New Insight into Laryngo-Tracheal Surgery: High-Flow Oxygen Therapy to Prevent Early Complications after Surgery.

BACKGROUND: Early post-operative airway management after laryngo-tracheal surgery is crucial. Acute respiratory failure due to glottis' edema may occur, requiring reintubation. This can prolong ventilatory assistance, jeopardizing anastomosis. To date, only judicious steroid administration and fluid management are available to avoid more invasive procedures. High-flow oxygen therapy (HFOT) is a noninvasive O2 support method providing humidification, warmed air, and Positive End-Expiratory Pressure (AIRVO2). No data about HFOT use to prevent early complications after laryngo-tracheal surgery are reported in the literature. METHODS: Between September 2020 and September 2022, 107 consecutive patients who underwent laryngo-tracheal surgery received HFOT (Group A). Data and long-term results were compared with those of 80 patients operated between September 2018 and August 2020 (Group B), when HFOT was not available. All patients were operated in a single center. No pre- or post-operative settings changed, except for HFOT introduction. We analyzed and compared the risk for "delayed" reintubation (unexpected reintubation within the first 24-48 h after extubating/laryngeal mask removal) in the two groups. RESULTS: No patients reported HFOT-related adverse events. The control group (B) presented "delayed" reintubation in 37% (p = 0.027), intensive care unit admission in 67% (p = 0.005) and longer hospital stay (p = 0.001) compared to the HFOT group (A). The minor complications' rate was 3% in both group and overall mortality was 0%. Re-stenosis was described in 4.6% of the HFOT group, without a statistically significant difference (p = 0.7006). CONCLUSIONS: Our study is the first to investigate HFOT use in patients undergoing laryngo-tracheal surgery, potentially representing a consistent innovation in the peri-operative management of these patients. With the limitation of a retrospective series, we would suggest HFOT use for preventing post-operative reintubation rate, possibly reducing ICU admissions and hospital stays.

New perspectives on tracheal resection for COVID-19-related stenosis: A propensity score matching analysis.

OBJECTIVE: The large number of patients with COVID-19 subjected to prolonged invasive mechanical ventilation has been expected to result in a significant increase in tracheal stenosis in the next years. The aim of this study was to evaluate and compare postoperative outcomes of patients who survived COVID-19 critical illness and underwent tracheal resection for postintubation/posttracheostomy tracheal stenosis with those of non-COVID-19 patients. METHODS: It was single-center, retrospective study. All consecutive patients with post-intubation/posttracheostomy tracheal stenosis who underwent tracheal resection from February 2020 to March 2022 were enrolled. A total of 147 tracheal resections were performed: 24 were in post-COVID-19 patients and 123 were in non-COVID-19 patients. A 1:1 propensity score matching analysis was performed, considering age, gender, body mass index, and length of stenosis. After matching, 2 groups of 24 patients each were identified: a post-COVID-19 group and a non-COVID group. RESULTS: No mortality after surgery was registered. Posttracheostomy etiology of stenosis resulted more frequently in post-COVID-19 patients (n = 20 in the post-COVID-19 group vs n = 11 in the non-COVID-19 group; P = .03), as well as intensive care unit admissions during the postoperative period (16 vs 9 patients; P = .04). Need for postoperative reintubation for glottic edema and respiratory failure was higher in the post-COVID-19 group (7 vs 2 postoperative reintubation procedures; P = .04). Postoperative dysphonia was observed in 11 (46%) patients in the post-COVID-19 group versus 4 (16%) patients in the non-COVID-19 group (P = .03). CONCLUSIONS: Tracheal resection continues to be safe and effective in COVID-19-related tracheal stenosis scenarios. Intensive care unit admission rates and postoperative complications seem to be higher in post-COVID-19 patients who underwent tracheal resection compared with non-COVID-19 patients.

Prognostic Factors of Non-Predominant-Lepidic Lung Adenocarcinoma Presenting as Ground Glass Opacity: Results of a Multicenter Study.

This study aims to define the clinicopathological characteristics and prognosis of non-predominant lepidic invasive adenocarcinoma presenting as Ground Glass Opacity (GGO) nodules. The goal is to assess statistical relationships between histology, tumor size, location, and the incidence of relapse and lymph node dissemination. A retrospective multicenter study was conducted, including patients with GGO observed on CT scans between 2003 and 2021. Anamnestic, radiological, and histological data, as well as SUV values, lymphatic and vascular invasion, pathological stage, resection type, and adjuvant treatment, were analyzed. The primary endpoints were to evaluate prognostic factors for death and recurrence using Cox regression analysis. All 388 patients, including 277 with non-predominant lepidic invasive adenocarcinoma and 161 with lepidic adenocarcinoma, underwent curative anatomical resection. Non-predominant lepidic invasive adenocarcinoma demonstrated a worse prognosis than lepidic adenocarcinoma (p = 0.001). Independent prognostic factors for death and recurrence included lymph node involvement (p = 0.002) and vascular and lymphatic invasion (p < 0.001). In conclusion, non-predominant lepidic invasive adenocarcinoma and lymphatic and vascular invasion are prognostic factors for death and recurrence in GGO patients. Results suggest adjuvant treatment in the case of pN1-N2 disease, emphasizing the necessity of lymphadenectomy (sampling or systematic) for accurate staging and subsequent therapeutic procedures.

Biomarkers for Salvage Therapy in Testicular Germ Cell Tumors.

The outcome of metastatic testicular germ cell tumor patients has been dramatically improved by cisplatin-based chemotherapy combinations. However, up to 30% of patients with advanced disease relapse after first-line therapy and require salvage regimens, which include treatments with conventional-dose chemotherapy or high-dose chemotherapy with autologous stem cell transplantation. For these patients, prognosis estimation represents an essential step in the choice of medical treatment but still remains a complex challenge. The available histological, clinical, and biochemical parameters attempt to define the prognosis, but they do not reflect the tumor's molecular and pathological features and do not predict who will exhibit resistance to the several treatments. Molecular selection of patients and validated biomarkers are highly needed in order to improve current risk stratification and identify novel therapeutic approaches for patients with recurrent disease. Biomolecular biomarkers, including microRNAs, gene expression profiles, and immune-related biomarkers are currently under investigation in testicular germ cell tumors and could potentially hold a prominent place in the future treatment selection and prognostication of these tumors. The aim of this review is to summarize current scientific data regarding prognostic and predictive biomarkers for salvage therapy in testicular germ cell tumors.

Do More with Less? Lobectomy vs. Segmentectomy for Patients with Congenital Pulmonary Malformations.

BACKGROUND: Congenital Pulmonary Malformations (CPMs) are rare benign lesions potentially causing infective complications and/or malignant transformation, requiring surgery even when asymptomatic. CPMs are rare in adulthood but potentially detected at any age. There is not a consensus on the correct extent of resection in both adults and paediatrics. This retrospective multicentric study aims to identify the appropriate surgical resection to prevent the recurrence of the related respiratory symptoms. METHODS: Between 2010 and 2020, a total of 96 patients (adults and pediatrics) underwent surgery for CPMs in 4 centers. A 2:1 propensity score matching (considering sex and lesion side) was performed, identifying 2 groups: 50 patients underwent lobectomy (group A) and 25 sub-lobar resections (group B). Clinical and histopathological characteristics, early and late complications, and symptom recurrence were retrospectively analyzed and compared between the two groups by univariate and multivariate analysis. RESULTS: Patients who underwent lobectomy had a statistically significant lower rate of recurrence (4% vs. 24% of group B, p = 0.014) and a lower rate of intraoperative complications (p = 0.014). Logistic regression identified sub-lobar resection (p = 0.040), intra- and post-operative complications (p = 0.105 and 0.022),and associated developed neoplasm (p = 0.062) as possible risk factors for symptom recurrence after surgery. CONCLUSIONS: Pulmonary lobectomy seems to be the most effective surgical treatment for CPMs, guaranteeing the stable remission of symptoms and a lower rate of intra- and postoperative complications. To our knowledge, this is one of the largest studies comparing lobectomy and sub-lobar resections in patients affected by CPMs, considering the low incidence worldwide.

Preoperative SARS-CoV-2 Infection Screening before Thoracic Surgery during COVID-19 Pandemic: A Multicenter Retrospective Study.

Objectives: During coronavirus disease (COVID-19) pandemic, preoperative screening before thoracic surgery is paramount in order to protect patients and staff from undetected infections. This study aimed to determine which preoperative COVID-19 screening tool was the most effective strategy before thoracic surgery. Methods: This retrospective cohort multicenter study was performed at 3 Italian thoracic surgery centers. All adult patients scheduled for thoracic surgery procedures from 4th March until 24th April, 2020, and submitted to COVID-19 preoperative screenings were included. The primary outcome was the yield of screening of the different strategies. Results: A total of 430 screenings were performed on 275 patients; 275 anamnestic questionnaires were administered. 77 patients were screened by an anamnestic questionnaire and reverse transcriptase polymerase chain reaction (RT-PCR). 78 patients were selected to combine screening with anamnestic questionnaire and chest computed tomography (CT). The positive yield of screening using a combination of anamnestic questionnaire and RT-PCR was 7.8% (95% CI: 2.6-14.3), while using a combination of anamnestic questionnaire and chest CT was 3.8% (95% CI: 0-9). Individual yields were 1.1% (95% CI: 0-2.5) for anamnestic questionnaire, 5.2% (95% CI: 1.3-11.7) for RT-PCR, and 3.8% (95% CI: 0-9). Conclusions: The association of anamnestic questionnaire and RT-PCR is able to detect around 8 positives in 100 asymptomatic patients. This combined strategy could be a valuable preoperative SARS-CoV-2 screening tool before thoracic surgery.

Immune checkpoint inhibitors and Chimeric Antigen Receptor (CAR)-T cell therapy: Potential treatment options against Testicular Germ Cell Tumors.

Germ cell tumors (GCTs) represent a heterogeneous neoplasm family affecting gonads and rarely occurring in extragonadal areas. Most of patients have a good prognosis, often even in the presence of metastatic disease; however, in almost 15% of cases, tumor relapse and platinum resistance are the main challenges. Thus, novel treatment strategies with both improved antineoplastic activity and minor treatment-related adverse events compared with platinum are really expected. In this context, the development and the high activity demonstrated by immune checkpoint inhibitors in solid tumors and, subsequently, the interesting results obtained from the use of chimeric antigen receptor (CAR-) T cell therapy in hematological tumors, have stimulated research in this direction also in GCTs. In this article, we will analyze the molecular mechanisms underlying the immune action in the development of GCTs, and we will report the data from the studies that tested the new immunotherapeutic approaches in these neoplasms.

Remote Adipose Tissue-Derived Stromal Cells of Patients with Lung Adenocarcinoma Generate a Similar Malignant Microenvironment of the Lung Stromal Counterpart.

Cancer alters both local and distant tissue by influencing the microenvironment. In this regard, the interplay with the stromal fraction is considered critical as this latter can either foster or hamper the progression of the disease. Accordingly, the modality by which tumors may alter distant niches of stromal cells is still unclear, especially at early stages. In this short report, we attempt to better understand the biology of this cross-talk. In our "autologous stromal experimental setting," we found that remote adipose tissue-derived mesenchymal stem cells (mediastinal AMSC) obtained from patients with lung adenocarcinoma sustain proliferation and clonogenic ability of A549 and human primary lung adenocarcinoma cells similarly to the autologous stromal lung counterpart (LMSC). This effect is not observed in lung benign diseases such as the hamartochondroma. This finding was validated by conditioning benign AMSC with supernatants from LAC for up to 21 days. The new reconditioned media of the stromal fraction so obtained, was able to increase cell proliferation of A549 cells at 14 and 21 days similar to that derived from AMSC of patients with lung adenocarcinoma. The secretome generated by remote AMSC revealed overlapping to the corresponding malignant microenvironment of the autologous local LMSC. Among the plethora of 80 soluble factors analyzed by arrays, a small pool of 5 upregulated molecules including IL1-ß, IL-3, MCP-1, TNF-α, and EGF, was commonly shared by both malignant-like autologous A- and L-MSC derived microenvironments vs those benign. The bioinformatics analysis revealed that these proteins were strictly and functionally interconnected to lung fibrosis and proinflammation and that miR-126, 101, 486, and let-7-g were their main targets. Accordingly, we found that in lung cancer tissues and blood samples from the same set of patients here employed, miR-126 and miR-486 displayed the highest expression levels in tissue and blood, respectively. When the miR-126-3p was silenced in A549 treated with AMSC-derived conditioned media from patients with lung adenocarcinoma, cell proliferation decreased compared to control media.

Subungual Metastasis from Ovarian Cancer: Case Report and Brief Review of the Literature.

Introduction: Visceral solid cancers can metastasize in almost any organ, including the skin and its appendages. Case Presentation: We report here the case of a 19-year-old Caucasian girl carrying a diagnosis of malignant germ cell tumor of the ovary, with pulmonary and brain metastases, that developed a painful red-violaceous subungual papule of the 4th finger of the left hand, associated with an over-curvature of the nail plate. Dermoscopy was characterized initially by different shades of pink and red, while after few weeks, it showed black pigmentation due to subcorneal hematomas, hemorrhagic crusts, and a rainbow pattern. Histology confirmed a diagnosis of a metastasis from a poorly differentiated carcinoma of ovarian origin. Discussion and Conclusion: A brief review on the diagnosis and treatment of subungual metastases is reported.

Parenchymal Sparing Surgery for Lung Cancer: Focus on Pulmonary Artery Reconstruction.

Reconstruction of the pulmonary artery (PA) associated with lobectomy for the radical resection of lung cancer has been progressively gaining diffusion in lung cancer surgery as a safe and effective therapeutic option that may allow radical resection when lobectomy is not technically feasible, avoiding pneumonectomy. There are some controversial aspects concerning the intraoperative and perioperative management of a sleeve resection with PA reconstruction that may influence the outcome. In the present article, the authors have analyzed some of the main technical and oncological aspects to take stock of what they have learned from their lung-sparing operations experience over time. PA reconstruction may require prosthetic materials including different options with variable cost. A main concern in vascular reconstructive procedures is avoiding tension on the anastomosis. When PA reconstruction is required, appropriate anticoagulation management is crucial. Results from the main literature data confirm the reliability of lobectomy associated with PA reconstruction in terms of perioperative morbidity and long-term survival. Sleeve lobectomy and PA reconstruction can be performed safely and effectively even after induction therapy.

Bilateral Ultrasound-Guided Erector Spinae Plane Block for Pectus Excavatum Surgery: A Retrospective Propensity-Score Study.

OBJECTIVE: Pectus excavatum (PE) repair is burdened by severe postoperative pain. This retrospective study aimed to determine whether the analgesic effect of ultrasound-guided erector spinae plane block (ESPB) plus standard intravenous analgesia (SIVA) might be superior to SIVA alone in pain control after PE surgical repair via Ravitch or Nuss technique. DESIGN: A retrospective cohort study. SETTING: At a university hospital. PARTICIPANTS: All participants were scheduled for surgical repair of PE. INTERVENTIONS: From January 2017 to December 2019, all patients who received ESPB plus SIVA or SIVA alone were investigated retrospectively. A 2:1 propensity-score matching analysis considering preoperative variables was used to compare analgesia efficacy in 2 groups. All patients received a 24-hour continuous infusion of tramadol, 0.1 mg/kg/h, and ketorolac, 0.05 mg/kg/h, via elastomeric pump, and morphine, 2 mg, intravenously as a rescue drug. The ESPB group received preoperative bilateral ESPB block. Postoperative pain, reported using a numerical rating scale at 1, 12, 24, and 48 hours after surgery; the number of required rescue doses; total postoperative morphine milligram equivalents consumption; and the incidence of postoperative nausea and vomit were analyzed. MEASUREMENT AND MAIN RESULTS: A total of 105 patients were identified for analysis. Propensity-score matching resulted in 38 patients in the SIVA group and 19 patients in the ESPB group. Postoperative pain, the number of rescue doses, and postoperative nausea and vomit incidences were lower in the ESPB group (p < 0.005). CONCLUSIONS: Erector spinae plane block may be an effective option for pain management after surgical repair of PE as part of a multimodal approach. This study showed good perioperative analgesia, opioid sparing, and reduced opioid-related adverse effects.

Inflammatory Biomarkers for Outcome Prediction in Patients With Metastatic Testicular Cancer.

Germ cell tumors are the most common malignant tumors in male young adults. Platinum-based chemotherapy has dramatically improved the outcome of metastatic germ cell tumor patients and overall cure rates now exceed 80%. The choice of medical treatment can be guided by the prognosis estimation which is an important step during the decision-making process. IGCCCG classification plays a pivotal role in the management of advanced disease. However, histological and clinical parameters are the available factors that condition the prognosis, but they do not reflect the tumor's molecular and pathological features and do not predict who will respond to chemotherapy. After first-line chemotherapy 20%-30% of patients relapse and for these patients, the issue of prognostic factors is far more complex. Validated biomarkers and a molecular selection of patients that reflect the pathogenesis are highly needed. The association between cancer-related systemic inflammation, tumorigenesis, and cancer progression has been demonstrated. In the last years, several studies have shown the prognostic utility of immune-inflammation indexes in different tumor types. This review analyzed the prognostic impact of inflammatory markers retrieved from routine blood draws in GCT patients.

Successful Total Tracheal Replacement by Cryopreserved Aortic Allograft in a Patient Post-COVID-19 Infection.

This is the first report to our knowledge of a successful total tracheal replacement in a post-COVID-19 patient by cryopreserved aortic allograft. The graft was anastomosed to the cricoid and carina; a silicon stent was inserted to ensure patency. The patient was extubated on the operative table and was immediately able to breathe, speak, and swallow. No immunosuppression was administered. Three weeks after surgery, the patient was discharged from hospital in excellent health, and was able to resume his normal lifestyle, work, and activity as an amateur cyclist. Two months after surgery, the patient assumes aerosol with saline solution three times per day and no other therapy; routine bronchoscopy to clear secretions is no longer needed.

Anesthetic Management of an Adult Patient With Down Syndrome for Thoracic Surgery.

The anesthetic management of adult patient with Down syndrome (DS) can be challenging due to poor patient cooperation, age-related comorbidities, and a possible difficult airway. Thoracic anesthesia requires an advanced airway management; thus, treatment of DS patients can be particularly demanding. An accurate preoperative assessment is paramount in order to plan a well-designed perioperative strategy in advance. This report describes the anesthetic management of an adult patient affected by DS who underwent pleural decortication for pleural empyema.

Case Report: Stevens-Johnson Syndrome and Hepatotoxicity Induced by Osimertinib Sequential to Pembrolizumab in a Patient With EGFR-Mutated Lung Adenocarcinoma.

Background: Lung cancer is a complex disease with many subtypes. However, histochemical characteristics, and genetic mutation determinations are contributing to better define therapeutic targets and new drugs. Although this guarantees patients the possibility of obtaining tailored treatment, it makes it more difficult for clinicians patient management more difficult for clinicians who have to define the most suitable therapeutic strategy and to deal with new treatment-related adverse events (TRAEs). It has been seen that the administration of a tyrosine kinase inhibitor (TKI) sequential to an immune checkpoint inhibitor (ICI) can lead to a higher rate of severe and life-threatening TRAEs. We report the case of a patient with advanced non-small cell lung cancer (NSCLC) who experienced severe hepatotoxicity and Stevens-Johnson syndrome (SJS) induced by osimertinib sequential to pembrolizumab. Case presentation: A 54-year-old woman with advanced NSCLC received one cycle of chemotherapy plus pembrolizumab after diagnosis. Ten days later she began osimertinib 80 mg daily because epidermal growth factor receptor (EGFR) analysis had revealed an exon 19 deletion. On day 23 of osimertinib the patient experienced an episode of grade (G) 3 hepatotoxicity resolved by discontinuing osimertinib and corticosteroid therapy. The patient restarted osimertinib 80 mg daily after the remission of symptoms but was hospitalized 14 days later following a second episode of severe G3 hepatotoxicity and the onset of SJS, successfully treated with high-dose corticosteroids. Despite the short exposure to osimertinib, the patient obtained a good pathological response. Conclusion: It is important to alert clinicians to carefully evaluate the sequential therapeutic strategy in patients with NSCLC who are candidates for TKI- or ICI-based treatment. Our experience suggests that the use of tyrosine kinase inhibitors (TKIs) as front-line treatment is a more reasonable and safe option for EGFR-mutated lung adenocarcinoma, with ICIs considered as a possible further treatment in sequential approaches.

Melphalan as a Promising Treatment for BRCA-Related Ovarian Carcinoma.

INTRODUCTION: Melphalan, as a bifunctional alkylating agent has been shown to be selectively efficient in BRCA-deficient case reports of epithelial ovarian cancer (EOC). The clinical benefit of melphalan on unselected platinum-resistant EOC population and stratified by BRCA status has not been clearly elucidated. We aimed to determine the response to melphalan in patients with recurrent EOC after platinum-based therapy. MATERIAL AND METHODS: This retrospective observational study included patients with recurrent EOC treated with melphalan between February 2007 to July 2020. Eligibility criteria included having a histological confirmation of EOC, previous treatment with carboplatin plus paclitaxel regimens, and disease recurrence during treatment with or within 6 months of the end of the platinum-based chemotherapy. RESULTS: A total of 75 platinum-resistant EOC patients were enrolled. Median age was 69 years (range 41-82). Median of previous therapies before melphalan was 4 (range 1-7). We observed a median follow-up of 32 months (range 1-62), progression-free survival (PFS) and overall survival (OS) of 3.6 months (range 2.9-4.7) and 9.5 months (range 8.0-14.1), respectively. In the whole population, 1 complete response, 6 partial responses and 37 stable diseases were registered with an overall clinical benefit rate of 58.7%. In BRCA1/2 mutant patients, we showed a significant longer PFS compared to BRCA1/2 wild type patients (6.2 versus 2.6 months; hazard ratio (HR) 0.25, 95% confidence interval (CI) 0.10-0.61; p=0.002). Moreover, a trend was seen for BRCA1/2 mutants to have a better OS (25.9 versus 8.0 months; HR 0.38; 95% CI 0.12-1.19; p=0.097). CONCLUSIONS: Our study represents the largest cohort of heavily-pretreated EOC patients receiving melphalan treatment. Here, we report a considerable clinical activity of melphalan chemotherapy, more evident in a subset of BRCA1/2 mutated patients. Prospective studies to validate these findings are warranted.

Vitamin D Deficiency in Testicular Cancer Survivors: A Systematic Review.

Testicular cancer (TC) is the most frequent tumor in young males. In the vast majority of cases, it is a curable disease; therefore, very often patients experience a long survival, also due to their young age at diagnosis. In the last decades, the role of the vitamin D deficiency related to orchiectomy has become an increasingly debated topic. Indeed, vitamin D is essential in bone metabolism and many other metabolic pathways, so its deficiency could lead to various metabolic disorders especially in long-term TC survivors. In our article, we report data from studies that evaluated the incidence of hypovitaminosis D in TC survivors compared with cohorts of healthy peers and we discuss molecular mechanisms and clinical implications.

Laryngeal mask versus endotracheal tube for airway management in tracheal surgery: a case-control matching analysis and review of the current literature.

OBJECTIVES: The endotracheal tube (ETT) and the laryngeal mask airway (LMA) are possible strategies for airway management during tracheal resection and reconstruction for tracheal and laryngotracheal stenosis. The goal of the study was to analyse and compare outcomes in the LMA and ETT groups. METHODS: Between 2003 and 2020, a total of 184 patients affected by postintubation, post-tracheostomy and idiopathic stenosis who had tracheal or laryngotracheal resections and reconstructions via a cervicotomy were retrospectively enrolled in this single-centre study. In 29 patients, airway management was achieved through LMA during tracheal surgery, whereas in 155 patients, it was achieved through ETT. A case-control matching analysis was performed with a 1:1 ratio, according to age, gender, body mass index, aetiology and length of stenosis (1-4 cm), resulting in 22 patients managed through LMA (LMA group) matched with 22 patients managed through ETT (ETT group). RESULTS: No significant differences were found in the reintubation rate, 30-day mortality and postoperative length of stay. Operative time was shorter in patients with LMA (96.23 ± 34.72 min in the ETT group vs 76.14 ± 26.94 min in the LMA group; P = 0.043). Intensive care unit (ICU) admission rate and stay were lower in the LMA group [18 in the ETT group vs 8 in the LMA group, odds ratio = 10.17, confidence interval (CI) 95% 1.79-57.79; P = 0. 009; 22.77 ± 16.68 h in ETT group vs 9.23 ± 13.51 h in LMA group; P = 0.005]. Dysphonia was more frequent in the ETT group than in the LMA group (20 in the ETT group vs 11 in the LMA group, odds ratio = 13.79, CI 95% 1.86-102; P = 0.010). CONCLUSIONS: LMA is a feasible option for airway management in tracheal surgery, with lower operative time, ICU admission rate, ICU length of stay and postoperative dysphonia occurrence.