Raman hyperspectroscopy of saliva and machine learning for Sjögren's disease diagnostics.

Sjögren's disease is an autoimmune disorder affecting exocrine glands, causing dry eyes and mouth and other morbidities. Polypharmacy or a history of radiation to the head and neck can also lead to dry mouth. Sjogren's disease is often underdiagnosed due to its non-specific symptoms, limited awareness among healthcare professionals, and the complexity of diagnostic criteria, limiting the ability to provide therapy early. Current diagnostic methods suffer from limitations including the variation in individuals, the absence of a single diagnostic marker, and the low sensitivity and specificity, high cost, complexity, and invasiveness of current procedures. Here we utilized Raman hyperspectroscopy combined with machine learning to develop a novel screening test for Sjögren's disease. The method effectively distinguished Sjögren's disease patients from healthy controls and radiation patients. This technique shows potential for development of a single non-invasive, efficient, rapid, and inexpensive medical screening test for Sjögren's disease using a Raman hyper-spectral signature.

Acute Onset of Delayed Facial Nerve Paralysis After an Uncomplicated Total Parotidectomy for an Oncocytoma.

Facial nerve injury is one of the most substantial potential sequelae of parotid surgery. Pulling, stretching, and otherwise disturbing the facial nerve during parotid surgery can lead to post-surgical neural paresis and consequential deficits in facial movement. Furthermore, transection of the main facial nerve trunk or its branches, either purposeful or incidental, can lead to complete paralysis of the related facial musculature. Facial nerve injury is often diagnosed immediately post-operatively as evident by deficits in ipsilateral facial motion on examination of the patient in the recovery unit or, at most, by one week post-operatively. Although delayed onset facial nerve paralysis is seen in traumatic injury and otologic surgery, it is uncommon that facial nerve paralysis presents late after parotid surgery in the absence of hematoma development, viral reactivation, or secondary insult. Here, we present the case of a 70-year-old man developing a delayed acute onset of hemi-facial paralysis 12 days after right-sided total parotidectomy for an oncocytoma; a facial nerve examination done immediately post-operatively and at the one-week post-operative follow-up was found to be normal. The patient was treated with two courses of high-dose oral steroids with close-to-complete resolution.

Medical student otolaryngology research: Involvement, perceptions, motivations.

OBJECTIVE: Otolaryngology is a competitive specialty that emphasizes research. This study explored medical student involvement in otolaryngology research including training, productivity, perceptions and career goals. STUDY DESIGN: Cross-sectional survey. METHODS: A 27 question multiple choice survey was generated using Qualtrics and posted on an otolaryngology forum (Otomatch) from 10/09/2022 to 12/11/2022. RESULTS: Thirty fourth year medical students (MS4) applying to U.S. otolaryngology residency programs responded. Nearly all (26/30 = 86.7 %) believe there should be dedicated time to research in medical school. MS4 produced an average of 3.23 otolaryngology papers (± 3.13), 5.23 poster presentations (± 9.22) and 2.50 oral presentations (± 5.06). MS4 feel it is more important for physicians to read (mean 4.47 on a 5-point scale; ± 0.76) than to conduct research (3.03 ± 0.87) or to emphasize it in evaluating residency applicants (2.79 ± 0.96). Seventeen respondents (17/30 = 56.7 %) lack interest in continuing research after medical school. Twenty-eight MS4 were evenly split (14/30 = 46.7 %) between a research-heavy or traditional residency. Students felt pressure to publish in low-impact journals (3.93 ± 0.94) for career advancement. CONCLUSION: All respondents were involved in research yet the majority (16/30 = 53.3 %) eschew a research-heavy residency. Using research to evaluate success entices involvement for some who may not be interested. Pressure to publish may exacerbate ethical issues like inaccurately assigned authorship and deceptive reporting of publications. A decreased emphasis on research will enable students truly interested to continue without pressure to publish, leading to a potential increase in generalizable studies.

Oropharyngeal Secondary Syphilis Mimicking Metastatic Lymphoma in an HIV-Positive Patient.

Syphilis is a bacterial infection commonly transmitted by sexual contact. It has variable manifestations and can mimic other disease processes or infections. This report presents the case of a 48-year-old HIV-positive male who was referred to our head and neck clinic with complaints of tonsillar hypertrophy and ulceration accompanied by a one-month history of ipsilateral cervical lymphadenopathy and facial pain in the setting of recent unexplained weight loss and abnormal radiographic imaging of the neck. In-office tonsillar biopsy and fine-needle aspiration of a neck mass revealed a non-diagnostic atypical lymphoid proliferation. Surgical pathology following an open biopsy in the operating room showed Treponema pallidum infection, which was diagnostic for secondary syphilis.

Oral Tongue Spontaneous Tumor Regression after Biopsy: A Case Report and Genomic Profile.

Spontaneous regression of a neoplasm is a rare oncologic phenomenon. Certain neoplasms, such as melanomas and neuroblastomas, display this phenomenon. To date, spontaneous regression of oral cavity squamous cell carcinomas has been documented in only a handful of case reports. We present a novel case of spontaneous regression of an oral tongue squamous cell carcinoma following biopsy. We discuss the tumor's unique genetic profile, immune response to cancer, and review the literature on possible mechanisms of spontaneous regression. Small-volume persistent cancer in our patient reinforces that tissue confirmation remains crucial to avoid missing remaining tumor. Further investigation is required to understand mechanisms of spontaneous regression and how these may be exploited to improve head and neck squamous cell carcinoma treatment.

Marsupialization of a Floor-of-Mouth Dermoid Cyst to Temporize Airway Distress.

Dermoid cysts are benign masses of embryologic origin that can present in various anatomical locations throughout the human body. This article presents the case of a 30-year-old male who presented to our emergency department with complaints of tongue swelling accompanied by worsening dysphagia and dysphonia in the context of a chronic, midline mass in the floor of the mouth. Computed tomography (CT) imaging and surgical pathology of the mass ultimately revealed findings consistent with a dermoid cyst causing inferior displacement of the mylohyoid muscle. Initial management consisted of bedside drainage to temporize the airway, with marsupialization and in-office follow-up. Definitive treatment was achieved with surgical excision at a later date.

A SEER database study of malignant teratomas in the head and neck region.

OBJECTIVE: To review tumor and patient characteristics as well as survival of pediatric head and neck malignant teratomas (HNMT) in comparison to the adult population. DESIGN: This investigation was a retrospective cohort study. The Surveillance, Epidemiology, and End Results (SEER) database (SEER-18 Regs Custom registry, November 2018) was reviewed for all cases of head and neck malignant teratomas from 1975 to 2016. A log rank test was used to compare survival between infant, pediatric, and adult HNMT, and between head and neck and non-head and neck malignant teratomas. Infant, pediatric, and adult patients were defined as younger than one year old, younger than 18 years old, and older than 18 years old, respectively. RESULTS: Sixty-three malignant teratoma cases (1.96%) occurred in the head and neck region from 1975 to 2016, including 11 adult (17.46%) and 52 (82.54%) pediatric patients. 79.37% (50 patients) were diagnosed during infancy. The most common location was the soft tissue of the head and neck in pediatric patients (65.38%) and the thyroid gland in adults (54.54%). The 5-year survival was 45.83% (±7.19%) in infants and 46.00% (±7.05%) in pediatric patients. There were differences in 1-year and 5-year survival between pediatric HNMT and non-head and neck malignant teratomas, (76.01% versus 86.20%) (p = 0.022) and (46.00% versus 67.10%) (p < 0.001), respectively. There was no difference in 1-year and 5-year survival between pediatric patients and adults with HNMT, (76.01% versus 81.81%) (p = 0.618) and (46.00% versus 54.54%) (p = 0.560), respectively. CONCLUSION: HNMT occurred most frequently in patients under the age of 1. Prognosis of pediatric HNMT is poor in comparison to pediatric non-head and neck malignant teratomas. Repeat studies after accumulating more patients in the database would be beneficial to confirm our findings.

Development of video otoscopy quiz using a smartphone adaptable otoscope.

BACKGROUND: Otoscopy examination can be challenging. Traditional teaching uses still image illustrations. Newer attempts use video samples to simulate the otoscopy exam which is a dynamic process.Aims/Objective: To assess whether recorded otoscopy videos from a smartphone adaptable otoscope can be used to develop a video-based otoscopy quiz which may be used for instructing and familiarizing participants to normal anatomy and pathologic ear conditions. To use this quiz to assess current pediatric residents' competency of common otoscopy diagnosis. METHOD AND MATERIALS: This study was conducted in 2018. Video samples of ear pathology were collected at the Albany Medical Center using a smartphone adaptable otoscope- Cellscope. The videos were used to create a video otoscopy quiz (VOQ) without clinical vignettes. 45 pediatric residents from 3 academic institutions were evaluated with the quiz. RESULTS: The weighted mean for the VOQ was 66.90% (95%CI 58.89%-68.42%). The breakdown by questions are: myringosclerosis 72.88%, retraction pocket 80.65%, cholesteatoma 42.22%, hemotympanum 75.04%, tympanic membrane perforation 79.62%, cerumen impaction 95.46%, otitis externa 52.54%, otitis media with effusion 63.30%, acute otitis media 75.55%, normal ear 36.39%. CONCLUSION: We found that videos of otoscopy exams can be obtained with a smartphone adaptable otoscope and validated to develop a video-based quiz, which may be used to supplement otoscopic instruction. Following our testing process, we found pediatric residents are relatively well equipped to identify ear pathology on VOQ.

Associations of insurance, urbanity, and comorbidity with types of palliative care received by patients with head and neck cancer.

BACKGROUND: Our study examined some of the social and medical factors associated with receiving pain palliation alone over more aggressive cytoreductive palliative measures, such as surgery, chemotherapy, or radiation among patients with head and neck cancer. METHODS: This retrospective study used the National Cancer Database 2016 for data analysis. Patient and tumor characteristics were examined using bivariate analysis and logistic regression to identify their association with receiving pain palliation alone versus cytoreductive palliation treatment. RESULTS: Using multivariate logistic regression analysis, insurance status (odds ratio [OR]: 0.27, 95% confidence interval [CI]: 0.15-0.50, p < 0.001), urbanity (OR: 1.73, 95%CI: 1.21-2.46, p = 0.002), and Charlson-Deyo scores greater than 3 (OR: 2.49, 95%CI: 1.38-4.47, p = 0.002) were significantly associated with receipt of pain palliation alone. CONCLUSIONS: Clinicians should be aware of non-health-related factors, such as insurance status, that may influence patients' receipt of treatments in head and neck cancer.

Association of Surrogate Objective Measures With Work Relative Value Units.

Background: The determination of accurate measures of evaluating surgeon work for reimbursement is poorly characterized. This study defines the correlation of surgical work relative value units (work RVUs) with several surrogate objective measures for otolaryngologic work. The defined surrogate objective measures evaluated in this study are length of hospital stay (LOS), operative time, 30-day mortality, 30-day unplanned readmission, 30-day reoperation, and 30-day morbidity. Methods: We collected data on otolaryngologic cases from 2016 to 2018 from the American College of Surgeons National Surgical Quality Improvement Program. Pearson correlation coefficient was used to associate work RVUs with objective measures of surgeon work. Linear regressions were used to identify predictors of work RVUs from the surrogate objective measures. Studentized residuals were used to identify outlying procedures. Results: Work RVUs correlated strongly with operative time (R=0.6775), 30-day readmission (R=0.6100), and LOS (R=0.6083); moderately with 30-day reoperation (R=0.5257) and 30-day morbidity (R=0.4842); and very weakly with 30-day mortality (R=0.1383). The best predictors for work RVUs based on multivariable linear regression analysis were morbidity, reoperation, and operative time. Analysis revealed that the projected work RVU is 12.23 units higher than the current value for excision of bone, mandible (Current Procedural Terminology [CPT] code 21025) and 19.48 units lower than the current value for resection/excision of lesion infratemporal fossa space apex extradural (CPT code 61605). Conclusion: Using objective surrogate measures for time and intensity of physician work in head and neck cases may improve work RVU assignment accuracy compared to the current system of physician survey. Future investigation with additional objective parameters may be beneficial to make work RVU assignments less subjective.

Trends in head and neck fellowship graduates in the United States from 1997 to 2017.

BACKGROUND: We investigated whether the supply of head and neck fellowship graduates matches head and neck cancer trends. METHODS: Graduates between 1997 and 2017 from the American Head and Neck Society (AHNS) and United States Otolaryngology fellowship program webpages were identified. Trends in graduates were compared with head and neck cancer incidence obtained from the Center of Disease Control. RESULTS: Of 538 fellows, 428 were from the United States. Of fellows practicing in the United States, 24.14% were female. Most practice locations were urban (98.44%). AHNS fellowship positions from 1997 to 2017 increased by nearly 1.82 per year (P < .00001). Graduates in academic positions increased by 1.03 per year (P < .00001). Concomitantly, the age-adjusted incidence rate of oral, oropharyngeal, and laryngeal cancers decreased (P = .0115). CONCLUSION: There is important geographic variability in the practice locations of Head and Neck Oncologic Surgeons in the United States and our data may be helpful in matching clinical supply and demand.

CO2 Laser for De-epithelialization in Tympanoplasty.

Tympanoplasty repairs tympanic membrane perforations but also covers an umbrella of procedures characterized by surgery of the mastoid bone. Tympanoplasty is widely regarded as a beneficial procedure with an over 90% graft closure success rate and an over 80% return to normal hearing range. Though surgical technique and graft type are important in determining surgical outcomes of the procedure, results are most greatly correlated with location of the perforation. Marginal perforations are associated with the most complications in reconstruction of the tympanic membrane, lack of vascularization and limited membrane area delaying the healing process (4). Lasers have been used in medical procedures dating back to the 1960s. The advantage of infrared lasers such as CO2 are the precision of cutting and the smooth interaction with tissues (5). The CO2 laser is absorbed by the tympanic membrane and does not damage the middle ear while visible lasers penetrate and can damage the ear drum (6). This retrospective study of 150 patients from 2013-2016 assesses and demonstrates the viability of using carbon dioxide laser as an alternative to the traditional method for de-epithelialization of tympanic perforation margins during tympanoplasty. By comparing closure rates and audiogram data, this study reveals parameters of use, benefits and adverse outcomes on healing and hearing restoration with the CO2 laser-assisted method. Perforation closure rate of 91% and hearing improvement in 66% of patients was observed. Fourteen patients did not undergo closure of the tympanic membrane with an overwhelming majority of the 14 having large and marginal perforations.

Use of Superelastic Nitinol and Highly-Stretchable Latex to Develop a Tongue Prosthetic Assist Device and Facilitate Swallowing for Dysphagia Patients.

We introduce a new tongue prosthetic assist device (TPAD), which shows the first prosthetic application for potential treatment of swallowing difficulty in dysphagia patients. The native tongue has a number of complex movements that are not feasible to mimic using a single mechanical prosthetic device. In order to overcome this challenge, our device has three key features, including (1) a superelastic nitinol structure that transfers the force produced by the jaws during chewing towards the palate, (2) angled composite tubes for guiding the nitinol strips smoothly during the motion, and (3) highly stretchable thin polymeric membrane as a covering sheet in order to secure the food and fluids on top of the TPAD for easy swallowing. A set of mechanical experiments has optimized the size and angle of the guiding tubes for the TPAD. The low-profile TPAD was successfully placed in a cadaver model and its mobility effectively provided a simplistic mimic of the native tongue elevation function by applying vertical chewing motions. This is the first demonstration of a new oral device powered by the jaw motions in order to create a bulge in the middle of the mouth mimicking native tongue behavior.

Intranasal Acetaminophen Abuse and Nasal, Pharyngeal, and Laryngotracheal Damage.

A young adult female originally presented with necrosis of the nasal cavity mucosa and septum after sniffing crushed acetaminophen. She underwent endoscopic sinus surgery and debridement but continued to use acetaminophen intranasally. Four months later, the destruction had extended to include the posterior pharyngeal wall and subglottis. The diagnosis was confirmed by polarizable talc found on biopsy of the subglottis. While nasal insufflation of cocaine and hydrocodone-acetaminophen has been well-documented, intranasal abuse of exclusively acetaminophen is not well understood. This case demonstrates the destructive potential of intranasal acetaminophen use and may help physicians recognize unusual signs and symptoms of intranasal drug abuse.

Ethnic differences in platysmal perforators and its relevance for the platysma myocutaneous flap.

BACKGROUND: Variable flap loss rates for the platysma myocutaneous flap have been reported for the Caucasian and the Asian population, which are 10.1% and 1.6%, respectively. This study was designed to investigate ethnic differences in the number and location of platysmal perforators that influence flap survival rates. METHODS: The number and location of platysmal perforators were investigated in a total of 60 platysma muscles: bilaterally in 20 Caucasian (13 males and 7 females) and 10 Asian (5 males and 5 females) specimens using cadaveric dissections. Adjustment for inter-individual variability in platysma length and width was performed by standardizing each x-value to mandibular length and each y-value to mandibulo-clavicular distance. RESULTS: A total of 64% of all detected platysmal perforators were found in the medial half of the muscle following the pathway of the external carotid artery. Individuals of Caucasian ethnicity had a mean number of 7.60 ± 2.0 perforators per side, whereas individuals of Asian ethnicity had a mean number of 13.05 ± 1.76 perforators per side (p < 0.001). Individuals of Asian ethnicity had a statistically significant increased number of platysmal perforators in the medial middle (2.95 ± 1.05 vs. 1.60 ± 1.08; p < 0.001) and lower (1.60 ± 1.35 vs. 0.73 ± 0.85; p = 0.003) regions of the platysma compared to those of Caucasian individuals. CONCLUSION: A significantly higher number of platysmal perforators were identified in the investigated Asian population. This provides a potential explanatory model for the reported lower platysma myocutaneous flap loss rates in the Asian population than in the Caucasian population.

Tumor-infiltrating Tim-3+ T cells proliferate avidly except when PD-1 is co-expressed: Evidence for intracellular cross talk.

Programmed Death 1 (PD-1) and T cell Ig and mucin domain-3 protein (Tim-3) are immune checkpoint receptors highly expressed on tumor infiltrating T lymphocytes (TIL). PD-1 inhibits T cell activation and type-1 T cell responses, while Tim-3 is proposed to mark more extensively exhausted cells, although the mechanisms underlying Tim-3 function are not clear. Trials of anti-PD-1 therapy have identified a large subset of non-responder patients, likely due to expression of alternative checkpoint molecules like Tim-3. We investigated the phenotypic and functional characteristics of T cells with differential expression of PD-1 (high/low) and Tim-3 (positive/negative), using TIL directly isolated from head and neck squamous cell carcinomas (HNSCC). Unexpectedly, we found that expression of Tim-3 alone does not necessarily mark TIL as dysfunctional/exhausted. In Tim-3-TIL, PD-1 levels correlate with T cell dysfunction, with a PD-1low/intermed phenotype identifying recently activated and still functional cells, whereas PD-1hiTim-3- T cells are actually exhausted. Nonetheless, PD-1intermed cells are still potently suppressed by PD-L1. PD-1 expression was associated with reduced phosphorylation of ribosomal protein S6 (pS6), whereas Tim-3 expression was associated with increased pS6. Using a novel mouse model for inducible Tim-3 expression, we confirmed that expression of Tim-3 does not necessarily render T cells refractory to further activation. These results suggest the existence of PD-1 and Tim-3 crosstalk in regulating antitumor T cell responses, with important implications for anti-PD-1 immunotherapy.

Utility of up-front transoral robotic surgery in tailoring adjuvant therapy.

BACKGROUND: The purpose of this study was to describe how the up-front transoral robotic surgery (TORS) approach could be used to individually tailor adjuvant therapy based on surgical pathology. METHODS: Between January 2009 and December 2013, 76 patients received TORS for oropharyngeal squamous cell carcinoma (OPSCC). Clinical predictors of adjuvant therapy were analyzed and comparisons were made between recommended treatment guidelines for up-front surgery versus definitive nonsurgical approaches. RESULTS: Advanced N classification, human papillomavirus (HPV)-positive tumor, extracapsular spread (ECS; 26 of 76), perineural invasion (PNI; 14 of 76), and positive margins (7 of 76) were significant predictors of adjuvant chemoradiotherapy (CRT) (p < .05). Up-front TORS deintensified adjuvant therapy; 76% of stage I/II and 46% of stage III/IV patients avoided CRT. Conversely, pathologic staging resulted in 33% of patients who would have received radiotherapy (RT) alone based on clinical staging, to be intensified to receive adjuvant CRT. CONCLUSION: The TORS approach deintensifies adjuvant therapy and provides valuable pathologic information to intensify treatment in select patients. TORS may be less effective in deintensification of adjuvant therapy in patients with clinically advanced N classification disease. © 2016 Wiley Periodicals, Inc. Head Neck 38:1201-1207, 2016.

Selection of Ideal Candidates for Surgical Salvage of Head and Neck Squamous Cell Carcinoma: Effect of the Charlson-Age Comorbidity Index and Oncologic Characteristics on 1-Year Survival and Hospital Course.

IMPORTANCE: Salvage surgery for recurrent head and neck squamous cell carcinoma (HNSCC) carries substantial risks of morbidity and mortality. Risk factors for death within 1 year should be better defined. OBJECTIVES: To report preoperative oncologic prognostic factors predictive of short-term (<1 year) survival after salvage surgery in patients with HNSCC, to assess whether preoperative age and comorbidity predicts 1-year mortality, and to report hospital courses after salvage surgery within 1 year. DESIGN, SETTING, AND PARTICIPANTS: A retrospective medical record review of 191 patients with recurrent HNSCC treated with salvage surgery from January 1, 2003, through December 31, 2013, at a tertiary academic center. INTERVENTIONS: Surgical salvage of HNSCC (larynx, oral cavity, oropharynx, or hypopharynx) with curative intent. MAIN OUTCOMES AND MEASURES: Primary outcome was survival 1 year after salvage surgery. Secondary outcomes were length of inpatient hospital stay, days of admissions, and skilled nursing facility disposition within 1 year stratified by survival status. Presalvage Charlson-Age Comorbidity Index (CACI) was calculated. Associations among CACI, oncologic risk factors, and risk of death within 1 year after salvage surgery are investigated using multivariable analysis. RESULTS: Of 191 patients studied, 53 (27.7%) died within 1 year after salvage surgery. Patients who died within 1 year had more total inpatient admissions (P < .001), longer total length of stay (P < .001), and higher risk of discharge to a skilled nursing facility (P < .001) and spent 17.3% (interquartile range, 5.2-36.3) of their remaining days in the hospital. Independent risk factors for death within 1 year are CACI (relative risk [RR], 1.43; 95% CI, 1.16-1.76), primary T3 or T4 stage (RR, 2.34; 95% CI, 1.27-4.31), and disease-free interval of less than 6 months (RR, 5.61; 95% CI, 1.78-16.7). CONCLUSIONS AND RELEVANCE: Medical comorbidity and age as measured by the CACI, primary T3 or T4 stage, and short disease-free interval must be considered in selecting patients ideal for surgical salvage surgery for recurrent HNSCC. Patients with these risk factors should be more strongly considered for palliative measures.

Myeloid-Derived Suppressor Cells as an Immune Parameter in Patients with Concurrent Sunitinib and Stereotactic Body Radiotherapy.

PURPOSE: The clinical effects of sunitinib on human myeloid-derived suppressor cell (MDSC) subsets and correlation of the T-cell-mediated immune responses and clinical outcomes in patients with oligometastases treated by stereotactic body radiotherapy (SBRT) have been evaluated. EXPERIMENTAL DESIGN: The numbers of granulocytic and monocytic MDSC subsets, effector T cells, and regulatory T cells in the peripheral blood were evaluated pre- and post-sunitinib treatment and concurrent with SBRT. Correlations between MDSC, Treg, and T-cell responses and clinical outcomes were analyzed. RESULTS: Patients with oligometastases of various cancer types had elevated granulocytic MDSC and certain subsets of monocytic MDSC population. Sunitinib treatment resulted in a significant reduction in monocytic MDSC, phosphorylated STAT3, and arginase levels in monocytic MDSC (CD33(+)CD14(+)CD16(+)), and an increase in T-cell proliferative activity in cancer patients. Interestingly, the effects of sunitinib on reducing the accumulation and immune-suppressive function of MDSC were significantly correlated with Treg reduction, in responders but not in nonresponding patients. SBRT synergized the therapeutic effects of sunitinib, especially as related to decreased numbers of monocytic MDSC, Treg, and B cells, and augmented Tbet expression in primary CD4 and CD8 T cells. These effects were not observed in patients receiving radiation therapy alone. Most interestingly, the responders, defined by sunitinib-mediated reduction in CD33(+)CD11b(+) myeloid cell populations, tend to exhibit improved progression-free survival and cause-specific survival. CONCLUSIONS: Sunitinib treatment increased the efficacy of SBRT in patients with oligometastases by reversing MDSC and Treg-mediated immune suppression and may enhance cancer immune therapy to prevent tumor recurrence post-SBRT.

PD-1/SHP-2 inhibits Tc1/Th1 phenotypic responses and the activation of T cells in the tumor microenvironment.

Immune rejection of tumors is mediated by IFNγ production and T-cell cytolytic activity. These processes are impeded by PD-1, a coinhibitory molecule expressed on T cells that is elevated in tumor-infiltrating lymphocytes (TIL). PD-1 elevation may reflect T-cell exhaustion marked by decreased proliferation, production of type I cytokines, and poor cytolytic activity. Although anti-PD-1 antibodies enhance IFNγ secretion after stimulation of the T-cell receptor (TCR), the mechanistic link between PD-1 and its effects on T-cell help (Tc1/Th1 skewing) remains unclear. In prospectively collected cancer tissues, we found that TIL exhibited dampened Tc1/Th1 skewing and activation compared with peripheral blood lymphocytes (PBL). When PD-1 bound its ligand PD-L1, we observed a marked suppression of critical TCR target genes and Th1 cytokines. Conversely, PD-1 blockade reversed these suppressive effects of PD-1:PD-L1 ligation. We also found that the TCR-regulated phosphatase SHP-2 was expressed higher in TIL than in PBL, tightly correlating with PD-1 expression and negative regulation of TCR target genes. Overall, these results defined a PD-1/SHP-2/STAT1/T-bet signaling axis mediating the suppressive effects of PD-1 on Th1 immunity at tumor sites. Our findings argue that PD-1 or SHP-2 blockade will be sufficient to restore robust Th1 immunity and T-cell activation and thereby reverse immunosuppression in the tumor microenvironment.