Subsequent Metastatic Disease Research Articles

The utility of inflammatory biomarkers in predicting overall survival and recurrence in skull base chordoma.

Numerous studies have investigated the impact of inflammatory factors in cancer, yet few attempts have been made to investigate these markers in skull base chordoma (SBC). Inflammatory values including neutrophil-lymphocyte ratio (NLR), platelet-lymphocyte ratio (PLR), lymphocyte-monocyte ratio (LMR), systemic immune inflammation index (SII), and systemic inflammation response index (SIRI) can serve as prognostic markers in various cancers. This study aimed to determine whether these inflammatory factors influence overall survival (OS) or progression-free survival (PFS) in patients with primary SBC. The electronic medical records of patients with primary SBC who underwent resection from 2001 to 2020 were retrospectively reviewed for the associations of sex, age at diagnosis, preoperative steroid use, tumor volume, extent of resection, adjuvant radiation after surgery, tumor metastasis, Ki-67 index, percent homozygous deletion of 9p23 and percent 1p36 loss, and potential prognostic inflammatory markers of NLR, PLR, LMR, SII, and SIRI with the primary outcome measures of OS and PFS. Maximum log-rank statistical tests were used to determine inflammatory marker thresholds for grouping prior to Kaplan-Meier and Cox proportional hazards analysis for OS and PFS of the elucidated groups. The cohort included 115 primary SBC patients. The mean ± SD tumor volume was 23.0 ± 28.0 cm3, 73% of patients received gross-total resection, 40% received postoperative radiation, 25% had local recurrence, and 6% had subsequent metastatic disease (mean follow-up 47.2 months). Univariable Cox analysis revealed that NLR (p < 0.01), PLR (p = 0.04), LMR (p = 0.04), SII (p < 0.01), and SIRI (p < 0.01) were independently associated with PFS. Additionally, NLR (p = 0.05) and SII (p = 0.03) were significant in multivariable Cox analysis of PFS. However, both univariable and multivariable Cox analysis revealed no correlations with OS. The routine assessment of inflammatory biomarkers such as NLR and SIRI could have prognostic value in postresection SBC patients.

TOP2A Expression in Pheochromocytoma and Abdominal Paraganglioma: a Marker of Poor Clinical Outcome?

Pheochromocytoma and abdominal paraganglioma (PPGL) are rare neuroendocrine tumors originating from chromaffin cells. Even though only 10–15% of the tumors metastasize, all PPGLs are considered potentially malignant. Topoisomerase 2A (TOP2A) is a protein involved in cell proliferation and has been found to be over-expressed in metastatic PPGL. To provide support whether TOP2A could serve as a prognostic marker, 88 PPGLs (of which 8 metastatic/relapsing) and 10 normal adrenal gland samples were assessed for TOP2A mRNA expression using quantitative real-time PCR (qRT-PCR) and TOP2A immunohistochemistry. Comparisons to clinical parameters connected to metastatic behavior were made, and The Cancer Genome Atlas was used for validation of the results. A significant association between high TOP2A mRNA expression in primary PPGL and subsequent metastatic events (p = 0.008) was found, as well as to specific histological features and clinical parameters connected to metastatic behavior and mutations in SDHB. TOP2A immunoreactivity was calculated as an index of positive nuclei divided by the total amount of nuclei, and this index associated with TOP2A mRNA levels (p = 0.023) as well as the Ki-67 labeling index (p = 0.001). To conclude, TOP2A is a potential prognostic marker as it is frequently elevated in PPGL displaying subsequent metastatic disease, and future studies in larger cohorts are warranted to determine if a TOP2A index as assessed by immunohistochemistry could be a marker of poor outcome. Additionally, elevated levels of TOP2A could indicate a potential actionable event, and future studies with topoisomerase inhibitors would be of interest.

Atypical Molecular Features of Pediatric Tectal Glioma: A Single Institutional Series.

We present 4 children (diagnosed between 1 and 8y, 3 females and 1 male) with molecularly distinct tectal gliomas (2 KRAS mutant, 1 EGFR mutant, 1 SRGAP3-RAF-1 fusion) that contributes to the growing literature of this uncommonly biopsied tumor. The patient with EGFR R222C mutation had a more severe course, earlier diagnosis, subsequent leptomeningeal metastatic disease, required more aggressive therapies, and died 9 years after diagnosis. Patients with KRAS mutations and SRGAP3-RAF-1 fusion had a more indolent course. Our series expands the molecular phenotype of tectal glioma with the potential for leptomeningeal dissemination. Future studies on establishing genotypic/phenotypic correlation from those who undergo biopsy are needed.

Comparative Analysis of Primary Prostate Cancer Treatment and Subsequent Metastatic Disease

ObjectiveTo compare the association between previous local treatment modalities and the progression to castrate-resistant prostate cancer (CRCP) and overall survival (OS) in men with newly diagnosed metastatic prostate cancer.MethodsWe conducted a retrospective analysis using a nationwide, de-identified electronic health record (EHR)-derived database (Flatiron). Eligible patients had previously received radiation therapy (RT) or radical prostatectomy (RP) for their local disease, and had progressed to metastatic disease. Stratified Kaplan-Meier estimates by local treatment were used to measure OS from the date of metastasis diagnosis. Cox proportional models were used to test the association between prior local treatment, progression to CRPC, and death, after adjusting for patient-and disease-specific parameters. Also, we conducted a propensity score-matched analysis.ResultsOf the 1,338 patients who met the inclusion criteria, 46% underwent RP with or without adjuvant RT and 54% received RT. Median follow up for RP group and RT group were 38.6 months (32.6-45.4) and 26.0 months (I24.3-29.9), respectively. After adjusting for patient-and disease-specific parameters, the patients who received RT had a higher risk of developing CRPC than those in the RP group 1.36 [1.05-1.76]. After propensity score matching and adjusting for patient and disease-specific parameters, men who received RT had higher risk of death compared to their counterparts (HR:1.36, 95% CI:1.1-1.65, P= 0.003)ConclusionReal-world data suggest that patients with metastatic disease who had undergone prior RP might have a lower risk of developing a castrate-resistant state and improved OS compared to patients who had received RT. Significant amount of bias limits validity and strength of our findings. Whether type of local treatment influence the disease behavior remains open question and should be answered only within randomized trial.

Abstract 515: Single-cell transcriptomic analysis of HR+/HER2- breast cancer identifies gene signatures that predict outcomes of luminal A and B subtypes

Abstract Introduction: Patients with luminal A and B early-stage ER+/HER2- breast cancer (BrCa) are uniformly treated with adjuvant endocrine therapy (ET) (±chemotherapy). A better understanding of drivers of ET resistance is required as subsequent lethal metastatic disease remains a major clinical problem. Therefore, there is an unmet clinical need to identify biomarkers that select low- and high-risk patients who may benefit from de-escalation of current treatments or alternative therapeutic interventions. In the present study, we hypothesized that while luminal A and B tumors both arise from normal hormone-responsive cells, they are transcriptionally distinct, hence allowing the identification of unique gene signatures that can predict outcomes in each subtype. Methods: Tumors from 10 early-stage ER+/HER2- BrCa patients were subjected to single-cell RNA-sequencing (scRNA-seq) analysis (10X Genomics); 6/10 tumors were classified as luminal A and 4/10 as luminal B based on combined PAM50 and immunohistochemical classification (Ki67 cut-off=20%). We performed a direct transcriptional comparison between luminal A and B tumors, using well-established signatures and unbiased differential gene expression analysis. To identify unique luminal A and B tumor-specific genes, we compared the gene expression profile of each luminal subtype with 10 non-neoplastic breast tissues. A predictive model (LASSO) was applied to select genes with the highest frequency using a training dataset. This resulted in 5- and 4-gene signatures for luminal A and B, respectively, which were used to calculate risk scores that divided each subtype into low- and high-risk groups. The prognostic value of the above signatures was validated in an independent dataset. Results: The integrated scRNA-seq analysis of luminal A and B tumors revealed transcriptionally distinct tumor cell clusters while tumor microenvironment (TME) clusters were well intermixed. Luminal B tumors had higher cell cycle and BrCa-specific scores, low ER pathway-gene expression scores, and increased 8q amplifications. IFNγ, OXPHOS, p53, hypoxia and MYC targets were the most upregulated pathways in the luminal B subtype. The TME of luminal B tumors was comprised of lower CD4+ and CD8+ T cell but higher Treg levels. Comparison with normal breast tissues revealed that early-stage ER+ BrCa arises from hormone-responsive epithelial cells and provided a number of tumor-specific genes that were used to generate prognostic signatures. These signatures were capable of differentiating high- from low-risk patients within each subtype and predicting survival outcomes in two large-scale training and validation cohorts. Conclusions: We developed a novel prognostic tool that can be used to determine duration of adjuvant ET and/or new therapeutic strategies for high-risk luminal A and B patients in the early-stage ER+/HER2- setting. Citation Format: Sofia Mastoraki, Jerome Lin, Xiayu Rao, Sophie R. Liu, Harsh Batra, Maria G. Raso, Edwin R. Parra Cuentas, Akshara S. Raghavendra, Komal S. Rasaputra, Min Yi, Jing Wang, Aysegul Sahin, Debasish Tripathy, Kelly K. Hunt, Nicholas E. Navin, Khandan Keyomarsi. Single-cell transcriptomic analysis of HR+/HER2- breast cancer identifies gene signatures that predict outcomes of luminal A and B subtypes [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 515.

Histopathological growth distribution of ductal carcinoma in situ: tumor size is not "one size fits all".

Ductal carcinoma in situ (DCIS) is a group of preinvasive breast neoplasms. Studies have shown excellent survival among patients with lumpectomy-amenable disease. Patients requiring mastectomy have been less well characterized. We aim to characterize this cohort and identify whether growth distribution pattern is associated with sentinel lymph node involvement at time of surgery or subsequent development of metastatic disease. Patients were identified using local cancer registry data and were chart reviewed using electronic medical records. Growth pattern was classified as unifocal, multifocal, or diffuse. Chi-squared, Analysis of Variance (ANOVA), and Kaplan-Meier analyses were performed. Two hundred and twenty-six patients were identified with median age at diagnosis 49 and follow up 7.1 years. 42 had unifocal, 51 had multifocal and 20 had diffuse lesions. 3/20 patients with diffuse type lesions developed subsequent distant metastatic disease, while none of the patients with unifocal or multifocal lesions did. 1/20 patients with diffuse and 2/51 with multifocal disease had sentinel lymph node involvement (SLNI) at surgery. Tumor extent was not associated with sentinel lymph node involvement or distant metastatic disease (P=0.2, Kaplan-Meier analysis) but growth pattern was (P=0.01). It was also associated on Kaplan-Meier with development of distant metastatic disease alone (P=0.01). Patients with diffuse growth pattern DCIS were more likely to have SLNI or development of distant metastatic disease. Our findings suggest that patients with diffuse type lesions are at greater risk of metastatic disease and therefore breast cancer death from DCIS. Optimal therapy for these patients will need further elucidation.

Cardiac Metastasis in a Living Patient With Laryngeal Squamous Cell Carcinoma

Metastatic cardiac tumors are mainly diagnosed postmortem, while cardiac metastases of laryngeal cancer are exceedingly rare. We report a case of laryngeal carcinoma with subsequent metastatic disease to the heart diagnosed nine months after surgical resection of laryngeal cancer. Additionally, we attempted to summarize published case reports of laryngeal cancer with cardiac metastasis. Retrospective chart review and literature search via PubMed and Google Scholar were performed. Twenty cases of laryngeal squamous cell carcinoma (SCC) with cardiac metastatic tumors were identified. We described demographics, typical features seen on diagnostic studies, and analyzed current literature on incidence, diagnostic studies, treatment options, and prognosis of secondary cardiac tumors. More data are needed to decide on the optimal treatment strategy for metastatic cardiac disease.

Hormonal Receptors and Human Epidermal Growth Factor Receptor 2 Discordance between Primary and Recurrent Breast Cancer in Sample of Iraqi Patients

Background: Though progesterone receptor and estrogen receptor are weak prognostic indicators,they are greatly predictive of response to endocrine therapy. HER2 overexpression or amplification is apowerful predictive factor for response to specific systemic therapies. Variation in estrogen receptor (ER),progesterone receptor (PR), and HER2 status between primary breast carcinoma and subsequent relapse ofis clearly recognized. Aim of study: The study aims at determining the rate of discordance in progesteronereceptor, estrogen receptor and human epidermal growth factor receptor 2 status between primary tumor andsubsequent locoregional and metastatic disease in a sample of patients attend oncology teaching hospital.Patients and Methods: A retrospective study conducted included 80 females patients attending oncologyteaching hospital between December 2013 – December 2017 for whom the ER,PR,and HER2 status wereknown on tissue samples of both primary and subsequent locoregional and metastatic disease .Results: The ER,PR,and HER2 status discordance rate for between primary breast cancer and subsequentlocoregional relapse and distant metastasis was 27.5%, 42.5% and 22.5% respectivelyConclusion: The rate of discordance in ER and PR status primary and relapsed breast carcinoma in patientsmanaged at oncology teaching hospital was similar to other studies. While the rate of discordance for HER2status between primary and relapsed breast carcinoma was slightly higher than international studies.

Pseudohypoxic pheochromocytomas and paragangliomas dominate in children.

Pheochromocytomas and paragangliomas (PPGLs) are rare neuroendocrine tumors that are associated with cancer predisposition syndromes in up to 80% of affected children. PPGLs can be divided into molecularly defined groups with comparable pathogenesis and biology: (1) pseudohypoxic, (2) kinase signaling, and (3) Wnt-altered. We report the data of children and adolescents diagnosed with PPGL who have been registered with the German GPOH-MET registry since 1997. By December 2019, a total of 88 patients with PPGL were reported. Pheochromocytoma occurred in 56%, paraganglioma in 35%, and synchronous PPGLs in 9.1%. A total of 16% of patients presented with lymph node (5.7%) and distant metastases (10%). Median follow-up was 4.2years (range 0-17.1). Overall and disease-free survival (DFS) were 98.6% and 54.0%, respectively. Local relapses, metastases, and subsequent PPGLs occurred in 11%, 4.5%, and 15% of patients. Germline mutations were detected in 83% of patients (51% in VHL, 21% in SDHB, 7.8% in SDHD, and one patient each in RET and NF1). One patient was diagnosed with Pacak-Zhuang syndrome. A total of 96% of patients presented with PPGL of the pseudohypoxic subgroup (34% TCA cycle-related, 66% VHL/EPAS1-related). In multivariate analyses, extent of tumor resection was a significant prognostic factor for DFS. Most pediatric PPGLs belong to the pseudohypoxia subgroup, which is associated with a high risk of subsequent PPGL events and metastatic disease. Comprehensive molecular profiling of children and adolescents with newly diagnosed PPGLs will open new avenues for personalized diagnosis, treatment, and surveillance.

Neoadjuvant Chemotherapy without Radiation in Colorectal Cancer.

In colon cancer, primary surgery followed by postoperative chemotherapy represents the standard of care. In rectal cancer, the standard of care is preoperative radiotherapy or chemoradiation, which significantly reduces local recurrence but has no impact on subsequent metastatic disease or overall survival. The administration of neoadjuvant chemotherapy (NACT) before surgery can increase the chance of a curative resection and improves long-term outcomes in patients with liver metastases. Hence, NACT is being explored in both primary rectal and colon cancers as an alternative strategy to shrink the tumor, facilitate a curative resection, and simultaneously counter the risk of metastases. Yet, this lack of clarity regarding the precise aims of NACT (downstaging, maximizing response, or improving survival) is hindering progress. The appropriate cytotoxic agents, the optimal regimen, the number of cycles, or duration of NACT prior to surgery or in the postoperative setting remains undefined. Several potential strategies for integrating NACT are discussed with their advantages and disadvantages.

Postpartum Involution and Cancer: An Opportunity for Targeted Breast Cancer Prevention and Treatments?

Childbirth at any age confers a transient increased risk for breast cancer in the first decade postpartum and this window of adverse effect extends over two decades in women with late-age first childbirth (>35 years of age). Crossover to the protective effect of pregnancy is dependent on age at first pregnancy, with young mothers receiving the most benefit. Furthermore, breast cancer diagnosis during the 5- to 10-year postpartum window associates with high risk for subsequent metastatic disease. Notably, lactation has been shown to be protective against breast cancer incidence overall, with varying degrees of protection by race, multiparity, and lifetime duration of lactation. An effect for lactation on breast cancer outcome after diagnosis has not been described. We discuss the most recent data and mechanistic insights underlying these epidemiologic findings. Postpartum involution of the breast has been identified as a key mediator of the increased risk for metastasis in women diagnosed within 5-10 years of a completed pregnancy. During breast involution, immune avoidance, increased lymphatic network, extracellular matrix remodeling, and increased seeding to the liver and lymph node work as interconnected pathways, leading to the adverse effect of a postpartum diagnosis. We al discuss a novel mechanism underlying the protective effect of breastfeeding. Collectively, these mechanistic insights offer potential therapeutic avenues for the prevention and/or improved treatment of postpartum breast cancer.

Milia en plaque

The aim of this 8-year retrospective review was to determine the clinical significance of gadolinium-enhanced magnetic resonance imaging (MRI) findings in retinoblastoma patients after enucleation, particularly the presence of abnormal contrast enhancement of the transected optic nerve.Retrospective chart review.A review was done on 88 patients with retinoblastoma undergoing 90 enucleations between January 2008 and December 2015.These patients underwent 233 MRI scans: 90 preoperative and 143 postoperative that were included for review.The primary outcome measure assessed was abnormal MRI findings in the preoperative and postoperative MRI scans, specifically enhancement of the optic nerve and correlations between abnormal MRI findings and clinical outcomes for the 88 patients.On the preoperative MRI, 4 optic nerves out of 90 scans showed positive enhancement. Fifty orbits had ≥1 postoperative MRI. Overall, 41 of 50 orbits (82%) of enucleated patients demonstrated postoperative contrast enhancement on MRI after enucleation, at a mean interval of 10 months after surgery. The percentage of MRI scans with optic nerve enhancement was 77% from 0 to 6 months after enucleation and 68% at >24 months after surgery. Postenucleation optic nerve enhancement did not correlate with preoperative optic nerve enhancement, chemotherapy administration, or the presence of optic nerve invasion on histopathology. No child required an orbital biopsy. None of the 88 patients were found to have subsequent orbital or metastatic disease at the last clinical follow-up visit (average, 29 months; range, 1–71).Optic nerve contrast enhancement on follow-up MRI after enucleation for retinoblastoma seems to be a common, benign radiographic finding; none of the patients in this series developed extraocular tumor relapse. The presence of postenucleation enhancement on MRI did not correlate with preoperative chemotherapy or the presence of optic nerve invasion on histopathology. Based on our findings, intervention for isolated optic nerve enhancement on MRI is not indicated in the absence of other abnormal clinical or radiographic signs. A prospective trial with a validated radiographic grading system would be helpful to clarify the MRI features to differentiate orbital recurrence from benign postoperative enhancement.

Incidence of internal mammary node in locally advanced breast cancer and its correlation with metastatic disease: a retrospective observational study.

To determine incidence of internal mammary nodes (IMN) at baseline CT of locally advanced breast cancer (LABC) and ascertain prognostic implication. Retrospective review of all LABC patients from 1 January 2012 through 31 December 2014 was performed after approval from institutional review board. CTs of 182 patients enrolled were reviewed by two radiologists independently, and IMNs were documented based on size, location and relation with location of breast primary. 3-year follow-up was analysed and incidence of metastases was calculated as overall incidence, incidence in patients with and without discernible IMN at baseline imaging. Results are presented as numbers and percentages. Differences in metastases of two groups were compared using χ2 test. 95% CI was calculated and p < 0.05 was considered significant. 77 of 182 had identifiable IMN (42.3% incidence). Majority of identifiable nodes were on ipsilateral side of primary (incidence 90.90%) with higher incidence in patients with upper-outer quadrant tumours (55.9%). Majority were seen in second intercostal space (44.4%). 36 (19.7%) developed distant metastases within 3 years of therapy. Of these, 21 (27.3%) had IMN as compared with 15 (14.3 %) without IMN on baseline imaging. Patients with identifiable IMN on baseline CT had significantly higher incidence of distant metastases (p = 0.0321). Significant number LABC patients have identifiable IMN on baseline imaging with patients showing IMN on baseline CT showing significantly higher rate of metastatic disease following therapy. Many LABC patients have identifiable IMNs on baseline imaging which show higher incidence of subsequent metastatic disease.

Association between prolonged metastatic free interval and recurrent metastatic breast cancer survival: findings from the SEER database.

The prevalence of patients living with prolonged interval between initial breast cancer diagnosis and development of subsequent metastatic disease may be increasing with improved treatment. In order to counsel these patients as to their prognosis, we investigated the association between metastatic free interval (MFI) and subsequent survival from newly diagnosed metastatic breast cancer (MBC) in a population-level U.S. cohort. The Surveillance, Epidemiology and End Results database was used to identify patients with both an initial stage 1-3 breast cancer diagnosis and subsequent MBC diagnosis recorded from 1988 to 2014. Patients were stratified by MFI (< 5years, 5-10years, > 10years). The association between MFI and metastatic breast cancer-specific mortality (MBCSM) was analyzed with Fine-Gray competing risks regression. Five-year recurrent metastatic breast cancer-specific survival rate was 23%, 26%, and 35% for patients with MFI < 5, 5-10, and > 10years, respectively. Patients with > 10year MFI were less likely to die of breast cancer when compared with a referent group with < 5years MFI (standard hazard ratio (SHR) 0.77 [95% CI 0.65-0.90] P < 0.001). There was no significant difference for patients with MFI of 5-10years (SHR 0.92 [95% CI 0.81-1.04, P 0.191]) compared to < 5years. Other prognostic factors like White race, lower tumor grade, and ER/PR-positive receptors were also associated with improved cancer-specific survival after diagnosis of MBC. Prolonged MFI greater than 10years between initial breast cancer diagnosis and subsequent metastatic disease was found to be associated with improved recurrent MBC 5-year survival and decreased risk of breast cancer-specific mortality. This has potential implications for counseling patients as to prognosis, choice of treatment, as well as the stratification of patients considered for MBC clinical trials.

Association between metastatic free interval and recurrent metastatic breast cancer survival: Findings from the Surveillance, Epidemiology and End Results database.

e13069Background: The prevalence of patients living with prolonged interval between initial breast cancer diagnosis and development of subsequent metastatic disease may be increasing with improved ...

Intra-Articular Hip Injection Is a Valuable and Cost-Effective Diagnostic Tool but Replacing Advanced Diagnostic Methods Is Not Currently the Way to Go: Commentary on an article by Daniel J. Cunningham, MD, MHS, et al.: "Advanced Imaging Adds Little Value in the Diagnosis of Femoroacetabular Impingement Syndrome".

Commentary Cunningham et al. conducted a cost-effectiveness analysis of the diagnostic process for femoroacetabular impingement (FAI) syndrome. With the tremendous increase of the therapeutic and diagnostic costs of this pathology, the data presented in this study are noteworthy from a clinical and a financial standpoint. The article concludes that advanced imaging, including magnetic resonance imaging (MRI) and magnetic resonance arthrography (MRA), are not cost-effective methods when compared with the history and physical examination (H&P) with or without diagnostic hip injection, and thus should not be routinely performed to diagnose FAI. It was suggested that hip MRI and MRA should have a place in the diagnostic algorithm of FAI only in cases of “challenging clinical scenarios.” The use of diagnostic hip injection was proven to be favorable for general practitioners and less useful for hip specialists. FAI syndrome was redefined in an international consensus statement and was endorsed by 25 clinical societies1. Hip pain can be the result of bone lesions and cartilage damage, as well as labral, capsular, and ligamentum teres pathology. Although the H&P and hip radiographs can identify osseous abnormalities, labral or capsular pathology is left undiagnosed, and evaluation of the cartilage is impossible without MRI. With the substantial expansion of hip arthroscopic techniques2, it is possible to address osseous and soft-tissue lesions that, if left untreated, result in deterioration of hip biomechanical function and osteoarthritis3. The novelty of and rapid progression in diagnostic and treatment modalities in hip preservation surgery have resulted in an imbalance of medical knowledge between general practitioners and hip specialists. Cunningham et al. propose that H&P with injection is more likely to be cost effective for general practitioners. Administration of hip injection requires technical expertise since severe damage can occur in the hip when performed inappropriately. The former point is reflected in the results of the study: the willingness to pay (WTP) was $57,000/quality-adjusted life year (QALY) using the injection sensitivity rate in the general practitioner scenario. This amount is almost 50% lower than the accepted WTP threshold in the United States, which is $100,000. The elimination of the use of MRI and MRA in cases of “challenging clinical scenarios” would be reasonable if the level of education was equal between general practitioners and hip specialists because characterizing a clinical scenario as “clinically challenging” relies substantially on clinical expertise, which can differ considerably even among hip specialists. Hip joint ultrasonography in the diagnosis of FAI syndrome has attracted research interest. Ultrasound is less expensive and more accessible than MRI and MRA examination, but diagnostic accuracy depends on the examiner’s skills. Buck et al. reported that the acetabular labrum can be visualized using ultrasound, but only partially4. Evaluation of the interference of the labrum with the other joint structures during hip motion under ultrasound visualization could help to better understand the patient’s symptomatology and aid in preoperative planning. MRI has been used in studies as the gold standard to validate ultrasound for the diagnosis of cam impingement, with promising outcomes4,5, but not enough evidence exists to establish it as a reliable examination to diagnose FAI syndrome. Another advantage of preoperative MRI examination is the detection of occult malignant bone or soft-tissue tumors concomitant with FAI pathology, where arthroscopic hip intervention could cause tissue spread and subsequent metastatic disease. While Cunningham et al. support the reduction of MRI and MRA usage to diagnose FAI syndrome, currently there is no other validated tool to diagnose hip soft-tissue and cartilage lesions. A possible solution to limit the financial burden when diagnosing FAI syndrome would be an increase in training opportunities for health-care professionals to advance their knowledge of FAI syndrome (apart from the cam and pincer mechanisms), with specialized physical examination tests and radiographic views (cross-table lateral, Dunn view, or false-profile view). This would eliminate the need for repeated radiographs by specialized physicians who usually encounter a patient who has been diagnosed with FAI syndrome based on symptomatology, impingement tests, and/or anteroposterior pelvic radiographs. Overuse of MRI and MRA and the associated costs need to be addressed by establishing validated hip-screening protocols to diagnose FAI syndrome. This will bridge the “gap” between general practitioners and hip specialists when diagnosing this disease and prevent the misuse of MRI and MRA and overcharging of the health-care system.

Perioperative Management of Extremity Soft Tissue Sarcomas.

Surgery is potentially curative for primary nonmetastatic extremity soft tissue sarcomas. After surgery alone, patients may remain at risk for local recurrences and/or metastatic disease. To reduce the likelihood of a local relapse, the addition of radiotherapy (RT) to limb-sparing surgery may result in higher local control rates of at least 85%. Generally, it can be stated that local control after both preoperative and postoperative RT is comparable, but that preoperative RT comes with a more favorable toxicity profile after prolonged follow-up, albeit at the cost of a higher wound complication rate. Furthermore, recent data suggest that preoperative RT is more cost effective. To reduce the risk of subsequent metastatic disease, systemic chemotherapy can be introduced early during the primary management of these patients. These systemic chemotherapy regimens can also be applied both preoperatively and postoperatively. Finally, with the aim of increasing the antitumor response of perioperative RT, these agents may even be combined with RT, concurrently and sequentially. While designing new preoperative combination regimens, responses should be carefully monitored by both sophisticated radiologic and pathologic evaluations. This article reviews all these aspects, in addition to limb-sparing surgery.

Expanded molecular profiling of myxofibrosarcoma reveals potentially actionable targets

Myxofibrosarcomas are morphologically heterogeneous soft tissue sarcomas lacking a specific immunohistochemical expression profile and recurrent genetic changes. The study was designed to gain further insights into the molecular landscape of myxofibrosarcomas by targeted re-sequencing of known cancer driver hotspot mutations and the analysis of genomewide somatic copy number alterations. A well-defined group of myxofibrosarcomas, including myxofibrosarcomas G1 (n=6), myxofibrosarcomas G3 (n=7), myxofibrosarcomas with morphologically heterogeneous and independently selectable G1 and G3 areas within a tumor (n=8), and myxofibrosarcomas G3 with subsequent tumor recurrence (n=1) or metastatic disease (n=3) were evaluated. Mutational analysis demonstrated mutations in TP53, PTEN, FGFR3, CDKN2A, and RB1. TP53 mutations were seen in 11 (44%) of patients and detected in myxofibrosarcomas G1, G3, with heterogeneous morphology and G3 with subsequent metastases in 1 patient (16%), 3 patients (42%), 2 patients (62.5%), and 3 patients (75%), respectively. Additional mutations were detected in 2 patients, intratumoral mutational heterogeneity in 1 patient. We observed a variety of copy number alterations typical for myxofibrosarcomas, with higher numbers in G3 compared with G1 myxofibrosarcomas. Cluster analysis revealed distinctive features especially in metastatic and recurrent disease. Focal alterations affected CDKN2A, CCND1, CCNE1, EGFR, EPHA3, EPHB1, FGFR1, JUN, NF1, RB1, RET, TP53, and additional novel amplifications in CCNE1, KIT, EGFR, RET, BRAF, NTRK2 were seen in G3 compared with the G1 tumor areas. The total number of focal events in G1 versus G3 tumors differed significantly (P=0.0014). TRIO and RICTOR co-amplification was seen in 8 (44%) G3 and 1 (10%) G1 myxofibrosarcomas and RICTOR amplification alone in 4 (40%) G1 myxofibrosarcomas. TRIO amplification was significantly (P=0.0218) higher in G3 myxofibrosarcomas indicating a late genetic event. These findings support the use of expanded molecular profiling in myxofibrosarcomas to detect drug-able targets to allow patients to participate in basket trials.

Reduced number of CD169+ macrophages in pre-metastatic regional lymph nodes is associated with subsequent metastatic disease in an animal model and with poor outcome in prostate cancer patients.

BackgroundTumor‐derived antigens are captured by CD169+ (SIGLEC1+) sinus macrophages in regional lymph nodes (LNs), and are presented to effector cells inducing an anti‐tumor immune response. Reduced CD169 expression in pre‐metastatic regional LNs is associated with subsequent metastatic disease and a poor outcome in several tumor types, but if this is the case in prostate cancer has not been explored.MethodsCD169 expression was measured with immunohistochemistry in metastasis‐free regional LNs from 109 prostate cancer patients treated with prostatectomy (January 1996 to April 2002). Possible associations of CD169 expression with PSA‐relapse, prostate cancer death, Gleason score, and other clinical data were assessed using Kaplan‐Meier survival‐ and Cox regression analysis. In addition, the Dunning rat prostate tumor model was used to examine CD169 expression in pre‐metastatic LNs draining either highly metastatic MatLyLu‐ or poorly metastatic AT1‐tumors.ResultsIn patients with low CD169 immunostaining in metastasis‐free regional LNs, 8 of the 27 patients died from prostate cancer compared with only three of the 82 patients with high immunostaining (P < 0.001). CD169 expression in regional LNs was not associated with PSA‐relapse. Rats with highly metastatic tumors had decreased CD169 immunoreactivity in pre‐metastatic regional LNs compared with rats with poorly metastatic tumors.ConclusionLow expression of CD169 in metastasis‐free regional LNs indicates a reduced anti‐tumor immune response. If verified in other studies, CD169 expression in regional LNs could, in combination with other factors, potentially be used as a marker of prostate cancer aggressiveness.

Clinical Significance of Optic Nerve Enhancement on Magnetic Resonance Imaging in Enucleated Retinoblastoma Patients

The aim of this 8-year retrospective review was to determine the clinical significance of gadolinium-enhanced magnetic resonance imaging (MRI) findings in retinoblastoma patients after enucleation, particularly the presence of abnormal contrast enhancement of the transected optic nerve. Retrospective chart review. A review was done on 88 patients with retinoblastoma undergoing 90 enucleations between January 2008 and December2015. These patients underwent 233 MRI scans: 90 preoperative and 143 postoperative that were included for review. The primary outcome measure assessed was abnormal MRI findings in the preoperative and postoperative MRI scans, specifically enhancement of the optic nerve and correlations between abnormal MRI findings and clinical outcomes for the 88 patients. On the preoperative MRI, 4 optic nerves out of 90 scans showed positive enhancement. Fifty orbits had ≥1 postoperative MRI. Overall, 41 of 50 orbits (82%) of enucleated patients demonstrated postoperative contrast enhancement on MRI after enucleation, at a mean interval of 10 months after surgery. The percentage of MRI scans with optic nerve enhancement was 77% from 0 to 6 months after enucleation and 68% at >24 months after surgery. Postenucleation optic nerve enhancement did not correlate with preoperative optic nerve enhancement, chemotherapy administration, or the presence of optic nerve invasion on histopathology. No child required an orbital biopsy. None of the 88 patients were found to have subsequent orbital or metastatic disease at the last clinical follow-up visit (average, 29 months; range, 1-71). Optic nerve contrast enhancement on follow-up MRI after enucleation for retinoblastoma seems to be a common, benign radiographic finding; none of the patients in this series developed extraocular tumor relapse. The presence of postenucleation enhancement on MRI did not correlate with preoperative chemotherapy or the presence of optic nerve invasion on histopathology. Based on our findings, intervention for isolated optic nerve enhancement on MRI is not indicated in the absence of other abnormal clinical or radiographic signs. A prospective trial with a validated radiographic grading system would be helpful to clarify the MRI features to differentiate orbital recurrence from benign postoperative enhancement.