Microbial Composition of the Laryngotracheal Region: A Systematic Review.

INTRODUCTION: Microbiome research has predominantly focused on the oral cavity and oropharynx's role in disease, while the upper airway, specifically the larynx and trachea, has been relatively overlooked. Examining the microbial communities in these regions can shed light on how dysbiosis influences diseases and their management. This review evaluates laryngotracheal microbial compositions in both healthy and diseased patients. METHODS: We conducted a systematic review in EMBASE, MEDLINE, and Cochrane Central databases, yielding 1383 studies in the initial search. Inclusion criteria involved participants aged over 18 years and the use of next-generation 16s ribosomal sequencing methods. RESULTS: We included 10 studies-seven focused on larynx sequencing and four on trachea sequencing (one investigated both sites). In a healthy larynx, diverse species such as Streptococcus, Cloacibacterium, Prevotella, and Helicobacter were found. Benign laryngeal diseases exhibited reduced microbial diversity, mainly dominated by Streptococcus. Subglottic stenosis patients showed diminished diversity in both idiopathic and iatrogenic scars. Laryngeal squamous cell carcinoma displayed increased diversity, primarily featuring Fusobacterium. Among non-respiratory-compromised surgery patients, the tracheal microbiome was more diverse in diabetics and those later developing lower respiratory infections. Pneumonia patients exhibited an abundance of Prevotella and Streptococcus, linked to an increased 28-day survival rate, while Streptococcus and Haemophilus abundance correlated with successful extubation. CONCLUSIONS: The laryngotracheal region hosts a unique microbial community influenced by both benign and malignant conditions. Many lesions remain unexplored, underscoring the need for future studies encompassing diverse laryngotracheal conditions. Clinical trials assessing microbiome modifications may unveil novel therapeutic avenues. LEVEL OF EVIDENCE: NA Laryngoscope, 2024.

Adjuvant Reirradiation With Proton Therapy in Head and Neck Squamous Cell Carcinoma.

Purpose: For patients with head and neck squamous cell carcinoma (HNSCC), locoregional failure and second primary tumors are common indications for adjuvant reirradiation (re-RT). Given an absence of clear consensus on the role of adjuvant re-RT, we sought to assess histopathologic risk factors of patients with HNSCC and their resulting outcomes after adjuvant re-RT with proton therapy. Methods and Materials: We conducted a retrospective analysis of patients with HNSCC who underwent salvage surgery at our institution followed by adjuvant re-RT with proton therapy over 1.5 years. All included patients received prior radiation therapy. The Kaplan-Meier method was used to evaluate locoregional recurrence-free survival and overall survival. Results: The cohort included 22 patients, with disease subsites, including oropharynx, oral cavity, hypopharynx, larynx, and nasopharynx. Depending on adverse pathologic features, adjuvant re-RT to 66 Gy (32% of cohort) or 60 Gy (68%), with (59%) or without (41%) concurrent systemic therapy was administered. The majority (86%) completed re-RT with no reported treatment delay; 3 patients experienced grade ≥3 acute Common Terminology Criteria for Adverse Events toxicity and no patient required enteral feeding tube placement during re-RT. Median follow-up was 21.0 months (IQR, 11.7-25.2 months). Five patients had biopsy-proven disease recurrences a median of 5.9 months (IQR, 3.8-9.7 months) after re-RT. Locoregional recurrence-free survival was 95.2%, 70.2%, 64.8% at 6, 12, and 24 months, respectively. OS was 100%, 79.2%, and 79.2% at 6, 12, and 24 months, respectively. Four patients had osteoradionecrosis on imaging a median of 13.2 months (IQR, 8.7-17.4 months) after re-RT, with 2 requiring surgical intervention. Conclusions: Adjuvant re-RT for patients with HNSCC was well-tolerated and offered reasonable local control in this high-risk cohort but appears to be associated with a risk of osteoradionecrosis. Additional study and longer follow-up could help define optimal patient management in this patient population.

Pleasurable and problematic receptive anal intercourse and diseases of the colon, rectum and anus.

The ability to experience pleasurable sexual activity is important for human health. Receptive anal intercourse (RAI) is a common, though frequently stigmatized, pleasurable sexual activity. Little is known about how diseases of the colon, rectum, and anus and their treatments affect RAI. Engaging in RAI with gastrointestinal disease can be difficult due to the unpredictability of symptoms and treatment-related toxic effects. Patients might experience sphincter hypertonicity, gastrointestinal symptom-specific anxiety, altered pelvic blood flow from structural disorders, decreased sensation from cancer-directed therapies or body image issues from stoma creation. These can result in problematic RAI - encompassing anodyspareunia (painful RAI), arousal dysfunction, orgasm dysfunction and decreased sexual desire. Therapeutic strategies for problematic RAI in patients living with gastrointestinal diseases and/or treatment-related dysfunction include pelvic floor muscle strengthening and stretching, psychological interventions, and restorative devices. Providing health-care professionals with a framework to discuss pleasurable RAI and diagnose problematic RAI can help improve patient outcomes. Normalizing RAI, affirming pleasure from RAI and acknowledging that the gastrointestinal system is involved in sexual pleasure, sexual function and sexual health will help transform the scientific paradigm of sexual health to one that is more just and equitable.

Risk-Tailoring Radiotherapy for Endometrial Cancer: A Narrative Review.

Endometrial cancer is the most common gynecologic cancer in the United States and it contributes to the second most gynecologic cancer-related deaths. With upfront surgery, the specific characteristics of both the patient and tumor allow for risk-tailored treatment algorithms including adjuvant radiotherapy and systemic therapy. In this narrative review, we discuss the current radiation treatment paradigm for endometrial cancer with an emphasis on various radiotherapy modalities, techniques, and dosing regimens. We then elaborate on how to tailor radiotherapy treatment courses in combination with other cancer-directed treatments, including chemotherapy and immunotherapy. In conclusion, this review summarizes ongoing research that aims to further individualize radiotherapy regimens for individuals in an attempt to improve patient outcomes.

Head and Neck Cancer Patient Population, Management, and Oncologic Outcomes from the COVID-19 Pandemic.

The COVID-19 pandemic precipitated drastic changes in cancer care. Its impact on the U.S. head and neck cancer population has yet to be fully understood. This study aims to understand the impact of pandemic-related changes on the head and neck cancer population. An observational study of head and neck cancer patients at a single institution during the spring of 2020 and 2019 was performed. Clinical characteristics and survival outcomes were analyzed. In 2020, 54 head and neck cancer patients were evaluated in the department of radiation oncology vs. 74 patients seen in 2019; 42% of the patients were female in 2019 versus 24% in 2020 (p = 0.036). The median follow-up time was 19.4 and 31 months for 2020 and 2019, respectively. After adjusting for stage, the relapse-free survival probability at 6 and 12 months was 79% and 69% in 2020 vs. 96% and 89% in 2019, respectively (p = 0.036). There was no significant difference in the overall survival, with 94% and 89% in 2020 and 2019, respectively (p = 0.61). Twenty-one percent of patients received induction chemotherapy in 2020 versus 5% in 2019 (p = 0.011); significantly more treatment incompletions occurred in 2020, 9% vs. 0% in 2019 (p = 0.012). Moreover, the stage-adjusted RFS differed between cohorts, suggesting head and neck cancer patients seen during the initial wave of COVID-19 may experience worse oncologic outcomes.

Dose and fractionation regimen for brachytherapy boost in cervical cancer in the US.

PURPOSE: Curative-intent radiotherapy for locally advanced and select early stage cervical cancer in the US includes external beam radiotherapy (EBRT) with brachytherapy. Although there are guidelines for brachytherapy dose and fractionation regimens, there are limited data on practice patterns. This study aims to evaluate the contemporary utilization of cervical cancer brachytherapy in the US and its association with patient demographics and facility characteristics. METHODS: We retrospectively analyzed clinical covariates of cervical cancer patients diagnosed and treated in 2018-2020 with curative-intent radiotherapy from the 2020 National Cancer Database. Associations between patient and institutional factors with the number of brachytherapy fractions were identified with logistic regression. Factors with association (p < 0.10) were then included in a multivariable logistic regression model. All tests were two-sided with significance <0.05 unless specified otherwise. RESULTS: Among the eligible 2517 patients, 97.3% received HDR or LDR and is further analyzed. More patients received HDR than LDR brachytherapy (98.9% vs 1.1%) and intracavitary than interstitial brachytherapy (86.4% vs 13.6%). The most common number of HDR fractions prescribed were 5 (51.0%), 4 (32.9%), and 3 (8.6%). After adjusting for the other variables in the model, ethnicity, private insurance status, overall insurance status, and facility type were the only factors that were significantly associated with the number of brachytherapy factions (p < 0.0001, p = 0.028, p = 0.001, and p < 0.0001, respectively, n = 2184). CONCLUSIONS: In the US, various HDR brachytherapy regimens are utilized depending on patient and institutional factors. Future research may optimize cervical cancer brachytherapy by correlating specific dose and fractionation regimens with patient outcomes.

A Multicenter Evaluation of Different Chemotherapy Regimens in Older Adults With Head and Neck Squamous Cell Carcinoma Undergoing Definitive Chemoradiation.

PURPOSE: The number of older adults with head and neck squamous cell carcinoma (HNSCC) is increasing, and treatment of these patients is challenging. Although cisplatin-based chemotherapy concomitantly with radiation therapy is considered the standard regimen for patients with locoregionally advanced HNSCC, there is substantial real-world heterogeneity regarding concomitant chemotherapy in older patients with HNSCC. METHODS AND MATERIALS: The SENIOR study is an international multicenter cohort study including older patients (≥65 years) with HNSCC treated with definitive radiation therapy at 13 academic centers in the United States and Europe. Patients with concomitant chemoradiation were analyzed regarding overall survival (OS) and progression-free survival (PFS) via Kaplan-Meier analyses. Fine-Gray competing risk regressions were performed regarding the incidence of locoregional failures and distant metastases. RESULTS: Six hundred ninety-seven patients with a median age of 71 years were included in this analysis. Single-agent cisplatin was the most common chemotherapy regimen (n = 310; 44%), followed by cisplatin plus 5-fluorouracil (n = 137; 20%), carboplatin (n = 73; 10%), and mitomycin C plus 5-fluorouracil (n = 64; 9%). Carboplatin-based regimens were associated with diminished PFS (hazard ratio [HR], 1.39 [1.03-1.89]; P < .05) and a higher incidence of locoregional failures (subdistribution HR, 1.54 [1.00-2.38]; P = .05) compared with single-agent cisplatin, whereas OS (HR, 1.15 [0.80-1.65]; P = .46) was comparable. There were no oncological differences between single-agent and multiagent cisplatin regimens (all P > .05). The median cumulative dose of cisplatin was 180 mg/m2 (IQR, 120-200 mg/m2). Cumulative cisplatin doses ≥200 mg/m2 were associated with increased OS (HR, 0.71 [0.53-0.95]; P = .02), increased PFS (HR, 0.66 [0.51-0.87]; P = .003), and lower incidence of locoregional failures (subdistribution HR, 0.50 [0.31-0.80]; P = .004). Higher cumulative cisplatin doses remained an independent prognostic variable in the multivariate regression analysis for OS (HR, 0.996 [0.993-0.999]; P = .009). CONCLUSIONS: Single-agent cisplatin can be considered in the standard chemotherapy regimen for older patients with HNSCC who can tolerate cisplatin. Cumulative cisplatin doses are prognostically relevant in older patients with HNSCC.

Effects of trauma history on cancer-related screening, diagnosis, and treatment.

Trauma has substantial effects on human health and is recognised as a potential barrier to seeking or receiving cancer care. The evidence that exists regarding the effect of trauma on seeking cancer screening, diagnosis, and treatment and the gaps therein can define this emerging research area and guide the development of interventions intended to improve the cancer care continuum for trauma survivors. This Review summarises current literature on the effects of trauma history on screening, diagnosis, and treatment among adult patients at risk for or diagnosed with cancer. We discuss a complex relationship between trauma history and seeking cancer-related services, the nature of which is influenced by the necessity of care, perceived or measured health status, and potential triggers associated with the similarity of cancer care to the original trauma. Collaborative scientific investigations by multidisciplinary teams are needed to generate further clinical evidence and develop mitigation strategies to provide trauma-informed cancer care for this patient population.

Immune checkpoint inhibition and single fraction stereotactic radiosurgery in brain metastases from non-small cell lung cancer: an international multicenter study of 395 patients.

PURPOSE: Approximately 80% of brain metastases originate from non-small cell lung cancer (NSCLC). Immune checkpoint inhibitors (ICI) and stereotactic radiosurgery (SRS) are frequently utilized in this setting. However, concerns remain regarding the risk of radiation necrosis (RN) when SRS and ICI are administered concurrently. METHODS: A retrospective study was conducted through the International Radiosurgery Research Foundation. Logistic regression models and competing risks analyses were utilized to identify predictors of any grade RN and symptomatic RN (SRN). RESULTS: The study included 395 patients with 2,540 brain metastases treated with single fraction SRS and ICI across 11 institutions in four countries with a median follow-up of 14.2 months. The median age was 67 years. The median margin SRS dose was 19 Gy; 36.5% of patients had a V12 Gy ≥ 10 cm3. On multivariable analysis, V12 Gy ≥ 10 cm3 was a significant predictor of developing any grade RN (OR: 2.18) and SRN (OR: 3.95). At 1-year, the cumulative incidence of any grade and SRN for all patients was 4.8% and 3.8%, respectively. For concurrent and non-concurrent groups, the cumulative incidence of any grade RN was 3.8% versus 5.3%, respectively (p = 0.35); and for SRN was 3.8% vs. 3.6%, respectively (p = 0.95). CONCLUSION: The risk of any grade RN and symptomatic RN following single fraction SRS and ICI for NSCLC brain metastases increases as V12 Gy exceeds 10 cm3. Concurrent ICI and SRS do not appear to increase this risk. Radiosurgical planning techniques should aim to minimize V12 Gy.

Outside-in signaling through the major histocompatibility complex class-I cytoplasmic tail modulates glutamate receptor expression in neurons.

The interplay between AMPA-type glutamate receptors (AMPARs) and major histocompatibility complex class I (MHC-I) proteins in regulating synaptic signaling is a crucial aspect of central nervous system (CNS) function. In this study, we investigate the significance of the cytoplasmic tail of MHC-I in synaptic signaling within the CNS and its impact on the modulation of synaptic glutamate receptor expression. Specifically, we focus on the Y321 to F substitution (Y321F) within the conserved cytoplasmic tyrosine YXXΦ motif, known for its dual role in endocytosis and cellular signaling of MHC-I. Our findings reveal that the Y321F substitution influences the expression of AMPAR subunits GluA2/3 and leads to alterations in the phosphorylation of key kinases, including Fyn, Lyn, p38, ERK1/2, JNK1/2/3, and p70 S6 kinase. These data illuminate the crucial role of MHC-I in AMPAR function and present a novel mechanism by which MHC-I integrates extracellular cues to modulate synaptic plasticity in neurons, which ultimately underpins learning and memory.

Combining Radiotherapy and Immunotherapy in Head and Neck Cancer.

Head and neck squamous cell carcinoma (HNSCC) is a leading cause of morbidity and mortality globally. Despite significant advances in well-established treatment techniques, prognosis for advanced-stage HNSCC remains poor. Recent, accumulating evidence supports a role for immunotherapy in HNSCC treatment. Radiation therapy (RT), a standard treatment option for HNSCC, has immunomodulatory and immunostimulatory effects that may enhance the efficacy of immunotherapy. In several cancer types, combining RT and immunotherapy has been shown to improve tumor response rates, increase survival, and reduce toxicity compared to traditional chemotherapy and radiation therapy. This review provides a timely overview of the current knowledge on the use of RT and immunotherapy for treating HNSCC. It highlights the potential advantages of combining these therapies, such as improved tumor response rates, increased survival, and reduced toxicity. The review also discusses the challenges that need to be addressed when redefining the standard of care in HNSCC, and proposes further research to optimize treatment combinations, minimize radiation-induced toxicity, and identify suitable patient populations for treatment.

The incorporation of cognitive-sparing techniques into prophylactic cranial irradiation in the management of small cell lung cancer.

The use of prophylactic cranial irradiation (PCI) remains an important component in the management of small cell lung cancer (SCLC). This is due to the high rates of subclinical brain metastases at the time of diagnosis. Following a response to initial treatment, PCI historically has been associated with improvements in overall survival and decreased development of brain metastases in patients with limited stage (LS-SCLC) and extensive stage (ES-SCLC) SCLC. However, PCI is commonly withheld in these settings in favor of observation, largely due to its association with cognitive sequelae following treatment. While randomized data has demonstrated that in patients with ES-SCLC, PCI may be withheld in favor of close MRI surveillance without a detriment in overall survival or cognitive functioning, these patients did not undergo formal neuropsychological assessments. In recent years, cognitive sparing techniques incorporated into whole brain radiation therapy and PCI, such as the addition of memantine and hippocampal avoidance, have demonstrated significant improvements in cognitive outcomes. As the overall survival in patients with SCLC continues to improve due to the incorporation of novel systemic therapies (e.g., immune checkpoint inhibitors), the role of PCI and maximizing quality of life remains a highly relevant topic. This article reviews the role of PCI and cognitive-sparing techniques in the management of SCLC.

Radiotherapy and Immunotherapy in Lung Cancer.

The emergence of immune checkpoint inhibitors (ICIs) as a pillar of cancer treatment has emphasized the immune system's integral role in tumor control and progression through cancer immune surveillance. ICIs are being investigated and incorporated into the treatment paradigm for lung cancers across stages and histology. To date, definitive concurrent chemoradiotherapy followed by consolidative durvalumab is the only National Comprehensive Cancer Network's recommended treatment paradigm including radiotherapy with ICI in lung cancers, although there are other recommendations for ICI with chemotherapy and/or surgery. This narrative review provides an overall view of the evolving integration and synergistic role of immunotherapy and radiotherapy and outlines the use of immunotherapy with radiotherapy for the management of small cell lung cancer and non-small cell lung cancer. It also reviews selected, practice-changing clinical trials that led to the current standard of care for lung cancers.

Gender-Affirming Surgery and Cancer: Considerations for Radiation Oncologists for Pelvic Radiation in Transfeminine Patients.

Access to gender-affirming surgery is increasing for many transgender and nonbinary people in the United States, and radiation oncologists must be equipped to care for patients who have undergone such surgery in the region of their planned radiation treatment field. There are no guidelines for radiation treatment planning after gender-affirming surgery, and most oncologists do not receive training in the unique needs of transgender people with cancer. We review common gender-affirming genitopelvic surgeries for transfeminine people, including vaginoplasty, labiaplasty, and orchiectomy, and summarize the existing literature on the treatment of cancers of the neovagina, anus, rectum, prostate, and bladder in these patients. We also describe our systematic treatment approach and rationale for pelvic radiation treatment planning.

Sexual health and treatment-related sexual dysfunction in sexual and gender minorities with prostate cancer.

Prostate cancer treatment has substantial effects on sexual health and function. Sexual function is a vital aspect of human health and a critical component of cancer survivorship, and understanding the potential effects of different treatment modalities on sexual health is crucial. Existing research has extensively described the effects of treatment on male erectile tissues necessary for heterosexual intercourse; however, evidence regarding their effects on sexual health and function in sexual and gender minority populations is minimal. These groups include sexual minority - gay and bisexual - men, and transgender women or trans feminine people in general. Such unique effects in these groups might include altered sexual function in relation to receptive anal and neovaginal intercourse and changes to patients' role-in-sex. Sexual dysfunctions following prostate cancer treatment affecting quality of life in sexual minority men include climacturia, anejaculation, decreased penile length, erectile dysfunction, and problematic receptive anal intercourse, including anodyspareunia and altered pleasurable sensation. Notably, clinical trials investigating sexual outcomes after prostate cancer treatment do not collect sexual orientation and gender identity demographic data or outcomes specific to members of these populations, which perpetuates the uncertainty regarding optimal management. Providing clinicians with a solid evidence base is essential to communicate recommendations and tailor interventions for sexual and gender minority patients with prostate cancer.

The intracellular domain of major histocompatibility class-I proteins is essential for maintaining excitatory spine density and synaptic ultrastructure in the brain.

Major histocompatibility complex class I (MHC-I) proteins are expressed in neurons, where they regulate synaptic plasticity. However, the mechanisms by which MHC-I functions in the CNS remains unknown. Here we describe the first structural analysis of a MHC-I protein, to resolve underlying mechanisms that explains its function in the brain. We demonstrate that Y321F mutation of the conserved cytoplasmic tyrosine-based endocytosis motif YXXΦ in MHC-I affects spine density and synaptic structure without affecting neuronal complexity in the hippocampus, a region of the brain intimately involved in learning and memory. Furthermore, the impact of the Y321F substitution phenocopies MHC-I knock-out (null) animals, demonstrating that reverse, outside-in signalling events sensing the external environment is the major mechanism that conveys this information to the neuron and this has a previously undescribed yet essential role in the regulation of synaptic plasticity.

Clinical and Therapeutic Considerations for Older Adults with Head and Neck Cancer.

Approximately 30% of patients with head and neck squamous cell carcinoma (HNSCC) are at least 70 years of age, and this percentage is expected to increase as the population increases and lives longer. Elderly patients are underrepresented in head and neck oncology clinical trials, and there is minimal evidence on the management of HNSCC for this population. Subsequently, despite their best intentions, physicians may unknowingly recommend an ill-suited course of therapy, which may result in suboptimal oncological or functional outcomes or adverse events. Surgical approaches have the potential to carry a higher risk of morbidity and mortality in older adults, especially in patients with multiple comorbidities. Definitive radiation therapy treatment in patients with HNSCC frequently involves 7 weeks of daily radiation, sometimes with concurrent chemotherapy, and this demanding treatment can be difficult for older adult patients, which may lead to treatment interruptions, potential removal of concurrent systemic therapy, compromised outcomes, and diminished quality of life. There are clinical trials currently underway investigating altered fractionation regimens and novel, less toxic systemic treatments in this population. This review provides an overview of how best to approach an older adult with HNSCC, from initial work-up to treatment selection.