs accumulated with tumor progression and correlated with depletion of effector immune cells. Selective depletion of gMDSC restored tumor and draining lymph node antigen-specific T-lymphocyte responses lost with tumor progression. A subset of T-cell inflamed tumors responded to CTLA-4 mAb alone, but the addition of gMDSC depletion induced CD8 T-lymphocyte-dependent rejection of established tumors in all treated mice that resulted in immunologic memory. MDSCs differentially expressed chemokine receptors. Analysis of the head and neck cancer TCGA cohort revealed high CTLA-4 and MDSC-related chemokine and an MDSC-rich gene expression profile with a T-cell inflamed phenotype in > 60% of patients. CXCR2 and CSF1R expression was validated on sorted peripheral blood MDSCs from HNSCC patients. CONCLUSIONS: MDSCs are a major contributor to local immunosuppression that limits responses to checkpoint inhibition in head and neck cancer. Limitation of MDSC recruitment or function represents a rational strategy to enhance responses to CTLA-4-based checkpoint inhibition in these patients.

Dose-dependent enhancement of T-lymphocyte priming and CTL lysis following ionizing radiation in an engineered model of oral cancer.

OBJECTIVES: Determine if direct tumor cell cytotoxicity, antigen release, and susceptibility to T-lymphocyte killing following radiation treatment is dose-dependent. MATERIALS AND METHODS: Mouse oral cancer cells were engineered to express full-length ovalbumin as a model antigen. Tumor antigen release with uptake and cross presentation of antigen by antigen presenting cells with subsequent priming and expansion of antigen-specific T-lymphocytes following radiation was modeled in vitro and in vivo. T-lymphocyte mediated killing was measured following radiation treatment using a novel impedance-based cytotoxicity assay. RESULTS: Radiation treatment induced dose-dependent induction of executioner caspase activity and apoptosis in MOC1 cells. In vitro modeling of antigen release and T-lymphocyte priming demonstrated enhanced proliferation of OT-1 T-lymphocytes with 8Gy treatment of MOC1ova cells compared to 2Gy. This was validated in vivo following treatment of established MOC1ova tumors and adoptive transfer of antigen-specific T-lymphocytes. Using a novel impedance-based cytotoxicity assay, 8Gy enhanced tumor cell susceptibility to T-lymphocyte killing to a greater degree than 2Gy. CONCLUSION: In the context of using clinically-relevant doses of radiation treatment as an adjuvant for immunotherapy, 8Gy is superior to 2Gy for induction of antigen-specific immune responses and enhancing tumor cell susceptibility to T-lymphocyte killing. These findings have significant implications for the design of trials combining radiation and immunotherapy.

Anti-PD-L1 Efficacy Can Be Enhanced by Inhibition of Myeloid-Derived Suppressor Cells with a Selective Inhibitor of PI3Kδ/γ.

Checkpoint inhibitors are relatively inefficacious in head and neck cancers, despite an abundance of genetic alterations and a T-cell-inflamed phenotype. One significant barrier to efficacy may be the recruitment of myeloid-derived suppressor cells (MDSC) into the tumor microenvironment. Here we demonstrate functional inhibition of MDSC with IPI-145, an inhibitor of PI3Kδ and PI3Kγ isoforms, which enhances responses to PD-L1 blockade. Combination therapy induced CD8+ T lymphocyte-dependent primary tumor growth delay and prolonged survival only in T-cell-inflamed tumor models of head and neck cancers. However, higher doses of IPI-145 reversed the observed enhancement of anti-PD-L1 efficacy due to off-target suppression of the activity of tumor-infiltrating T lymphocytes. Together, our results offer a preclinical proof of concept for the low-dose use of isoform-specific PI3Kδ/γ inhibitors to suppress MDSC to enhance responses to immune checkpoint blockade. Cancer Res; 77(10); 2607-19. ©2017 AACR.

Established T Cell-Inflamed Tumors Rejected after Adaptive Resistance Was Reversed by Combination STING Activation and PD-1 Pathway Blockade.

Patients with head and neck squamous cell carcinoma harbor T cell-inflamed and non-T cell-inflamed tumors. Despite this, only 20% of patients respond to checkpoint inhibitor immunotherapy. Lack of induction of innate immunity through pattern-recognition receptors, such as the stimulator of interferon (IFN) genes (STING) receptor, may represent a significant barrier to the development of effective antitumor immunity. Here, we demonstrate robust control of a T cell-inflamed (MOC1), but not non-T cell-inflamed (MOC2), model of head and neck cancer by activation of the STING pathway with the synthetic cyclic dinucleotide RP,RP dithio-c-di-GMP. Rejection or durable tumor control of MOC1 tumors was dependent upon a functional STING receptor and CD8 T lymphocytes. STING activation resulted in increased tumor microenvironment type 1 and type 2 IFN and greater expression of PD-1 pathway components in vivo Established MOC1 tumors were rejected and distant tumors abscopally controlled, after adaptive immune resistance had been reversed by the addition of PD-L1 mAb. These findings suggest that PD-1 pathway blockade may reverse adaptive immune resistance following cyclic dinucleotide treatment, enhancing both local and systemic antitumor immunity. Cancer Immunol Res; 4(12); 1061-71. ©2016 AACR.

The experience of adults who choose watchful waiting or active surveillance as an approach to medical treatment: a qualitative systematic review.

BACKGROUND: "Watchful waiting" or "active surveillance" is an alternative approach in the medical management of certain diseases. Most often considered appropriate as an approach to treatment for low-risk prostate cancer, it is also found in the literature in breast cancer surveillance, urinary lithiasis, lymphocytic leukemia, depression and small renal tumors. OBJECTIVES: This systematic review sought to:Identify and synthesize the best available international evidence on the experience of adults who choose watchful waiting or active surveillance as an approach to medical treatment. To this end the questions addressed in this review were:1. How do patients who have chosen watchful waiting or active surveillance describe the process of coming to the decision?2. What were the factors that influenced their decision to choose?3. How do patients who have chosen watchful waiting or active surveillance describe the experience? INCLUSION CRITERIA: Male or female patients, 18 years or older, who experience the phenomenon of choosing or not choosing watchful waiting or active surveillance as a treatment approach.The phenomena of interest were accounts of the experiences of adult patients who choose watchful waiting or active surveillance as an approach to medical treatment.This review considered studies that focused on qualitative data including, but not limited to, designs such as phenomenology, grounded theory, ethnography, action research and critical theory. Mixed method studies with narrative description and patient voice were also considered. Grey literature such as research reports and dissertations were also included. SEARCH STRATEGY: The search strategy aimed to find both published and unpublished studies through electronic databases, reference lists, and the World Wide Web. Extensive searches were undertaken of relevant databases to include CINAHL, PubMed, SCOPUS and PsycINFO. A three-step search strategy was used in each component of the review. Studies were limited to English language papers. The search considered papers from the year 2000 to January 2015. METHODOLOGICAL QUALITY: Qualitative papers selected for retrieval were assessed by two independent reviewers for methodological validity prior to inclusion in the review using the standardized critical appraisal instruments from the Joanna Briggs Institute Qualitative Assessment and Review Instrument (JBI-QARI). Any disagreements that arose between the reviewers were resolved through discussion, or with a third reviewer. DATA EXTRACTION: Qualitative data were extracted from papers included in the review using the standardized data extraction tool from. The data extracted included specific details about the phenomena of interest that described the experiences pertinent to the review questions DATA SYNTHESIS: The data were synthesized using the Joanna Briggs Institute approach to meta-synthesis by meta-aggregation using the JBI-QARI software and methods. RESULTS: A total of 16 studies, critically appraised by two independent reviewers and deemed to be of high quality, were included in the final review. One study was excluded after appraisal. One hundred and fifty-five findings from the 16 studies were extracted into 10 categories and then into three synthesized findings. The synthesized findings explicated: CONCLUSIONS: The synthesized findings of the review conclude that the process of making the decision to choose watchful waiting is complex. Through the process patients and their significant others experience an array of emotions that often lead to uncertainty and anxiety. Once the decision is made patients must cope with the knowledge that they have a troubling diagnosis and make the necessary adjustments. An empathic, reassuring relationship with a healthcare practitioner eases the burden of this process.Healthcare providers need to recognize that not all patients are "at peace" with the decision of choosing watchful waiting. Uncertainty and fear may intensify during this time as well as feelings of stress and anxiety. Patients and their significant others often attempt to adapt in the best way they know how but the effectiveness of their coping strategies needs to be assessed. In addition, healthcare providers need to also be aware that with the increased anxiety and stress associated with watchful waiting, patients' understanding of healthcare information and the ability to ask questions may be diminished. Both providers and patients benefit from open discussions related to the many aspects of uncertainty and fear related to making and living with the decision. Employing a shared decision making model with regard to the management of the array of issues that comes from both making the decision and living with it is recommended. It appears that patients are very sensitive to recognizing when the care they are receiving lacks empathy. Communication that is open, empathic, and non-judgmental is essential. A willingness to discuss sensitive issues such as sexual function needs to be conveyed. Lastly, providers and their staff need to remain attentive to the importance of articulating aspects of the situation that are hopeful and optimistic as many patients, during their visits, take their cues regarding their health status from non-verbal and verbal interactions.Future studies should investigate.

Enhanced Tumor Control with Combination mTOR and PD-L1 Inhibition in Syngeneic Oral Cavity Cancers.

Significant subsets of patients with oral cancer fail to respond to single-agent programmed death (PD) blockade. Syngeneic models of oral cancer were used to determine if blocking oncogenic signaling improved in vivo responses to PD-L1 monoclonal antibody (mAb). Anti-PD-L1 enhanced durable primary tumor control and survival when combined with mTOR (rapamycin), but not in combination with MEK inhibition (PD901) in immunogenic MOC1 tumors. Conversely, PD-L1 mAb did not enhance tumor control in poorly immunogenic MOC2 tumors. Rapamycin enhanced expansion of peripheral antigen-specific CD8 T cells and IFNγ production following ex vivo antigen stimulation. More CD8 T cells infiltrated and were activated after PD-L1 mAb treatment in mice with immunogenic MOC1 tumors, which were stable or increased by the addition of rapamycin, but suppressed when PD901 was added. Rapamycin increased IFNγ production capacity in peripheral and tumor-infiltrating CD8 T cells. In vivo antibody depletion revealed a CD8 T-cell-dependent, and not NK cell-dependent mechanism of tumor growth inhibition after treatment with rapamycin and PD-L1 mAb, ruling out significant effects from NK cell-mediated antibody-dependent cellular cytotoxicity. Rapamycin also enhanced IFNγ or PD-L1 mAb treatment-associated induction of MHC class I expression on MOC1 tumor cells, an effect abrogated by depleting infiltrating CD8 T cells from the tumor microenvironment. These data conflict with traditional views of rapamycin as a universal immunosuppressant, and when combined with evidence of enhanced antitumor activity with the combination of rapamycin and PD-L1 mAb, suggest that this treatment combination deserves careful evaluation in the clinical setting. Cancer Immunol Res; 4(7); 611-20. ©2016 AACR.

mTOR and MEK1/2 inhibition differentially modulate tumor growth and the immune microenvironment in syngeneic models of oral cavity cancer.

We investigated the effects of mTOR and MEK1/2 inhibition on tumor growth and the tumor microenvironment in immunogenic and poorly immunogenic models of murine oral cancer. In vitro, rapamycin and PD901 inhibited signaling through expected downstream targets, but only PD901 reduced viability and altered function of MOC cells. Following transplantation of MOC cells into immune-competent mice, effects on both cancer and infiltrating immune cells were characterized following rapamycin and/or PD901 treatment for 21 days. In vivo, both rapamycin and PD901 inhibition reduced primary growth of established MOC tumors on treatment. Following withdrawal of PD901, rapid rebound of tumor growth limited survival, whereas durable tumor control was observed following rapamycin treatment in immunogenic MOC1 tumors despite more robust inhibition of oncogenic signaling by PD901. Characterization of the immune microenvironment revealed diminished infiltration and activation of antigen-specific CD8+ T-cells and other immune cells following PD901 but not rapamycin in immunogenic tumors. Subsequent in vitro T-cell assays validated robust inhibition of T-cell expansion and activation following MEK inhibition compared to mTOR inhibition. CD8 cell depletion abrogated rapamycin-induced primary tumor growth inhibition in MOC1 mice. These data have critical implications in the design of combination targeted and immune therapies in oral cancer.