Metabolic targeting, immunotherapy and radiation in locally advanced non-small cell lung cancer: Where do we go from here?

In the US, there are ~250,000 new lung cancer diagnoses and ~130,000 deaths per year, and worldwide there are an estimated 1.6 million deaths per year from this deadly disease. Lung cancer is the most common cause of cancer death worldwide, and it accounts for roughly a quarter of all cancer deaths in the US. Non-small cell lung cancer (NSCLC) represents 80-85% of these cases. Due to an enormous tobacco cessation effort, NSCLC rates in the US are decreasing, and the implementation of lung cancer screening guidelines and other programs have resulted in a higher percentage of patients presenting with potentially curable locoregional disease, instead of distant disease. Exciting developments in molecular targeted therapy and immunotherapy have resulted in dramatic improvement in patients’ survival, in combination with new surgical, pathological, radiographical, and radiation techniques. Concurrent platinum-based doublet chemoradiation therapy followed by immunotherapy has set the benchmark for survival in these patients. However, despite these advances, ~50% of patients diagnosed with locally advanced NSCLC (LA-NSCLC) survive long-term. In patients with local and/or locoregional disease, chemoradiation is a critical component of curative therapy. However, there remains a significant clinical gap in improving the efficacy of this combined therapy, and the development of non-overlapping treatment approaches to improve treatment outcomes is needed. One potential promising avenue of research is targeting cancer metabolism. In this review, we will initially provide a brief general overview of tumor metabolism as it relates to therapeutic targeting. We will then focus on the intersection of metabolism on both oxidative stress and anti-tumor immunity. This will be followed by discussion of both tumor- and patient-specific opportunities for metabolic targeting in NSCLC. We will then conclude with a discussion of additional agents currently in development that may be advantageous to combine with chemo-immuno-radiation in NSCLC

Laparoscopic Splenectomy in Children

BACKGROUND: Laparoscopic splenectomy is being performed more commonly in children, although its advantages are not clear. We sought to determine whether laparoscopic splenectomy was superior to open splenectomy. METHODS: The records of all pediatric patients undergoing splenectomy without significant comorbidities over a 12-year period were examined. The patients were divided into those undergoing laparoscopic splenectomy and those undergoing open splenectomy. Demographics, operative time, estimated blood loss, spleen size, length of stay, and total charges were compared between the groups. RESULTS: Eighty-one (58%) children underwent laparoscopic splenectomy, and 59 (42%) children underwent open splenectomy. The groups were similar in age and sex; hereditary spherocytosis was more common in the LS group. Operating time was longer in the laparoscopic splenectomy group (231 +/- 10 min vs 138 +/- 9 min; P\u3c0.001), but blood loss and complication rates were similar. Twelve (15%) conversions were necessary primarily due to spleen size. Although children undergoing LS had a shorter length of stay (2.4 +/- 0.1 vs 4.1 +/- 0.3 days; P\u3c0.001), they incurred higher charges (dollars 21199 +/- 664 vs dollars 15723 +/- 1737; P\u3c0.002). CONCLUSION: Laparoscopic splenectomy is a safe procedure in children, resulting in shorter hospital stay, which may translate into earlier return to activity and a smaller burden on the child\u27s caretakers

Integrative genomic analysis reveals low T-cell infiltration as the primary feature of tobacco use in HPV-positive oropharyngeal cancer

Although tobacco use is an independent adverse prognostic feature in HPV(+) oropharyngeal squamous cell carcinoma (OPSCC), the biologic features associated with tobacco use have not been systematically investigated. We characterized genomic and immunologic features associated with tobacco use through whole exome sequencing, mRNA hybridization, and immunohistochemical staining in 47 HPV(+) OPSCC tumors. Low expression of transcripts in a T cell-inflamed gene expression profile (TGEP) was associated with tobacco use at diagnosis and lower overall and disease-free survival. Tobacco use was associated with an increased proportion of T \u3e C substitutions and a lower proportion of expected mutational signatures, but not with increases in mutational burden or recurrent oncogenic mutations. Our findings suggest that rather than increased mutational burden, tobacco\u27s primary and clinically relevant association in HPV(+) OPSCC is immunosuppression of the tumor immune microenvironment. Quantitative assays of T cell infiltration merit further study as prognostic markers in HPV(+) OPSCC

Moving from conventional to adaptive risk stratification for oropharyngeal cancer

Oropharyngeal cancer (OPC) poses a complex therapeutic dilemma for patients and oncologists alike, made worse by the epidemic increase in new cases associated with the oncogenic human papillomavirus (HPV). In a counterintuitive manner, the very thing which gives patients hope, the high response rate of HPV-associated OPC to conventional chemo-radiation strategies, has become one of the biggest challenges for the field as a whole. It has now become clear that for ~30-40% of patients, treatment intensity could be reduced without losing therapeutic efficacy, yet substantially diminishing the acute and lifelong morbidity resulting from conventional chemotherapy and radiation. At the same time, conventional approaches to de-escalation at a population (selected or unselected) level are hampered by a simple fact: we lack patient-specific information from individual tumors that can predict responsiveness. This results in a problematic tradeoff between the deleterious impact of de-escalation on patients with aggressive, treatment-refractory disease and the beneficial reduction in treatment-related morbidity for patients with treatment-responsive disease. True precision oncology approaches require a constant, iterative interrogation of solid tumors prior to and especially during cancer treatment in order to tailor treatment intensity to tumor biology. Whereas this approach can be deployed in hematologic diseases with some success, our ability to extend it to solid cancers with regional metastasis has been extremely limited in the curative intent setting. New developments in metabolic imaging and quantitative interrogation of circulating DNA, tumor exosomes and whole circulating tumor cells, however, provide renewed opportunities to adapt and individualize even conventional chemo-radiation strategies to diseases with highly variable biology such as OPC. In this review, we discuss opportunities to deploy developing technologies in the context of institutional and cooperative group clinical trials over the coming decade

Combined anterior cervical spine fusion and total laryngopharyngectomy with free flap reconstruction: A technical note

Background and importance: In complex cases such as dropped head cervical deformity due to post-radiation myopathy, anterior cervical discectomy and fusion (ACDF) could be done for deformity correction. In rare circumstances where there is a concurrent need for a total laryngopharyngectomy (TLP) and ACDF, there is a remarkable corridor for cervical discectomy and fusion from the extensive neck exposure. Clinical presentation: We present the case of a patient with history of primary oropharyngeal squamous cell carcinoma and left parotid carcinoma status post treatment, now with post-radiation laryngeal dysfunction and dropped head cervical spinal deformity. Patient underwent posterior fixation for deformity correction and also to create anterior access for total laryngopharyngectomy (TLP). He then underwent combined TLP with anterolateral thigh (ALT) free flap reconstruction and C3-5 ACDF with a vascularized pre-vertebral fascia flap coverage of the spinal hardware. Conclusion: This unique case report is the first of its kind where total laryngopharyngectomy with free flap reconstruction was performed together with an anterior cervical discectomy and fusion. Though complex, such procedures can be performed with satisfactory outcomes in well-established centers

Primary vs delayed surgery for spontaneous pneumothorax in children: which is better?

Controversy exists regarding the timing of surgery for spontaneous pneumothorax (SP), which can be performed either after the first development of pneumothorax or after a recurrent spontaneous pneumothorax has occurred. Treatment after recurrence is often adopted because of the purported low recurrence of SP treated nonoperatively and the historical morbidity of open surgery. However, the effectiveness of VATS (to video-assisted bullectomy and pleurodesis) has raised the possibility of performing primary VATS (PV) in all patients. The authors therefore hypothesized that PV is safe and effective for SP and sought to perform a cost-benefit analysis of PV vs secondary VATS (SV). After institutional review board approval, consecutive patients with SP (1991-2003) and no comorbidities were retrospectively divided into PV vs SV. Demographics, recurrent pneumothorax after VATS, length of stay, and costs were compared by Student's t test/ χ 2. The predicted incremental cost of PV was (cost of PV) − {[cost of nonoperative treatment × (1 − recurrence rate)] + cost of SV × recurrence rate}. Data are means ± SEM. There were 54 spontaneous pneumothoraces in 43 patients (11 bilateral), of whom 3 were excluded because of open thoracotomy. Of 51 pneumothoraces, nonoperative treatment was attempted in 37, of whom 20 recurred and thus required SV. Primary VATS was performed in 14. Both groups had similar age, sex, weight, height, admission heart rate, and room air oxygen saturation. Total treatment length of stay was significantly shorter for PV vs SV (7.1 ± 0.96 vs 10.5 ± 1.2, P = .04). However, morbidity from recurrent pneumothorax after VATS occurred more frequently after PV than SV (4/14 vs 0/20 P < .05). Based on the observed recurrence rate of 54%, performing PV on all patients with SP would increase cost by $4010 per patient and require a recurrence rate of 72% or more to financially justify this approach. Contrary to the hypothesis, the increased morbidity and cost do not justify a strategy of PV blebectomy/pleurodesis in children with SP. Instead, secondary treatment is recommended

Three-dimensional (3D) anatomic location, extension, and timing of severe osteoradionecrosis of the mandible

Background: The purpose of this study was to describe the topography, extension (volume), and timing of severe osteoradionecrosis (ORN) that required mandible resection in patients previously treated for head and neck cancer at a high-volume Veterans Affairs Medical Center. Materials and methods: The records from a reference hyperbaric oxygen clinic were retrospectively analyzed (n = 50, 2018–2021). Inclusion criteria were: I) severe ORN defined as progressive ORN that required resection; II) pathologic confirmation of ORN; and III) availability of pre-operative CT-imaging. Using a radiotherapy (RT) imaging software, we performed a detailed volumetric (3D) analysis of the bone involvement by ORN. Time intervals from RT to surgery for ORN and from surgery to the last follow-up were calculated. Results: All patients that met inclusion criteria (n = 10) were male with significant smoking history (median 47.5 pack-years) and a median age of 57 years old at the time of RT. The primary tumors were: oropharynx (n = 6), oral cavity (n = 3) and nasopharynx (n = 1). The median time from RT to ORN surgery was 8 years. The most common ORN location was the posterior lateral body (molar) and six patients had associated fractures. The mean ORN volume was 3.6 cc (range: 0.6–8.3), corresponding to a mean 6.3% (range: 0.7–14) of the total mandibular volume. After a median follow-up of 13.5 months, no recurrence of ORN occurred. Three patients died of non-cancer and non-ORN-recurrence related causes (1 y OS 77.1%). Conclusion: Severe ORN occurred after a median of 8 years from the previous RT and usually affected the posterior lateral body. Surgical resection achieved excellent ORN control

p90RSK pathway inhibition synergizes with cisplatin in TMEM16A overexpressing head and neck cancer

Abstract Head and neck squamous cell carcinoma (HNSCC) constitutes one of the most common types of human cancers and often metastasizes to lymph nodes. Platinum-based chemotherapeutic drugs are commonly used for treatment of a wide range of cancers, including HNSCC. Its mode of action relies on its ability to impede DNA repair mechanisms, inducing apoptosis in cancer cells. However, due to acquired resistance and toxic side-effects, researchers have been focusing on developing novel combinational therapeutic strategies to overcome cisplatin resistance. In the current study, we identified p90RSK, an ERK1/2 downstream target, as a key mediator and a targetable signaling node against cisplatin resistance. Our results strongly support the role of p90RSK in cisplatin resistance and identify the combination of p90RSK inhibitor, BI-D1870, with cisplatin as a novel therapeutic strategy to overcome cisplatin resistance. In addition, we have identified TMEM16A expression as a potential upstream regulator of p90RSK through the ERK pathway and a biomarker of response to p90RSK targeted therapy in the context of cisplatin resistance