Bexmarilimab-induced macrophage activation leads to treatment benefit in solid tumors:The phase I/II first-in-human MATINS trial

Macrophage Clever-1 contributes to impaired antigen presentation and suppression of anti-tumor immunity. This first-in-human trial investigates the safety and tolerability of Clever-1 blockade with bexmarilimab in patients with treatment-refractory solid tumors and assesses preliminary anti-tumor efficacy, pharmacodynamics, and immunologic correlates. Bexmarilimab shows no dose-limiting toxicities in part I (n = 30) and no additional safety signals in part II (n = 108). Disease control (DC) rates of 25%–40% are observed in cutaneous melanoma, gastric, hepatocellular, estrogen receptor-positive breast, and biliary tract cancers. DC associates with improved survival in a landmark analysis and correlates with high pre-treatment intratumoral Clever-1 positivity and increasing on-treatment serum interferon γ (IFNγ) levels. Spatial transcriptomics profiling of DC and non-DC tumors demonstrates bexmarilimab-induced macrophage activation and stimulation of IFNγ and T cell receptor signaling selectively in DC patients. These data suggest that bexmarilimab therapy is well tolerated and show that macrophage targeting can promote immune activation and tumor control in late-stage cancer

Recent advances in the genetics of SDH-related paraganglioma and pheochromocytoma

The last 10 years have seen enormous progress in the field of paraganglioma and pheochromocytoma genetics. The identification of the first gene related to paraganglioma, SDHD, encoding a subunit of mitochondrial succinate dehydrogenase (SDH), was quickly followed by the identification of mutations in SDHC and SDHB. Very recently several new SDH-related genes have been discovered. The SDHAF2 gene encodes an SDH co-factor related to the function of the SDHA subunit, and is currently exclusively associated with head and neck paragangliomas. SDHA itself has now also been identified as a paraganglioma gene, with the recent identification of the first mutation in a patient with extra-adrenal paraganglioma. Another SDH-related co-factor, SDHAF1, is not currently known to be a tumor suppressor, but may shed some light on the mechanisms of tumorigenesis. An entirely novel gene associated with adrenal pheochromocytoma, TMEM127, suggests that other new paraganglioma susceptibility genes may await discovery. In addition to these recent discoveries, new techniques related to mutation analysis, including genetic analysis algorithms, SDHB immunohistochemistry, and deletion analysis by MLPA have improved the efficiency and accuracy of genetic analysis. However, many intriguing questions remain, such as the striking differences in the clinical phenotype of genes that encode proteins with an apparently very close functional relationship, and the lack of expression of SDHD and SDHAF2 mutations when inherited via the maternal line. Little is still known of the origins and causes of truly sporadic tumors, and the role of oxygen in the relationships between high-altitude, familial and truly sporadic paragangliomas remains to be elucidated

Otitis media in children:detection of effusion and influence on hearing

Abstract This study was undertaken to improve the diagnosis of otitis media and to investigate possible hearing loss caused by middle ear effusion (MEE) in small children. The accuracy of minitympanometry in detecting MEE was evaluated in 162 children. The finding was compared with the amount of effusion found in myringotomy. Minitympanometry proved to be an accurate method to detect MEE in young children, the sensitivity and specificity values being 79% and 93% in cooperative children but it had no value in non-cooperative children. Minitympanometric examination could be performed successfully with good cooperation in 87% of a total of 206 children in paediatric outpatient clinic. Impaired mobility of the tympanic membrane (TM) was the best sign of MEE in pneumatic otoscopy of 76 children, with sensitivity and specificity values of 75% and 90%, respectively. The influence of nitrous oxide (N2O) on MEE was tested by weighting the effusion found in myringotomy during general anaesthesia with and without N2O in 39 and 37 children, respectively. The mean weight of the effusion in the oxygen-air group did not differ from the weight in the N2O group, and thus peroperative findings in myringotomy are reliable. Studies on symptomatology and the temporal development of acute otitis media (AOM) during upper respiratory tract infection (URI) were based on three-month follow-up of 857 children. Symptoms of URI only were compared with symptoms of URI complicated by AOM in the same child in 138 children. The most important symptom associated with AOM was earache, with a relative risk of 21.3. Sore throat, night restlessness and fever at days 3-6 were also significantly associated with AOM, with relative risks of 3.2, 2.6 and 1.8, respectively. In 44 children under two years of age, earache, conjunctival symptoms and cloudy rhinitis were significantly associated with AOM. Temporal development of AOM was assessed from 250 episodes in 184 children. Sixty-three per cent of cases of AOM occurred during the first week after the onset of URI, peaking on days 2 to 5. The onset of AOM in children with a history of recurrent episodes of AOM did not differ from that in those who had experienced only a few episodes of AOM. No individual tendency was noticed among children suffering more than one AOM episode during follow-up. To assess the influence of the quantity and quality of MEE on hearing in small children, transient evoked otoacoustic emission (TEOAE) was performed under general anaesthesia before myringotomy in 185 ears of 102 children. Reduced TEOAEs indicating hearing loss were found in 83% of the ears with mucoid effusion and in 56% of the ears with non-mucoid effusion, the difference being statistically significant (p < 0.01). A significant negative correlation between the reproducibility of TEOAE responses and the amount of effusion was found (Spearman rank correlation coefficient r = -0.589, p < 0.001). Findings in minitympanometry correlated with the responses of TEOAE. Although parents are able to predict AOM quite reliably, various symptoms and the duration of URI seems to be of little value in helping the diagnosis of AOM. Detection of effusion in OM may be improven by minitympanometry in cooperative children. Any kind of effusion may cause hearing loss in small children, which must be considered when treating OM

Periodic fever, aphthous stomatitis, pharyngitis, and cervical adenitis syndrome:relapse and tonsillar regrowth after childhood tonsillectomy

Abstract Objectives/Hypothesis: Tonsillectomy is an effective treatment for periodic fever, aphthous stomatitis, pharyngitis, and cervical adenitis (PFAPA) syndrome, but the role of adenoidectomy, as well as later tonsillar regrowth, is unclear. To find out if the volume of lymphoid tissue is pivotal to the efficacy, we analyzed the association between the relapse of the symptoms of PFAPA syndrome and regrowth of tonsillar tissue after tonsillectomy or adenotonsillectomy. Study Design: Prospective cohort study of operated PFAPA pateints. Methods: We invited all patients that had undergone tonsillectomy or adenotonsillectomy due to PFAPA syndrome at the Oulu University Hospital, Oulu, Finland, between the years 1990 and 2007, at the age of ≤12 years, to a follow-up visit, after an average period of 9.8 years after their diagnoses. Out of the 132 invited, 94 (71%) participated in the follow-up study. Results: At the follow-up study visit, 5 (5%) of the 94 PFAPA syndrome cases experienced recurrent fevers. The regrowth of palatine tonsillar tissue was seen in four of them (80%) as compared to 19/89 (21%) of symptom-free patients (P = 0.006). Two of the patients with clear PFAPA relapse at the time of the study visit were reoperated with clear effect on the symptoms. At the time of the study visit, 59/63 (94%) of the patients who had undergone adenotonsillectomy and 30/31 of the patients (97%) who had undergone tonsillectomy earlier were free of fever flares (P = 0.99). Conclusion: Palatine tonsil regrowth was associated with PFAPA syndrome relapse after tonsillectomy. Reoperation might be a treatment option in these patients

Quality of life after free flap reconstruction for the cancer of the head and neck:comparison between five-year survivors and non-survivors

Abstract Background: Free flap surgery due to the cancer of the head and neck includes high risk of postoperative complications and a five-year mortality up to 50%. We aimed to study the relation between the quality of life (QoL) reported two years after the operation and the mortality during a next three-year follow-up. We aimed to study the relation between the quality of life (QoL) reported two years after the operation and the mortality during a next three-year follow-up. Methods: Free flap surgery due to the cancer of the head and neck includes high risk of postoperative complications and a five-year mortality up to 50%. We aimed to study the relation between the quality of life (QoL) reported two years after the operation and the mortality during a next three-year follow-up. We aimed to study the relation between the quality of life (QoL) reported two years after the operation and the mortality during a next three-year follow-up. Results: A total of 14 (26.4%) patients died during the follow-up. The RAND-36 scores of the deceased were lower in domains “general health”, “energy”, “emotional role functioning” and “emotional well-being”. In UW-QOL tool, the domains “swallowing“ and “mood”, as well as experienced QoL were lower in the non-survivors. In EORTC QLQ assessment the non-survivors reported lower QoL in domains “global health status“, “physical functioning”, “role functioning“, “swallowing”, and “felt ill“. Conclusions: Based on our results, poor long-term survival is related to poor QoL reported two years after surgery. The difference was found in general domains of QoL tools indicating that poor QoL is a surrogate of chronic health problems having an impact on the long-term survival

Nielurisaleikkaus elämänlaatua parantamaan

Abstrakti Nielurisaleikkauksen yleisimmät aiheet ovat toistuva tai pitkäaikainen nielurisatulehdus, nielurisojen liikakasvu ja nielupaise. Leikkauksessa nielurisat poistetaan yleensä kokonaan, mutta säästävämmän osapoiston osuus on kasvanut etenkin lasten nielurisavaivojen hoidossa. Toipumisvaiheelle tyypillisiä ongelmia ovat kipu, jälkiverenvuoto ja nestehukka

Cause-specific mortality in patients with head and neck cancer:long-term follow-up of a population-based cohort from 1986 to 2012 accounting for competing risks

Abstract Objectives: Recent recommendations for treating head and neck cancer (HNC) patients favor an individualized approach. Expected long-term survival — together with short-term survival — after diagnosis is the primary focus in assessing the treatment modality and follow-up scheme. “Disease-specific” survival up to five years is often used for measuring the prognosis and for assessing treatment methods. However, especially long-term survival is strongly affected by competing causes of death among HNC patients. Materials and Methods: The long-term prognosis of patients with HNC in terms of mortality from both cancer and competing causes was analyzed according to recent methodological guidelines by examining cumulative incidence functions and models for cause-specific hazards and sub-distribution hazards in a population based cohort of 220 patients treated in a tertiary care center in Northern Finland. Results: In addition to well-known tumor-related factors, mortality from HNC was associated with older age. The mortality from other causes of death was strongly dependent on age and Charlson’s Comorbidity Index, but less on gender. When demonstrating the importance of individualized approach in simulated patients, the mortality was highly variable across patients with similar cancer status, but with different comorbidities or age. Conclusion: The overall survival pattern of HNC patients depends not only on their cancer characteristics, but also varies greatly according to their age and comorbidities. Our findings support the need for individualized treatment and follow-up protocols, and active management of comorbid diseases. Appropriate methods for analyzing competing risks should be used when presenting survival estimates of cancer patients

Tonsil mycobiome in PFAPA (periodic fever, aphthous stomatitis, pharyngitis, adenitis) syndrome:a case-control study

Abstract Periodic fever, aphthous stomatitis, pharyngitis and adenitis syndrome (PFAPA) is the most common periodic fever syndrome in children with unknown etiology, effectively treated with tonsillectomy. Earlier we have shown that tonsil microbiome is different in patients with PFAPA as compared to that in controls. Recently, fungal microbiome, mycobiome, has been linked to the pathogenesis of inflammatory diseases. We now investigated the role of mycobiome of tonsils in PFAPA. Random forest classification, a machine learning approach, was used for the analysis of mycobiome data. We examined tonsils from 30 children with PFAPA and 22 control children undergoing tonsillectomy for non-infectious reasons. We identified 103 amplicon sequence variants, mainly from two fungal phyla, Ascomycota and Basidiomycota. The mean relative abundance of Candida albicans in the tonsil mycobiome was 11% (95% CI: 19 to 27%) in cases and 3.4 % (95% CI: -0.8% to 8%) in controls, p =0.104. Mycobiome data showed no statistical difference in differentiating between PFAPA cases and controls compared to a random chance classifier (area under the curve (AUC) = 0.47, SD = 0.05, p = 0.809). In conclusion, in this controlled study, tonsillar mycobiome in children with PFAPA syndrome did not differ from that of the controls

Perioperative risk factors for one-year mortality in patients with free-flap reconstruction due to cancer of the head and neck

Abstract Purpose: Head and neck cancer requiring free-flap reconstruction is associated with relatively high mortality. We aimed to evaluate perioperative risk factors for 1-year mortality in this patient group. Methods: This is a single-center retrospective analysis of 204 patients operated during 2008 to 2018. Results: A total of 47 (23.0%) patients died within 1 year. In univariate analysis, there were no differences in the intraoperative course between 1-year survivors and nonsurvivors. Among the 1-year nonsurvivors, preoperative albumin level was lower (39 [36 to 43] vs 42 [39 to 44], P = 0.032) and the Sequential Organ Failure Assessment admission score was higher (4 [3 to 5] vs 3 [2 to 4], P = 0.003) than those of the 1-year survivors. Among the nonsurvivors, the preoperative and postoperative levels of leukocytes were higher (7.6 [6.7 to 9.5] vs 6.9 [5.5 to 8.4], P = 0.002; 11.4 [9.0 to 14.2] vs 8.7 [7.2 to 11.3], P < 0.001). The highest odds ratios for 1-year mortality in multivariate analysis were American Society of Anesthesiologists A classification greater than 2 (3.9 CI 1.4 to 10.5), male gender (4.0 CI 1.5 to 11), and increase in leukocyte count (1.3 CI 1.1 to 1.5). Conclusions: One-year nonsurvivors had higher American Society of Anesthesiologists classification and were more often men. The postoperative inflammatory markers were higher in nonsurvivors, while the intraoperative course did not have a significant impact on the 1-year mortality

Swallowing-related quality of life after free flap surgery due to cancer of the head and neck

Abstract Purpose: Treatment of head and neck cancers (HNC) often leads to impairment in speech and swallowing functions. This study evaluated swallowing problems and the impact of complications on swallowing-related QOL after free flap surgery for HNC. Methods: Swallowing-related QOL was assessed using MDADI and SWAL questionnaires. Results: Of 45 assessed patients, 25 (45.5%) had at least one postoperative complication. Patients reported less than <86 points in 8/9 SWAL-QOL domains. The SWAL-QL total score or MDADI composite scores were not related to surgical complications. Those with medical complications had lower scores in SWAL-QOL domains of mental health (82.8 (21.8) vs 65.5 (24.2), p = 0.024) and sleep (77.6 (23.0) vs 52.3 (24.3), p = 0.003). Conclusions: In conclusion, swallowing related QOL is significantly impaired after 2 years of the tumor resection and free flap reconstruction for cancer of the head and neck, when using the cut-off value of 86 points in SWAL-QOL assessment tool. Surgical complications did not have an impact on swallowing-related QOL but medical complications were related to impairment in general QOL-related domains