Late Recurrence of Completely Resected Stage I-IIIA Lung Adenocarcinoma.

OBJECTIVE: Research into the risk factors associated with late recurrence (>2 years after surgery) of lung adenocarcinoma (LUAD) is limited. We investigated the incidence of and clinicopathologic and genomic features associated with late recurrence of resected stage I-IIIA LUAD. METHODS: We performed a retrospective analysis of patients with completely resected pathologic stage I-IIIA LUAD (2010-2019). Patients with a history of lung cancer, neoadjuvant therapy, or mucinous or noninvasive LUAD, or with follow-up of <2 years were excluded. Cox and logistic regression modeling were used to compare clinicopathologic variables among patients with no, early (≤2 years), and late recurrence. Comparisons of genomic mutations were corrected for multiple testing. RESULTS: Of the 2349 patients included, 537 developed a recurrence during follow-up. Most recurrences (55% [297/537]) occurred early; 45% (240/537) occurred late. A larger proportion of late recurrences than early recurrences were locoregional (37% vs. 29%; p=0.047). Patients with late recurrence had more aggressive pathologic features (IASLC grade 2 and 3, lymphovascular invasion, visceral pleural invasion) and higher stage than patients without recurrence. Pathologic features were similar between patients with early and late recurrence, except stage IIIA disease was more common in the early cohort. No genomic mutations were associated with late recurrence. CONCLUSIONS: Late recurrence of LUAD following resection is more common than previously reported. Patients without disease >2 years after surgery who had aggressive pathologic features at the time of resection have an elevated risk of recurrence and may benefit from more-aggressive follow-up.

High-risk features associated with recurrence in stage I lung adenocarcinoma.

OBJECTIVE: There is a lack of knowledge regarding the use of prognostic features in stage I lung adenocarcinoma (LUAD). Thus, we investigated clinicopathologic features associated with recurrence after complete resection for stage I LUAD. METHODS: We performed a retrospective analysis of patients with pathologic stage I LUAD who underwent R0 resection from 2010 to 2020. Exclusion criteria included history of lung cancer, induction or adjuvant therapy, noninvasive or mucinous LUAD, and death within 90 days of surgery. Fine and Gray competing-risk regression assessed associations between clinicopathologic features and disease recurrence. RESULTS: In total, 1912 patients met inclusion criteria. Most patients (1565 [82%]) had stage IA LUAD, and 250 developed recurrence: 141 (56%) distant and 109 (44%) locoregional only. The 5-year cumulative incidence of recurrence was 12% (95% CI, 11%-14%). Higher maximum standardized uptake value of the primary tumor (hazard ratio [HR], 1.04), sublobar resection (HR, 2.04), higher International Association for the Study of Lung Cancer grade (HR, 5.32 [grade 2]; HR, 7.93 [grade 3]), lymphovascular invasion (HR, 1.70), visceral pleural invasion (HR, 1.54), and tumor size (HR, 1.30) were independently associated with a hazard of recurrence. Tumors with 3 to 4 high-risk features had a higher cumulative incidence of recurrence at 5 years than tumors without these features (30% vs 4%; P < .001). CONCLUSIONS: Recurrence after resection for stage I LUAD remains an issue for select patients. Commonly reported clinicopathologic features can be used to define patients at high risk of recurrence and should be considered when assessing the prognosis of patients with stage I disease.

The Emerging Role of Immunotherapy in Resectable Non-Small Cell Lung Cancer.

BACKGROUND: Despite surgical resection, long-term survival of patients with resectable non-small cell lung cancer (NSCLC) remains poor. Adjuvant chemotherapy, the standard of care for locally advanced NSCLC, provides a marginal 5.4% benefit in survival. Immune checkpoint inhibitors (ICIs) have shown a significant survival benefit in some patients with advanced NSCLC and are being evaluated for perioperative use in resectable NSCLC. METHODS: We conducted a literature search using the PubMed online database to identify clinical trials of immunotherapy in resectable NSCLC and studies analyzing biomarkers and immune priming strategies. RESULTS: Building on previous phase I and II trials, randomized phase III trials have shown efficacy of neoadjuvant nivolumab, perioperative pembrolizumab, adjuvant atezolizumab, and adjuvant pembrolizumab in the treatment of NSCLC with improvement of event-free/disease-free survival of 24% to 42%, leading to United States Food and Drug Administration approval of these drugs in the treatment of resectable NSCLC. Three additional phase III trials have also recently reported the use of immunotherapy both before and after surgery, with pathologic complete response rates of 17% to 25%, significantly better than chemotherapy alone. Perioperative ICI therapy has comparable perioperative morbidity to chemotherapy alone and does not impair surgical outcomes. CONCLUSIONS: Perioperative immunotherapy, in combination with chemotherapy, is safe and improves outcomes in patients with resectable NSCLC. Questions regarding patient selection, the need for adjuvant ICI therapy after neoadjuvant chemoimmunotherapy, and the duration of perioperative immunotherapy remain to be answered by future trials.

Immunotherapy for Resectable Locally Advanced Esophageal Carcinoma.

BACKGROUND: The current standard of care for locally advanced esophageal and gastroesophageal junction (GEJ) cancers includes neoadjuvant chemoradiotherapy or perioperative chemotherapy with surgical resection; however, disease-free survival in these patients remains poor. Immune checkpoint inhibitors (ICIs) are approved for adjuvant treatment of locally advanced esophageal and GEJ cancers, but their benefit in the perioperative and neoadjuvant settings remains under investigation. METHODS: We used the PubMed online database to conduct a literature search to identify studies that investigated immunotherapy for locally advanced esophageal and GEJ carcinoma. A review of ClinicalTrials.gov yielded a list of ongoing trials. RESULTS: Adjuvant nivolumab for residual disease after neoadjuvant chemoradiotherapy and surgery is the only approved immunotherapy regimen for locally advanced esophageal cancer. Early-phase trials investigating the addition of neoadjuvant or perioperative ICIs to standard-of-care multimodality approaches have observed pathologic complete response rates as high as 60%. Response rates are highest for ICIs plus chemoradiotherapy for esophageal squamous cell carcinoma and dual checkpoint inhibition in mismatch repair-deficient adenocarcinomas. Safety profiles are acceptable, with a pooled adverse event rate of 27%. Surgical morbidity and mortality with immunotherapy are similar to historical controls with no immunotherapy, and R0 resection rates are high. When reported, disease-free survival among patients treated with perioperative immunotherapy is promising. CONCLUSIONS: Outside of clinical trials, immunotherapy for resectable esophageal carcinoma is limited to the adjuvant setting. Phase III trials investigating neoadjuvant and perioperative immunotherapy are now underway and will provide much-needed data on survival that may ultimately lead to practice-changing recommendations.

Lung resection after initial nonoperative treatment for non-small cell lung cancer.

OBJECTIVES: The study objectives were to assess the outcomes of lung resection in patients with non-small cell lung cancer previously treated with nonoperative treatment and to identify prognostic factors associated with survival. METHODS: Patients who underwent surgery (2010-2022) after initial nonoperative treatment at a single institution were identified from a prospectively maintained database. Exclusion criteria included metachronous cancer, planned neoadjuvant therapy, and surgery for diagnostic or palliative indications. Cox models were constructed for overall survival and event-free survival. Survival of patients with stage IV disease was compared with survival of a nonstudy cohort who did not undergo surgery. RESULTS: In total, 120 patients met the inclusion criteria. Initial clinical stage was early stage in 16%, locoregionally advanced in 25%, and metastatic in 59% of patients. The indication for surgery was recurrence in 18%, local persistent disease in 23%, oligoprogression in 22%, and local control of oligometastatic disease in 38% of patients. Grade 3 or greater complications occurred in 5% of patients; 90-day mortality was 3%. Three-year event-free survival and overall survival were 39% and 73%, respectively. Male sex and lymphovascular invasion were associated with shorter event-free survival and overall survival; younger age and prior radiation therapy were associated with shorter overall survival. Patients with stage IV disease who received salvage lung resection had better overall survival than similar patients who received subsequent systemic therapy and no surgery. CONCLUSIONS: In this selected, heterogeneous population, lung resection after initial nonoperative treatment for non-small cell lung cancer was safe. Surgery as local consolidative therapy was associated with encouraging outcomes and should be considered for these patients.

Mediastinal Staging in Non-Small-Cell Lung Cancer: Saying Goodbye to Mediastinoscopy.

The Oncology Grand Rounds series is designed to place original reports published in the Journal into clinical context. A case presentation is followed by a description of diagnostic and management challenges, a review of the relevant literature, and a summary of the authors' suggested management approaches. The goal of this series is to help readers better understand how to apply the results of key studies, including those published in Journal of Clinical Oncology, to patients seen in their own clinical practice.Accurate staging of the mediastinal lymph nodes in resectable non-small-cell lung cancer (NSCLC) is critically important to determine the overall stage of the tumor and guide subsequent management. The staging process typically begins with positron emission tomography (PET) or computed tomography imaging; however, imaging alone is inadequate, and tissue acquisition is required for confirmation of nodal disease. Mediastinoscopy was long considered the gold standard for staging of mediastinal lymph nodes, but, recently, endobronchial ultrasound-guided (EBUS) fine-needle aspiration (FNA) has become the standard of care. EBUS-FNA, in combination with supplementary technologies, such as intranodal forceps biopsy and esophageal ultrasonography, has a high sensitivity and specificity for the diagnosis of nodal metastases. EBUS-FNA is also capable of assessing N1 disease and obtaining adequate tissue for tumor genomic analysis to help guide treatment. In the case of negative findings on EBUS, a confirmatory video mediastinoscopy is still recommended by the European Society of Thoracic Surgeons guidelines. However, whether confirmatory mediastinoscopy is necessary is a matter of debate, and it is not commonly performed in North America. To address this question, Bousema and colleagues performed a randomized noninferiority trial to determine rates of unforeseen nodal metastases after EBUS alone versus EBUS with confirmatory mediastinoscopy in patients with resectable NSCLC. The authors concluded that EBUS alone is noninferior to EBUS with confirmatory mediastinoscopy. These findings affirm our current practice to forgo confirmatory mediastinoscopy after negative findings on EBUS.

Genomic mapping of metastatic organotropism in lung adenocarcinoma.

We analyzed 2,532 lung adenocarcinomas (LUAD) to identify the clinicopathological and genomic features associated with metastasis, metastatic burden, organotropism, and metastasis-free survival. Patients who develop metastasis are younger and male, with primary tumors enriched in micropapillary or solid histological subtypes and with a higher mutational burden, chromosomal instability, and fraction of genome doublings. Inactivation of TP53, SMARCA4, and CDKN2A are correlated with a site-specific shorter time to metastasis. The APOBEC mutational signature is more prevalent among metastases, particularly liver lesions. Analyses of matched specimens show that oncogenic and actionable alterations are frequently shared between primary tumors and metastases, whereas copy number alterations of unknown significance are more often private to metastases. Only 4% of metastases harbor therapeutically actionable alterations undetected in their matched primaries. Key clinicopathological and genomic alterations in our cohort were externally validated. In summary, our analysis highlights the complexity of clinicopathological features and tumor genomics in LUAD organotropism.

Throat Spray With Blended Essential Oils Promotes Healthy Lung Function Among Women: A Randomized, Double Blinded, Placebo Controlled Clinical Trial.

INTRODUCTION: There are numerous internal and external environmental threats to lung health. Compromised respiratory health can affect a person's quality of life. This clinical trial evaluated the effects of Teramune Bronchus on lung health among healthy adult women. METHODS: The participants were women, aged 18 - 60 years old (n = 35). They sprayed either the proprietary essential oil based blended product (Teramune Bronchus) or a placebo into their throats 4-6 times per day during waking hours for 3 days. There was a baseline survey before using the spray and then follow-up data were collected at the end of day 3. The three primary outcomes for this study include a total bronchial symptom score, the chest domain in the Wisconsin Upper Respiratory Symptom Scale (WURSS), and subjective bronchial wellbeing. RESULTS: On day 3, the bronchial health of the participants who received the throat spray had significantly larger change scores when compared those with the placebo spray. All chest-related symptoms were resolved fully by the end of the trial for the participants who used Teramune. Participants using the intervention were almost twice as likely to say they felt better and believed the product helped them achieve lung health. CONCLUSION: This study provides evidence that the use of Teramune Bronchus supports respiratory health. Teramune Bronchus boosts respiratory health among healthy women through the use of plant-based essential oils.

Prevalence of endocrine disorders among children exposed to Lavender Essential Oil and Tea Tree Essential Oils.

Background: Lavender essential oil and tea tree essential oil have become popular ingredients in personal care and household products in recent decades. Questions regarding the safety of these oils in pediatric populations have been raised, proposing a link between these essential oils and endocrine disruption in children, specifically prepubertal gynecomastia. To date, no epidemiological studies have been conducted to evaluate this proposed link. Methods: This is a cross sectional study conducted among parents of children in the United States to identify the prevalence of endocrine disruption in children aged 2-15 years old. This study also evaluates the potential for a relationship between the exposure of lavender essential oil and tea tree essential oil products and endocrine disrupting outcomes. Results: In 556 children with a mean age of 6.33 (SD = 3.92), prevalence of endocrine disruption was .016 (SD = 0.13). No cases of prepubertal gynecomastia were identified in either group, and prevalence of precocious puberty, delayed puberty, growth hormone deficiency, and hypothyroidism were all consistent with population norms. Total risk of endocrine disorders among those exposed (0.0194) did not differ from the risk of those unexposed (0.0069). The risk ratio was 2.796 (95% CI: 0.352, 22.163, P = .458). Conclusion: Children who were regularly exposed to lavender or tea tree essential oils experienced the same risk of endocrine disorders as those who were not exposed.

Effects of antioxidant supplement on immune health and physical wellbeing: A randomized, controlled trial.

Background: Maintaining a healthy immune system came to the forefront of people's minds as SARS-CoV-2 (COVID-19) was introduced. Antioxidants contained in dark berries have been shown to support the physical wellbeing of otherwise healthy adults. Adding a supplement rich in dark berries and citrus essential oils contributes antioxidants to the body and serves as an aid to reduce free radicals. Aim: We evaluated the effects of an antioxidant rich supplement on immune health and overall physical wellbeing compared to a control group. Method: Participants were otherwise healthy adults, aged 18-60 years old, and were placed in either the antioxidant supplement group or control group using adaptive randomization. Data was collected at day 1 and 60. The Physical Health Questionnaire was used to measure the primary outcomes of this study. The immune health was reflected through the Jackson Symptom Scale. Results: 155 participants were analyzed. Participants who consumed the antioxidant beverage saw improvements to overall health which dramatically exceeded those of the control group. The sleep domain produced improvements which represented disturbances in sleep habits as they pertain to general health. Those in the supplement group who reported illness, had illnesses lasting 1-2 days while those in the control group had illnesses lasting from 1 to 9 days. Conclusion: Length of illness was shorter and sleep duration improved in the supplement group compared to the control group. Daily consumption of 60 ml of the antioxidant drink NingXia RedⓇ showed significant improvement after 60 days.

Aromatherapy blend of thyme, orange, clove bud, and frankincense boosts energy levels in post-COVID-19 female patients: A randomized, double-blinded, placebo controlled clinical trial.

BACKGROUND: A large proportion of individuals who have recovered from an acute COVID-19 infection continue to experience symptoms months later. Post-acute COVID-19 (long-haul COVID-19) can range from serious complications to quality of life symptoms such as fatigue or insomnia. The purpose of this study was to evaluate the potential for inhalation of essential oils to improve energy levels among otherwise healthy female survivors of acute COVID-19 who experience a lack of energy more than five months after recovery. This study was conducted in the United States in late 2021. METHOD: This was a randomized double blind, placebo controlled trial to evaluate the potential for inhalation of Longevity™, a proprietary essential oil blend manufactured by Young Living Essential Oils (Lehi, Utah, USA), on energy levels among female survivors of COVID-19 who continue to experience fatigue more than 5 months recovery from the acute infection. Forty women were randomized to two groups: intervention and placebo. Both groups inhaled the assigned product twice daily for fourteen consecutive days. Fatigue scores were measured using the Multidimensional Fatigue Symptom Inventory (MFSI). Secondary outcomes included scores on each of the MFSI's ten subscales. RESULTS: Individuals who inhaled the essential oil blend for 2 weeks had significantly lower fatigue scores after controlling for baseline scores, employment status, BMI, olfactory function, and time since diagnosis, with a large effect size (F (1,39) = 6.15, p = .020, partial eta squared = 0.198). Subscale analysis identified subscales of vigor, as well as global, behavioral, general, and mental fatigue as benefiting from the intervention. This study provides evidence that a proprietary aromatherapy blend can significantly improve energy levels among women who are experiencing fatigue after recovering from COVID-19.

Upper-limit agricultural dietary exposure to streptomycin in the laboratory reduces learning and foraging in bumblebees.

In the past decade, the broadcast-spray application of antibiotics in US crops has increased exponentially in response to bacterial crop pathogens, but little is known about the sublethal impacts on beneficial organisms in agroecosystems. This is concerning given the key roles that microbes play in modulating insect fitness. A growing body of evidence suggests that insect gut microbiomes may play a role in learning and behaviour, which are key for the survival of pollinators and for their pollination efficacy, and which in turn could be disrupted by dietary antibiotic exposure. In the laboratory, we tested the effects of an upper-limit dietary exposure to streptomycin (200 ppm)-an antibiotic widely used to treat bacterial pathogens in crops-on bumblebee (Bombus impatiens) associative learning, foraging and stimulus avoidance behaviour. We used two operant conditioning assays: a free movement proboscis extension reflex protocol focused on short-term memory formation, and an automated radio-frequency identification tracking system focused on foraging. We show that upper-limit dietary streptomycin exposure slowed training, decreased foraging choice accuracy, increased avoidance behaviour and was associated with reduced foraging on sucrose-rewarding artificial flowers flowers. This work underscores the need to further study the impacts of antibiotic use on beneficial insects in agricultural systems.

Recall and Interviewer Bias in Parental Report of Pediatric Exposure to Aromatic Plant Ingredients in Personal Care Products: Development and Validation of a More Accurate Approach.

Lavender and tea tree essential oils are traditionally considered to be mild, gentle, and safe for pediatric populations and are ubiquitous in personal care products. Recent case reports have proposed a potential association between exposure to these ingredients and endocrine disruption, but these reports contain misclassification bias. The purpose of this study is to develop a reliable and valid measurement instrument for the accurate classification of exposure to aromatic plant ingredients in personal care products to be used in epidemiological studies. This study tested the Aromatic Plant Ingredients and Child Health Survey (APICHS) for validity and reliability, contrasting it with the current approach used in clinician's offices. The APICHS was found to have exceptional sensitivity and specificity (100% and 92.86%, respectively) with a positive predictive value of 97.22%, far exceeding the sensitivity and specificity of the method currently in use. The APICHS is a valid, reliable tool for accurate classification of exposure to aromatic plant ingredients in personal care products and should be used for the avoidance of misclassification.

The relationship between lavender and tea tree essential oils and pediatric endocrine disorders: A systematic review of the literature.

OBJECTIVES: Essential oils are common ingredients in personal care products, little is known about the effects of chronic exposure to these ingredients in human health. It has been suggested that these two essential oils cause prepubertal gynecomastia and premature thelarche in children. The purpose of this study was to systematically review the evidence related to the proposed link between these essential oils and endocrine disruption METHODS: This study sought to investigate the proposed link between LEO and TTEO and endocrine disrupting outcomes by identifying and evaluating the clinical evidence regarding this topic. Studies qualified if the participants included prepubertal children who have experienced either prepubertal gynecomastia or premature thelarche. The Case Series Critical Appraisal Tool (CSCAT) was used to identify the reliability of the identified case series. The potential for evidence of causality was evaluated using the tool proposed by Murad. RESULTS: A total of four manuscripts were identified, describing a total of eleven cases reported to have experienced both the exposure and the outcome. Reporting of inclusion, demographic data, clinical data, and the potential for causality was found to be insufficient. This study did not find evidence to support the claim that tea tree essential oil is related to endocrine disruption in children, and little to no evidence to substantiate the proposed link between lavender essential oil and endocrine disruption in children. CONCLUSION: Because this potential link remains a concern among pediatric care providers and parents, epidemiological research to address the proposed link is needed.

Aromatherapy reduces fatigue among women with hypothyroidism: A randomized placebo-controlled clinical trial.

Background This randomized, blinded, placebo-controlled clinical trial identifies the effect of an aromatherapy blend of essential oils on fatigue, which is one of the most commonly unaddressed symptoms of hypothyroidism, by evaluating the effects of daily aromatherapy inhalation. Methods Participants included women aged 18-55 with a diagnosis of hypothyroidism. Women who had a history of thyroid cancer were excluded, due to the confounding effects of cancer on fatigue as the outcome of interest. Participants were randomized into two groups: the aromatherapy group, treated with inhalation of the essential oil blend, and the control group, treated with an odorless vegetable oil blend. The primary outcome was change from baseline in fatigue scores as measured by the Multidimensional Fatigue Symptom Inventory (MFSI), a validated instrument which measures multiple patterns of fatigue. Results After adjusting for baseline scores, no significant difference was found between the aromatherapy group and the control group at midpoint. Both groups experienced a reduction in symptoms during the first week of the intervention. At the endpoint, participants in the aromatherapy group had improved fatigue scores across all ten subscales, as compared to the control group. Not all improvements achieved statistical significance, indicating that the aromatherapy treatment has a greater effect on the subscales of global, affective, and general fatigue. Conclusions This is the first study to evaluate the effects of aromatherapy on fatigue among women with hypothyroidism. These findings provide evidence that regular inhalation of an aromatherapy blend may reduce fatigue among women with hypothyroidism, particularly in the areas of global, affective, and general fatigue.

Black elderberry (Sambucus nigra) supplementation effectively treats upper respiratory symptoms: A meta-analysis of randomized, controlled clinical trials.

Upper respiratory symptoms are often treated with over the counter drugs, antibiotics, and antiviral medications. Due to concerns about safety and efficacy, there is a demand for an alternative solution. Black elderberry (Sambucus nigra) has been used to treat cold and flu symptoms, but there are no large-scale studies or meta-analyses. This meta-analysis quantifies the effects of elderberry supplementation and evaluates moderators including vaccination status and the underlying pathology. This analysis included a total of 180 participants and evaluates moderators such as vaccination status and cause of the upper respiratory symptoms. Supplementation with elderberry was found to substantially reduce upper respiratory symptoms. The quantitative synthesis of the effects yielded a large mean effect size. These findings present an alternative to antibiotic misuse for upper respiratory symptoms due to viral infections, and a potentially safer alternative to prescription drugs for routine cases of the common cold and influenza.

Pattern and process in disclosure of health status by women with iatrogenically acquired hepatitis C.

Thirty-two women who acquired hepatitis C through prophylactic treatment for RH Haemolytic Disease participated in discussions about their decision to disclose their health status. Spouses, the woman's birth family and close friends were the most likely confidants. Children were either very likely or very unlikely to be informed. The women told spouses, own family members, friends, children and employers and 'near' co-workers if these latter groups were informed. Divulging to 'in laws' was more likely to be done by the partner. Disclosure to people in general was more likely to happen through third parties. Organizational aspects of the health system could result in exposure. Women seeking redress because of the iatrogenic nature of the infection disclosed through the media. The consequences of disclosure were varied. The results are discussed in the light of research on disclosure by comparable populations. Disclosure emerges as a stressful process demanding constant vigilance and active management.

Children's understanding of the causality of pain.

The ideas of 680 Irish schoolchildren aged 5-14 years about the causality of pain were studied as part of a wider investigation of children's understanding of pain. The results indicated an association between pain and 'transgression' consonant with the literature on children's beliefs about the causality of illness, but not reported in previous studies of children's ideas about pain. Developmental patterns were also noted in the data and one significant sex difference consistent with a previously reported trend.

Developmental aspects of children's definitions of pain.

As part of a wider research project aimed at investigating how children think about several aspects of pain, definitions of pain used by 680 Irish schoolchildren aged 5-14 years were examined to see if a developmental pattern could be identified in the acquisition of a verbally mediated concept of pain. The results are consonant with a Piagetian developmental model, suggesting the possibility of delineating typical concepts of pain which correspond to successive stages of cognitive development.