Quality of life after operative treatment of sinonasal inverted papilloma - a prospective study.

BACKGROUND: Studies assaying morbidity related to sinonasal inverted papilloma (SNIP) and its treatment are lacking. We evaluated how operative treatment of SNIP affects patients' health-related quality of life (HRQoL) and symptoms. METHODS: We prospectively recruited consecutive patients (n=52) operated for SNIP at Helsinki University Hospital, between years 2016 and 2019. In total, 42 patients filled in the 15D, a generic HRQoL instrument and a symptom questionnaire preoperatively and at 1 year and at 2 years postoperatively. The 15D HRQoL scores were compared to those of age- and sex-standardized general population. RESULTS: Patients' mean baseline score for discomfort and symptoms (one of the 15D dimensions) was significantly better compared to general population, but this difference faded postoperatively. Frequency of epistaxis, nasal obstruction, lowered sense of smell, headache, tinnitus and epiphora decreased significantly during follow-up whereas frequency of numbness of the face or mouth increased. Difference in the mean 15D score of the patients compared with general population was insignificant at baseline and at 1 year and at 2 years postoperatively. CONCLUSIONS: Measured by a generic HRQoL questionnaire, the mean score for discomfort and symptoms deteriorated after operative treatment of SNIP. Despite a relief of many symptoms, care should be taken when operating a benign tumour, as surgery may cause morbidity.

Patient injuries in operative rhinology during a ten-year period: Review of national patient insurance charts.

OBJECTIVES: To assess factors contributing to patient injuries in operative rhinology. DESIGN: Data of the accepted patient injury claims involving operative rhinology, between the years 2001 and 2011, were obtained from the Finnish Patient Insurance Centre registry. Two senior otolaryngologists analysed and evaluated the injury mechanisms. MAIN OUTCOME MEASURES: Analysis and classification of factors contributing to patient injuries. RESULTS: During the ten-year study period, there were 67 patient injuries in operative rhinology, comprising 36% of all patient injuries in otorhinolaryngologic surgery. The majority (78%) of patients were treated in university or central hospitals and almost all (90%) by fully trained otolaryngology specialists. The factors contributing to the injuries were errors in surgical technique, like lesions to the orbit, skull base and meninges, and adjacent nerves, as well as mistakes with removable packings left in situ. Nearly half of the patients had undergone endoscopic sinus surgery. One patient died because of bleeding from the intracranial artery. Fourteen patients (21%) needed a re-operation due to the injury. CONCLUSIONS: Patient injuries in rhinology were caused by typical complications of common operations performed by otorhinolaryngology specialists. The increased volume of endoscopic sinus surgery was evident also in patient injuries.

A tailored counseling and home-based rehabilitation program to increase physical activity and improve mobility among community-dwelling older people after hospitalization: protocol of a randomized controlled trial.

BACKGROUND: Physical activity (PA) decreases during hospitalization. In particular, the amount of PA engaged in by older people who are hospitalized following musculoskeletal injury is likely to be limited for months after discharge home. Given the importance of an active lifestyle for their recovery and the prevention of future adverse outcomes, there is clearly a need for interventions to increase PA. This article describes the protocol of a randomized controlled trial set up to investigate the effects of a physical activity oriented home rehabilitation program (ProPA) on PA and the restoration of mobility in community-dwelling older people. METHODS: Men and women aged 60 years or older hospitalized due to a musculoskeletal injury or disorder in the back or lower limbs are recruited. After discharge from hospital to home, participants are randomized into a six-month ProPA program or a standard care (control) group. The ProPA program consists of a motivational interview, goal attainment process, guidance for safe walking, a progressive home exercise program and physical activity counseling. In addition, frail participants who are not able to go outdoors alone receive support from volunteers. Primary outcomes are PA measured using a 3-dimentional accelerometer, and mobility assessed by the Short Physical Performance Battery and self-reports. Secondary outcomes are life space mobility, participation restriction, fear of falling, pain, mood, and grip strength. Information on barriers to and enablers of PA participation are also collected. Data on mortality and use of health services are collected from the national register. In this 6-month intervention, all participants are assessed in their homes at baseline and after three and six months, and at 12 months after randomization they will receive a follow-up questionnaire. DISCUSSION: This study investigates the effects of a rehabilitation program on PA and mobility among older people at risk for increased sedentary time and mobility problems. If positive effects are observed, the program can be considered for incorporation into the health care system and thereby contribute to the rehabilitation of older people who have recently been discharged from hospital. TRIAL REGISTRATION: ISRCTN13461584 . Registered 27 January 2016.

Association of breathing sound spectra with glottal dimensions in exercise-induced vocal cord dysfunction.

The objective of this study was to evaluate associations between the breathing sound spectra and glottal dimensions in exercise-induced vocal cord dysfunction (EIVCD) during a bicycle ergometry test. Nineteen subjects (mean age 21.8 years and range 13-39 years) with suspected EIVCD were studied. Vocal folds were continuously imaged with videolaryngoscopy and breathing sounds were recorded during the bicycle exercise test. Twelve subjects showed paradoxical movement of the vocal folds during inspiration by the end of the exercise. In seven subjects, no abnormal reactions in vocal folds were found; they served as control subjects. The glottal quotient (interarytenoid distance divided by the anteroposterior glottal distance) was calculated. From the same time period, the tracheal-vocal tract resonance peaks of the breathing sound spectra were analyzed, and stridor sounds were detected and measured. Subjects with EIVCD showed significantly higher resonance peaks during the inspiratory phase compared to the expiratory phase (p < 0.014). The glottal quotient decreased significantly in the EIVCD group (p < 0.001), but not in the control group. 8 out of 12 EIVCD patients (67%) showed stridor sounds, while none of the controls did. There was a significant inverse correlation between the frequencies of the breathing sound resonance peaks and the glottal quotient. The findings indicate that the typical EIVCD reaction of a paradoxical approximation of the vocal folds during inspiration, measured here as a decrease in the glottal quotient, is significantly associated with an increase in inspiratory resonance peaks. The findings are applicable in the documentation of EIVCD findings using videolaryngoscopy, in addition to giving clinicians tools for EIVCD recognition. However, the study is limited by the small number of subjects.

Towards better patient safety in otolaryngology: characteristics of patient injuries and their relationship with items on the WHO Surgical Safety Checklist.

OBJECTIVES: Increasing knowledge of factors contributing to medical adverse events has influenced the development of preventive policies and protocols, the WHO Surgical Safety Checklist being the most widely known. Despite growing evidence of the checklist's effectiveness in surgery, its role in preventing adverse events in otolaryngology is unclear. We assessed patient injury-contributing factors in otolaryngology and their relationship with WHO checklist items. STUDY DESIGN: A retrospective claim record study of national patient insurance charts in Finland. SETTING AND PARTICIPANTS: The records of all accepted patient injury claims in otolaryngology between 2001 and 2011 were searched and reviewed by two otolaryngologists. Operation-related injuries were evaluated in detail. Factors contributing to injury were identified, classified and compared with items on the WHO checklist. We also estimated whether the injury might have been prevented with a properly used checklist. RESULTS: In the 10-year study period, 188 (84.3%) of the 223 patient injuries were associated with operative care. Of these, 142 (75.5%) occurred in the operation theatre, and in 121 cases (64.4%), technical error in performing surgery was the primary cause of injury. In 18 injuries (9.6%), the error corresponded to a checklist item. Nine injuries (4.8%) could have been prevented with a properly used checklist. CONCLUSIONS: Patient injuries in otolaryngology are strongly related to operative care. The WHO checklist is one suitable tool for error prevention.

Mutation analysis of components of the Mediator kinase module in MED12 mutation-negative uterine leiomyomas.

BACKGROUND: Kinase module of Mediator complex ('CDK8 submodule') consists of four subunits: CDK8, Cyclin C, MED12, and MED13. Recently, we reported recurrent MED12 mutations in 70% of uterine leiomyomas. The aim of this study was to analyse whether mutations in other components of the module contribute to the development of these lesions. METHODS: Mutation screening of altogether 70 MED12 mutation-negative uterine leiomyomas was carried out by direct sequencing. RESULTS: None of the tumours displayed somatic mutations in the coding regions of CDK8/CDK19, CCNC, or MED13. CONCLUSIONS: Mutations in CDK8/CDK19, CCNC, and MED13 do not frequently contribute to genesis of uterine leiomyomas.

Identification of 33 candidate oncogenes by screening for base-specific mutations.

BACKGROUND: Genes with recurrent codon-specific somatic mutations are likely drivers of tumorigenesis and potential therapeutic targets. Hypermutable cancers may represent a sensitive system for generation and selection of oncogenic mutations. METHODS: We utilised exome-sequencing data on 25 sporadic microsatellite-instable (MSI) colorectal cancers (CRCs) and searched for base-specific somatic mutation hotspots. RESULTS: We identified novel mutation hotspots in 33 genes. Fourteen genes displayed mutations in the validation set of 254 MSI CRCs: ANTXR1, MORC2, CEP135, CRYBB1, GALNT9, KRT82, PI15, SLC36A1, CNTF, GLDC, MBTPS1, OR9Q2, R3HDM1 and TTPAL. A database search found examples of the hotspot mutations in multiple cancer types. CONCLUSIONS: This work reveals a variety of new recurrent candidate oncogene mutations to be further scrutinised as potential therapeutic targets.

Safety of intralesional cidofovir in patients with recurrent respiratory papillomatosis: an international retrospective study on 635 RRP patients.

Intralesional use of cidofovir (Vistide(®)) has been one of the mainstays of adjuvant therapy in patients with recurrent respiratory papillomatosis (RRP) since 1998. In 2011, a communication provided by the producer of cidofovir addressed very serious side effects concerning its off-label use. As this was a general warning, it was inconclusive whether this would account for its use in RRP. The aim of this study is to determine whether nephrotoxic, neutropenic, or oncogenic side effects have occurred after intralesional use of cidofovir in patients with RRP. Update of recent developments in RRP, a multicentre questionnaire and a multicentre retrospective chart review. Sixteen hospitals from eleven countries worldwide submitted records of 635 RRP patients, of whom 275 were treated with cidofovir. RRP patients received a median of three intralesional injections (interquartile range 2-6). There were no statistical differences in occurrence of neutropenia or renal dysfunction before and after cidofovir. There was no statistical difference in occurrence of upper airway and tracheal malignancies between the cidofovir and the non-cidofovir group. In this retrospective patient chart review, no clinical evidence was found for more long-term nephrotoxicity, neutropenia or laryngeal malignancies after the administration of intralesional cidofovir in RRP patients.

Loss of the wild type MLH1 gene is a feature of hereditary nonpolyposis colorectal cancer.

The mechanism by which germline mutations of DNA mismatch repair genes cause susceptibility to tumour formation is not yet understood. Studies in vitro indicate that heterozygosity for these mutations, unlike homozygosity, does not affect mismatch repair. Surprisingly, no loss of heterozygosity at the predisposing loci has so far been described in hereditary nonpolyposis colorectal cancers. Here, we show that loss of heterozygosity (LOH) of markers within or adjacent to the MLH1 gene on chromosome 3p occurs nonrandomly in tumours from members of families in which the disease phenotype cosegregates with MLH1. In every informative case, the loss affects the wild type allele. These results suggest that DNA mismatch repair genes resemble tumour suppressor genes in that two hits are required to cause a phenotypic effect.

Localization of a susceptibility locus for Peutz-Jeghers syndrome to 19p using comparative genomic hybridization and targeted linkage analysis.

Many human cancer susceptibility genes have been successfully mapped by genetic linkage studies. One that has so far eluded researchers is that for Peutz-Jeghers (P-J) syndrome, a condition characterized by intestinal hamartomatous polyposis and melanin spots of the lips, buccal mucosa and digits. A dramatically elevated risk of malignancy has also been documented. Gastrointestinal tumours as well as cancers of the breast, ovary, testis and uterine cervix appear to be overrepresented in families with this syndrome. The nature of hamartomatous polyps is equivicol. Hamartomas are usually considered histologically benign, but in the case of Peutz-Jeghers patients, there are reports of adenomatous and malignant changes in the polyps, and the possibility of a hamartoma-carcinoma sequence has been discussed. A search for a putative tumour suppressor locus was made using comparative genomic hybridization (CGH) of Peutz-Jeghers polyps, combined with loss of heterozygosity (LOH) study. Genetic linkage analysis in 12 families using markers from a deletion site demonstrated the presence of a high-penetrance locus in distal 19p with a multipoint lod score of 7.00 at marker D19S886 without evidence of genetic heterogeneity. The study demonstrates the power of CGH combined with LOH analysis in identifying putative tumour suppressor loci, and provides molecular evidence of malignant potential in hamartomas.

Somatic MED12 mutations in uterine leiomyosarcoma and colorectal cancer.

BACKGROUND: Mediator complex participates in transcriptional regulation by connecting regulatory DNA sequences to the RNA polymerase II initiation complex. Recently, we discovered through exome sequencing that as many as 70% of uterine leiomyomas harbour specific mutations in exon 2 of mediator complex subunit 12 (MED12). In this work, we examined the role of MED12 exon 2 mutations in other tumour types. METHODS: The frequency of MED12 exon 2 mutations was analysed in altogether 1158 tumours by direct sequencing. The tumour spectrum included mesenchymal tumours (extrauterine leiomyomas, endometrial polyps, lipomas, uterine leiomyosarcomas, other sarcomas, gastro-intestinal stromal tumours), hormone-dependent tumours (breast and ovarian cancers), haematological malignancies (acute myeloid leukaemias, acute lymphoid leukaemias, myeloproliferative neoplasms), and tumours associated with abnormal Wnt-signalling (colorectal cancers (CRC)). RESULTS: Five somatic alterations were observed: three in uterine leiomyosarcomas (3/41, 7%; Gly44Ser, Ala38_Leu39ins7, Glu35_Leu36delinsVal), and two in CRC (2/392, 0.5%; Gly44Cys, Ala67Val). CONCLUSION: Somatic MED12 exon 2 mutations were observed in uterine leiomyosarcomas, suggesting that a subgroup of these malignant tumours may develop from a leiomyoma precursor. Mutations in CRC samples indicate that MED12 may, albeit rarely, contribute to CRC tumorigenesis.

delGA (rs67491583) variant and colorectal cancer risk in an indigenous African population.

BACKGROUND: A recent study showed a higher frequency of GA deletion at rs67491583 in African American colorectal cancer (CRC) patients compared to controls, suggesting a likely contribution of this allele to racial disparity in CRC risk predisposition. We conducted a pilot study in an indigenous African population to evaluate this potential CRC risk variant. METHODS: We collected epidemiological data and biological specimen from consenting consecutive CRC cases and controls presenting at the Oncology Clinic of University College Hospital, Ibadan from 2001 to 2007. We examined germline DNA for delGA by PCR-amplification of two overlapping fragments using standard primers. The products were directly sequenced using Applied Biosystems BigDye v3.1 sequencing chemistry and AB 13730 automatic DNA sequencer. RESULTS: There were 45 cases and 45 controls of which genotyping was successful in 39 cases and 38 controls. There were 5 heterozygous and 2 homozygous GA deletions with frequency of 11.54% (9/78) among cases whereas there were 8 heterozygous and 1 homozygous GA deletions among controls with frequency of 13.15% (10/76). (p= 0.79, OR 0.88, 95% CI 0.34-2.28). CONCLUSION: This study suggests that there is no association between the delGA (rs67491583) variant and CRC risk in this indigenous African population. However our sample size was small and the participants were not ethnically homogenous. Further studies are required to evaluate this marker in African CRC.

Somatic microsatellite mutations as molecular tumor clocks.

Microsatellite (MS) mutations can potentially unravel the past of mutator phenotype tumors, with greater genetic diversity expected in older regions. Rapid clonal expansions of xenografts were characterized by relatively homogenous MS alleles, whereas greater diversity was observed in a colorectal cancer with the greatest variation in its adjacent adenoma. A subcutaneous lung cancer metastasis demonstrated diversity consistent with its one-month clinical duration and evidence of active mitosis during dormancy. The genetic legacy inherent to multistep tumorigenesis provides direct estimates of tumor ages, with up to thousands of cell divisions and high death rates necessary to yield the observed diversities. MS molecular tumor clocks have the unique potential to systematically reconstruct the early and occult evolution of individual human mutator phenotype tumors.

Founding mutations and Alu-mediated recombination in hereditary colon cancer.

By screening members of Finnish families displaying hereditary nonpolyposis colorectal cancer (HNPCC) for predisposing germline mutations in MSH2 and MLH1, we show that two mutations in MLH1 together account for 63% (19/30) of kindreds meeting international diagnostic criteria. Mutation 1, originally detected as a 165-base pair deletion in MLH1 cDNA comprising exon 16, was shown to consist of a 3.5-kilobase genomic deletion most likely resulting from Alu-mediated recombination. Mutation 2 destroys the splice acceptor site of exon 6. A simple diagnostic test based on polymerase chain reaction was designed for both mutations. Our results show that these two ancestral founding mutations account for a majority of Finnish HNPCC kindreds and represent the first report of Alu-mediated recombination causing a prevalent, dominantly inherited predisposition to cancer.

A large-scale meta-analysis to refine colorectal cancer risk estimates associated with MUTYH variants.

BACKGROUND: defective DNA repair has a causal role in hereditary colorectal cancer (CRC). Defects in the base excision repair gene MUTYH are responsible for MUTYH-associated polyposis and CRC predisposition as an autosomal recessive trait. Numerous reports have suggested MUTYH mono-allelic variants to be low penetrance risk alleles. We report a large collaborative meta-analysis to assess and refine CRC risk estimates associated with bi-allelic and mono-allelic MUTYH variants and investigate age and sex influence on risk. METHODS: MUTYH genotype data were included from 20 565 cases and 15 524 controls. Three logistic regression models were tested: a crude model; adjusted for age and sex; adjusted for age, sex and study. RESULTS: all three models produced very similar results. MUTYH bi-allelic carriers demonstrated a 28-fold increase in risk (95% confidence interval (CI): 6.95-115). Significant bi-allelic effects were also observed for G396D and Y179C/G396D compound heterozygotes and a marginal mono-allelic effect for variant Y179C (odds ratio (OR)=1.34; 95% CI: 1.00-1.80). A pooled meta-analysis of all published and unpublished datasets submitted showed bi-allelic effects for MUTYH, G396D and Y179C (OR=10.8, 95% CI: 5.02-23.2; OR=6.47, 95% CI: 2.33-18.0; OR=3.35, 95% CI: 1.14-9.89) and marginal mono-allelic effect for variants MUTYH (OR=1.16, 95% CI: 1.00-1.34) and Y179C alone (OR=1.34, 95% CI: 1.01-1.77). CONCLUSIONS: overall, this large study refines estimates of disease risk associated with mono-allelic and bi-allelic MUTYH carriers.

COGENT (COlorectal cancer GENeTics): an international consortium to study the role of polymorphic variation on the risk of colorectal cancer.

It is now recognised that a part of the inherited risk of colorectal cancer (CRC) can be explained by the co-inheritance of low-penetrance genetic variants. The accumulated experience to date in identifying these variants has served to highlight difficulties in conducting statistically and methodologically rigorous studies and follow-up analyses. The COGENT (COlorectal cancer GENeTics) consortium includes 20 research groups in Europe, Australia, the Americas, China and Japan. The overarching goal of COGENT is to identify and characterise low-penetrance susceptibility variants for CRC through association-based analyses. In this study, we review the rationale for identifying low-penetrance variants for CRC and our proposed strategy for establishing COGENT.

Dysregulation of the transcription factors SOX4, CBFB and SMARCC1 correlates with outcome of colorectal cancer.

The aim of this study was to identify deregulated transcription factors (TFs) in colorectal cancer (CRC) and to evaluate their relation with the recurrence of stage II CRC and overall survival. Microarray-based transcript profiles of 20 normal mucosas and 424 CRC samples were used to identify 51 TFs displaying differential transcript levels between normal mucosa and CRC. For a subset of these we provide in vitro evidence that deregulation of the Wnt signalling pathway can lead to the alterations observed in tissues. Furthermore, in two independent cohorts of microsatellite-stable stage II cancers we found that high SOX4 transcript levels correlated with recurrence (HR 2.7; 95% CI, 1.2-6.0; P=0.01). Analyses of approximately 1000 stage I-III adenocarcinomas, by immunohistochemistry, revealed that patients with tumours displaying high levels of CBFB and SMARCC1 proteins had a significantly better overall survival rate (P=0.0001 and P=0.0275, respectively) than patients with low levels. Multivariate analyses revealed that a high CBFB protein level was an independent predictor of survival. In conclusion, several of the identified TFs seem to be involved in the progression of CRC.

Genetic mapping of a locus predisposing to human colorectal cancer.

Genetic linkage analysis was used to determine whether a specific chromosomal locus could be implicated in families with a history of early onset cancer but with no other unique features. Close linkage of disease to anonymous microsatellite markers on chromosome 2 was demonstrated in two large kindreds. The pairwise lod scores for linkage to marker D2S123 in these kindreds were 6.39 and 1.45 at zero recombination, and multipoint linkage with flanking markers resulted in lod scores of 6.47 and 6.01. These results prove the existence of a genetically determined predisposition to colorectal cancer that has important ramifications for understanding and preventing this disease.

Clues to the pathogenesis of familial colorectal cancer.

A predisposition to colorectal cancer is shown to be linked to markers on chromosome 2 in some families. Molecular features of "familial" cancers were compared with those of sporadic colon cancers. Neither the familial nor sporadic cancers showed loss of heterozygosity for chromosome 2 markers, and the incidence of mutations in KRAS, P53, and APC was similar in the two groups of tumors. Most of the familial cancers, however, had widespread alterations in short repeated DNA sequences, suggesting that numerous replication errors had occurred during tumor development. Thirteen percent of sporadic cancers had identical abnormalities and these cancers shared biologic properties with the familial cases. These data suggest a mechanism for familial tumorigenesis different from that mediated by classic tumor suppressor genes.