Genomic characterisation of hormone receptor-positive breast cancer arising in very young women.

BACKGROUND: Very young premenopausal women diagnosed with hormone receptor-positive, human epidermal growth factor receptor 2-negative (HR+HER2-) early breast cancer (EBC) have higher rates of recurrence and death for reasons that remain largely unexplained. PATIENTS AND METHODS: Genomic sequencing was applied to HR+HER2- tumours from patients enrolled in the Suppression of Ovarian Function Trial (SOFT) to determine genomic drivers that are enriched in young premenopausal women. Genomic alterations were characterised using next-generation sequencing from a subset of 1276 patients (deep targeted sequencing, n = 1258; whole-exome sequencing in a young-age, case-control subsample, n = 82). We defined copy number (CN) subgroups and assessed for features suggestive of homologous recombination deficiency (HRD). Genomic alteration frequencies were compared between young premenopausal women (<40 years) and older premenopausal women (≥40 years), and assessed for associations with distant recurrence-free interval (DRFI) and overall survival (OS). RESULTS: Younger women (<40 years, n = 359) compared with older women (≥40 years, n = 917) had significantly higher frequencies of mutations in GATA3 (19% versus 16%) and CN amplifications (CNAs) (47% versus 26%), but significantly lower frequencies of mutations in PIK3CA (32% versus 47%), CDH1 (3% versus 9%), and MAP3K1 (7% versus 12%). Additionally, they had significantly higher frequencies of features suggestive of HRD (27% versus 21%) and a higher proportion of PIK3CA mutations with concurrent CNAs (23% versus 11%). Genomic features suggestive of HRD, PIK3CA mutations with CNAs, and CNAs were associated with significantly worse DRFI and OS compared with those without these features. These poor prognostic features were enriched in younger patients: present in 72% of patients aged <35 years, 54% aged 35-39 years, and 40% aged ≥40 years. Poor prognostic features [n = 584 (46%)] versus none [n = 692 (54%)] had an 8-year DRFI of 84% versus 94% and OS of 88% versus 96%. Younger women (<40 years) had the poorest outcomes: 8-year DRFI 74% versus 85% and OS 80% versus 93%, respectively. CONCLUSION: These results provide insights into genomic alterations that are enriched in young women with HR+HER2- EBC, provide rationale for genomic subgrouping, and highlight priority molecular targets for future clinical trials.

Unusual extension of a dental abscess through the pterygomandibular space in subcutaneous maxillofacial tissue.

Infections of maxillary teeth commonly spread to the buccal space, whereas infections originating in the mandible usually spread to the submandibular, pterygomandibular, and buccal spaces. The pterygomandibular space may serve as a path for spread to zygomatic areas and thus must always be a part of imaging evaluations.

Button Sequestrum Sign Due to Osteomyelitis of the Mandible Secondary to Malignant Infantile Osteopetrosis.

The button sequestrum sign is demonstrated in a number of medical conditions and refers to a lesion of devascularised bone which is surrounded by lucency. Although it may be difficult to arrive at a single diagnosis based on this sign, the combination of clinical and paraclinical findings, patient's medical history and imagistic presentation of this sign can lead to a great specificity in chronic osteomyelitis, even if osteomyelitis is accompanied by osteopetrosis, as in the present case.

Influence of education and residence on the parental search for pediatric surgical information on the internet.

BACKGROUND: The internet is a valuable tool for access to health-related information. There is limited literature regarding its use by parents of children with surgical conditions. AIM: To investigate internet usage by parents seeking information about the surgical conditions of their offspring in relation to epidemiological factors such as family residential area and parental educational level and to subsequently review the literature regarding this topic. METHODS: An anonymous questionnaire about internet usage was completed by eligible parents of children who were admitted to our clinic for minor surgical procedures during a six-month period. RESULTS: Our results demonstrated that the internet has been mostly used by mothers for children's health information. Google was the most commonly used search engine, while pediatricians were the first parental choice for 'live' information. Only one-quarter of the parents informed their doctor about the information found online. Nine of ten parents had a positive opinion of an official website managed by the doctors of our clinic. Our results mostly agreed with the international literature. CONCLUSION: In conclusion, the establishment of official websites (designed and managed by specialists) that parents can access to receive appropriate health information is mandatory in the internet era.

An Unexpected Location of Enostosis, a Pediatric "Never Mind" Bone Lesion.

Enostoses, also known as bone islands, are common benign sclerotic bone lesion that usually represent incidental findings. They constitute a small focus of compact bone within cancellous bone. Enostoses can be seen on radiographs, CT, and MRI, and are considered one of the skeletal do not touch lesions.

Any Etiquette for Sacrococcygeal Chordoma's Diagnosis?

The current paper focuses on a trial to understand the imaging manifestations in combination with the clinical presentation of the sacrococcygeal chordoma in a patient with referred back pain. Also, the steps for the final diagnosis are described and via this procedure, the paper demonstrates the crucial role of magnetic resonance imaging, computed tomography guided biopsy and histopathological examination in order to minimize the differential diagnosis and lead to the correct diagnosis.

Constipation and dilated bowel: Hirschsprung's disease is not always the case.

A case of a 2-month-old boy with constipation and a localized abdominal distension in the right abdomen and hypogastrium is presented. Plain radiograph, ultrasound exam as well as a barium enema were suggestive of Hirschsprung's disease (HD) (ultrashort segment disease). Nevertheless, rectal suction biopsy was negative for neuronal abnormalities and unexpectedly on plain radiograph vertebral abnormalities were noticed. Subsequently magnetic resonance imaging of the spine and abdomen was performed, to evaluate possible spinal cord lesions and potential abnormalities of the perineal region musculature. A syringe throughout medullary cone was noted. The well-known issue, that the diagnosis of HD does not depend on the imaging (radiological) findings, was confirmed. The step-bystep diagnostic approach from the initial thought of ultrashort segment HD to the later imaging-based diagnosis of syringomyelia is discussed in this present paper.

Identifying oncogenic drivers associated with increased risk of late distant recurrence in postmenopausal, estrogen receptor-positive, HER2-negative early breast cancer: results from the BIG 1-98 study.

BACKGROUND: In postmenopausal, estrogen receptor-positive, human epidermal growth factor receptor 2 (HER2)-negative early breast cancer, the risk for distant recurrence can extend beyond 5 years of adjuvant endocrine therapy. This study aims to identify genomic driver alterations associated with late distant recurrence. PATIENTS AND METHODS: Next generation sequencing was used to characterize driver alterations in primary tumors from a subset of 764 postmenopausal estrogen receptor-positive/HER2-negative patients from the BIG 1-98 randomized trial. Late distant recurrence events were defined as ≥5 years from time of randomization). The association of driver alterations with distant recurrence-free interval in early and late time periods was assessed using Cox regression models. Multivariable analyses were carried out to adjust for clinicopathological factors. Weighted analysis methods were used in order to correct for over-sampling of distant recurrences. RESULTS: A total of 538 of 764 (70%) samples were successfully sequenced including 88 (63%) early and 52 (37%) late distant recurrence events after a median follow up of 8.1 years. In univariable analysis for late distant recurrence, PIK3CA mutations (58.8%) were significantly associated with reduced risk [hazard ratio (HR) 0.40, 95% confidence interval (CI) 0.20-0.82, P = 0.012], whereas amplifications on chromosome 8p11 (10.9%) (HR 4.79, 95% CI 2.30-9.97, P < 0.001) and BRCA2 mutations (2.3%) (HR 5.39, 95% CI 1.51-19.29, P = 0.010) were significantly associated with an increased risk. In multivariable analysis, only amplifications on 8p11 (P = 0.002) and BRCA2 mutations (P = 0.013) remained significant predictors. CONCLUSIONS: In estrogen receptor-positive/HER2-negative postmenopausal early breast cancer, PIK3CA mutations were associated with reduced risk of late distant recurrence, whereas amplifications on 8p11 and BRCA2 mutations were associated with increased risk of late distant recurrence. The characterization of oncogenic driver alterations may aid in refining treatment choices in the late disease setting, and help identify potential drug targets for testing in future trials.

Identification of an excellent prognosis subset of human papillomavirus-associated oropharyngeal cancer patients by quantification of intratumoral CD103+ immune cell abundance.

BACKGROUND: Accurate prognostic stratification of human papillomavirus-associated oropharyngeal cancers (HPV+OPSCC) is required to identify patients potentially suitable for treatment deintensification. We evaluated the prognostic significance of CD103, a surface marker associated with tissue-resident memory T cells (TRMs), in two independent cohorts of patients with HPV+OPSCC. PATIENTS AND METHODS: The abundance and distribution of CD103+ immune cells were quantified using immunohistochemistry in a cohort of 189 HPV+OPSCC patients treated with curative intent and correlated with outcome. Findings were then validated in an independent cohort comprising 177 HPV+OPSCCs using univariable and multivariable analysis. Intratumoral CD103+ immune cells were characterized by multispectral fluorescence immunohistochemistry and gene expression analysis. RESULTS: High intratumoral abundance of CD103+ immune cells using a ≥30% cut-off was found in 19.8% of tumors in the training cohort of HPV+OPSCC patients and associated with excellent prognosis for overall survival (OS) with adjusted hazard ratio (HR) of 0.13 [95% confidence interval (CI) 0.02-0.94, P = 0.004]. In the independent cohort of HPV+OPSCCs, 20.4% had high intratumoral CD103+ abundance and an adjusted HR for OS of 0.16 (95% CI 0.02-1.22, P = 0.02). Five year OS of patients with high intratumoral CD103 was 100% across both cohorts. The C-statistic for the multivariate prognostic model with stage and age was significantly improved in both cohorts with the addition of intratumoral CD103+ cell abundance. On the basis of spatial location, co-expression of CD8 and CD69, and gene expression profiles, intratumoral CD103+ cells were consistent with TRMs. CONCLUSION: Quantification of intratumoral CD103+ immune cell abundance provides prognostic information beyond that provided by clinical parameters such as TNM-staging, identifying a population of low risk HPV+OPSCC patients who are good candidates for trials of deintensification strategies.

The prognostic impact of consensus molecular subtypes (CMS) and its predictive effects for bevacizumab benefit in metastatic colorectal cancer: molecular analysis of the AGITG MAX clinical trial.

Background: The consensus molecular subtypes (CMS) is a transcriptome-based classification of colorectal cancer (CRC) initially described in early-stage cohorts, but the associations of CMS with treatment outcomes in the metastatic setting are yet to be established. This study aimed to evaluate the prognostic impact of CMS classification and its predictive effects for bevacizumab benefit in metastatic CRC by correlative analysis of the AGITG MAX trial. Patients and methods: The MAX trial previously reported improved progression-free survival (PFS) for the addition of bevacizumab (B) to chemotherapy [capecitabine (C)±mitomycin (M)]. Archival primary tumours from 237 patients (50% of trial population) underwent gene expression profiling and classification into CMS groups. CMS groups were correlated to PFS and overall survival (OS). The interaction of CMS with treatment was assessed by proportional hazards model. Results: The distribution of CMS in MAX were CMS1 18%, CMS2 47%, CMS3 12%, CMS4 23%. CMS1 was the predominant subtype in right-sided primary tumours, while CMS2 was the predominant subtype in left-sided. CMS was prognostic of OS (P = 0.008), with CMS2 associated with the best outcome and CMS1 the worst. CMS remained an independent prognostic factor in a multivariate analysis. There was a significant interaction between CMS and treatment (P-interaction = 0.03), for PFS, with hazard ratios (95% CI) for CB+CBM versus C arms in CMS1, 2, 3 and 4: 0.83 (0.43-1.62), 0.50 (0.33-0.76), 0.31 (0.13-0.75) and 1.24 (0.68-2.25), respectively. Conclusions: This exploratory study found that CMS stratified OS outcomes in metastatic CRC regardless of first-line treatment, with prognostic effects of CMS groups distinct from those previously reported in early-stage cohorts. In CMS associations with treatment, CMS2 and possibly CMS3 tumours may preferentially benefit from the addition of bevacizumab to first-line capecitabine-based chemotherapy, compared with other CMS groups. Validation of these findings in additional cohorts is warranted. Clinical trial number: This is a molecular sub-study of MAX clinical trial (NCT00294359).

Scoring of tumor-infiltrating lymphocytes: From visual estimation to machine learning.

The extent of tumor-infiltrating lymphocytes (TILs), along with immunomodulatory ligands, tumor-mutational burden and other biomarkers, has been demonstrated to be a marker of response to immune-checkpoint therapy in several cancers. Pathologists have therefore started to devise standardized visual approaches to quantify TILs for therapy prediction. However, despite successful standardization efforts visual TIL estimation is slow, with limited precision and lacks the ability to evaluate more complex properties such as TIL distribution patterns. Therefore, computational image analysis approaches are needed to provide standardized and efficient TIL quantification. Here, we discuss different automated TIL scoring approaches ranging from classical image segmentation, where cell boundaries are identified and the resulting objects classified according to shape properties, to machine learning-based approaches that directly classify cells without segmentation but rely on large amounts of training data. In contrast to conventional machine learning (ML) approaches that are often criticized for their "black-box" characteristics, we also discuss explainable machine learning. Such approaches render ML results interpretable and explain the computational decision-making process through high-resolution heatmaps that highlight TILs and cancer cells and therefore allow for quantification and plausibility checks in biomedical research and diagnostics.

Somatic mutation, copy number and transcriptomic profiles of primary and matched metastatic estrogen receptor-positive breast cancers.

BACKGROUND: Estrogen receptor-positive (ER+) breast cancers (BCs) constitute the most frequent BC subtype. The molecular landscape of ER+ relapsed disease is not well characterized. In this study, we aimed to describe the genomic evolution between primary (P) and matched metastatic (M) ER+ BCs after failure of adjuvant therapy. MATERIALS AND METHODS: A total of 182 ER+ metastatic BC patients with long-term follow-up were identified from a single institution. P tumor tissue was available for all patients, with 88 having matched M material. According to the availability of tumor material, samples were characterized using a 120 mutational hotspot qPCR, a 29 gene copy number aberrations (CNA) and a 400 gene expression panels. ESR1 mutations were assayed by droplet digital PCR. Molecular alterations were correlated with overall survival (OS) using the Cox proportional hazards regression models. RESULTS: The median follow-up was 6.4 years (range 0.5-26.6 years). Genomic analysis of P tumors revealed somatic mutations in PIK3CA, KRAS, AKT1, FGFR3, HRAS and BRAF at frequencies of 41%, 6%, 5%, 2%, 1% and 2%, respectively, and CN amplification of CCND1, ZNF703, FGFR1, RSF1 and PAK1 at 23%, 19%, 17%, 12% and 11%, respectively. Mutations and CN amplifications were largely concordant between P and matched M (>84%). ESR1 mutations were found in 10.8% of the M but none of the P. Thirteen genes, among which ESR1, FOXA1, and HIF1A, showed significant differential expression between P and M. In P, the differential expression of 18 genes, among which IDO1, was significantly associated with OS (FDR < 0.1). CONCLUSIONS: Despite the large concordance between P and matched M for the evaluated molecular alterations, potential actionable targets such as ESR1 mutations were found only in M. This supports the importance of characterizing the M disease. Other targets we identified, such as HIF1A and IDO1, warrant further investigation in this patient population.

Hematogenous infantile infection presenting as osteomyelitis and septic arthritis: a case report.

The case of a 6-month old male infant presenting at the emergency department with fever and swelling at the left knee joint is discussed. Laboratory tests showed an inflammatory condition. Left knee plain radiograph demonstrated local soft tissue oedema. Percutaneous needle aspiration of articular fluid showed a positive culture for Staphylococcus aureus. The diagnosis of septic arthritis was confirmed. Because of inadequate response to treatment an MRI study was followed to evaluate possible abscesses. The presence of an abscess in the suprapatellar bursa was confirmed and an additional inflammatory process of the bone marrow was revealed, consistent with osteomyelitis. The pathophysiology, the imaging findings, the patient's management and a review of septic arthritis and osteomyelitis coexistence are presented in this paper.

Optic nerve sheath meningioma: a case report.

A case of a 75-year old male with right-sided exopthalmos is presented. Outside proptosis of the right eye was initially observed 6 years ago. Opthalmological and endocrinological clinical examination as well as laboratory tests revealed no pathology from optic nerve disc, optic bulb and thyroid related hormones. MRI study demonstrated an optic nerve meningioma. The key imaging findings and the differential diagnosis were discussed in this present paper.

Reversal of deep vein reflux after successful stenting in a patient with venous hypertension after thigh access graft creation.

Presented here is a case of reversal of deep vein reflux after successful stenting in a patient with venous hypertension and valve incompetence after thigh angioaccess creation. The patient with exhausted upper-extremity access sites underwent a loop graft in the upper thigh. Six months later, the patient developed leg edema and significant femoral vein reflux on duplex ultrasound. Fistulography revealed an iliac vein stenosis, which was treated successfully with stenting. The edema and reflux on duplex promptly resolved. In similar cases, reflux may be a consequence of functional valve incompetence and can be reverted by timely treating the underlying stenosis.

Rotational injuries of the distal tibial growth plate.

Nine rotational injuries of the distal tibial growth plate in combination with spiral fracture of the fibula were treated in our department between 1993 and 2000. The average age of the patients was 12 years. The injury was a result of sudden, forceful external rotation of the ankle and foot. Pain and slight swelling of the ankle and external rotation of the distal tibia of 20 degrees -40 degrees were present. Radiologically, irregularity and widening of the growth plate of the distal tibia were obvious. In all these cases we noted, on lateral views, the characteristic sign of an "open fish mouth," due to the changes in the shape of the physeal plate. The spiral fracture of the fibula was not obvious in all radiographic views. The treatment in all eight fresh cases was closed reduction and manipulation by reversing the mechanism of injury and long leg cast application in all nine cases (including the one neglected case) for 6-8 weeks. The final results were either excellent or very good in all nine patients after a mean follow-up of 6 years.