Reported Adverse Events in a Multicenter Cohort of Patients Ages 6-18 Years with Cystic Fibrosis and at Least one F508del Allele Receiving Elexacaftor/Tezacaftor/Ivacaftor.

OBJECTIVE: To describe reported adverse events (AEs) associated with elexacaftor/tezacaftor/ivacaftor (ETI) in a pediatric sample with cystic fibrosis (CF) aged 6-18 years, with at least one F508del variant, followed at multiple Italian CF centers. STUDY DESIGN: This was a retrospective, multicenter, observational study. All children receiving ETI therapy from October 2019 to December 2023 were included. We assessed the prevalence and type of any reported potential drug-related AEs, regardless of discontinuation necessity. Persistent AEs were defined as those continuing at the end of the observation period. RESULTS: Among 608 patients on ETI, 109 (17.9%) reported at least one AE. The majority (N=85, 77.9%) were temporary, with a median duration of 11 days (range 1-441 days). Only 7 (1.1%) patients permanently discontinued treatment, suggesting good overall safety of ETI. The most common AEs leading to discontinuation were transaminase elevations (temporary 14.1%, persistent 25.9%) and urticaria (temporary 41.2%, persistent 7.4%). Creatinine phosphokinase elevation was uncommon. No significant differences in AEs were observed based on sex, age groups (6-11 vs. 12-18 years), or genotype. Pre-existing CF-related liver disease was associated with an increased risk of transaminase elevations. We identified significant variability in the percentage of reported AEs (ANOVA p-value 0·026). CONCLUSIONS: This real-world study highlights significant variability in reported AEs. Our findings suggest that ETI is a safe and well-tolerated therapy in children and adolescents with CF. However, further long-term safety and effectiveness investigations are warranted.

Defining distal splenopancreatectomy by the mesopancreas.

BACKGROUND: The implementation of the pathologic CRM (circumferential resection margin) staging system for pancreatic head ductal adenocarcinomas (hPDAC) resulted in a dramatic increase of R1 resections at the dorsal resection margin, presumably because of the high rate of mesopancreatic fat (MP) infiltration. Therefore, mesopancreatic excision (MPE) during pancreatoduodenectomy has recently been promoted and has demonstrated better local disease control, fueling the discussion of neoadjuvant downsizing regimes in MP + patients. However, it is unknown to what extent the MP is infiltrated in patients with distal pancreatic (tail/body) carcinomas (dPDAC). It is also unknown if the MP infiltration status affects surgical margin control in distal pancreatectomy (DP). The aim of our study was to histopathologically analyze MP infiltration and elucidate the influence of resection margin clearance on recurrence and survival in patients with dPDAC. Furthermore, the results were compared to a collective receiving MPE for hPDAC. METHOD: Clinicopathological and survival parameters of 295 consecutive patients who underwent surgery for PDAC (n = 63 dPDAC and n = 232 hPDAC) were evaluated. The CRM evaluation was performed in a standardized fashion and the specimens were examined according to the Leeds pathology protocol (LEEPP). The MP area was histopathologically evaluated for cancerous infiltration. RESULTS: In 75.4% of dPDAC patients the MP fat was infiltrated by vital tumor cells. The rates of MP infiltration and R0CRM- resections were similar between dPDAC and hPDAC patients (p = 0.497 and 0.453 respectively). MP- infiltration status did not correlate with CRM implemented resection status in dPDAC patients (p = 0.348). In overall survival analysis, resection status and MP status remained prognostic factors for survival. In follow up analysis. surgical margin clearance in dPDAC patients was associated with a significant improvement in local recurrence rates (5.2% in R0CRM- resected vs. 33.3 in R1/R0CRM + resected, p = 0.002). CONCLUSION: While resection margin status was not affected by the MP status in dPDAC patients, the high MP infiltration rate, as well as improved survival in MP- dPDAC patients after R0CRM- resection, justify mesopancreatic excision during splenopancreatectomy. Larger scale studies are urgently needed to validate our results and to study the effect on neoadjuvant treatment in dPDAC patients.

Treatment outcome of atypical EGFR mutations in the German National Network Genomic Medicine Lung Cancer (nNGM).

BACKGROUND: Atypical EGFR mutations occur in 10%-30% of non-small-cell lung cancer (NSCLC) patients with EGFR mutations and their sensitivity to classical epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKI) is highly heterogeneous. Patients harboring one group of uncommon, recurrent EGFR mutations (G719X, S768I, L861Q) respond to EGFR-TKI. Exon 20 insertions are mostly insensitive to EGFR-TKI but display sensitivity to exon 20 inhibitors. Clinical outcome data of patients with very rare point and compound mutations upon systemic treatments are still sparse to date. PATIENTS AND METHODS: In this retrospective, multicenter study of the national Network Genomic Medicine (nNGM) in Germany, 856 NSCLC cases with atypical EGFR mutations including co-occurring mutations were reported from 12 centers. Clinical follow-up data after treatment with different EGFR-TKIs, chemotherapy and immune checkpoint inhibitors were available from 260 patients. Response to treatment was analyzed in three major groups: (i) uncommon mutations (G719X, S7681, L861Q and combinations), (ii) exon 20 insertions and (iii) very rare EGFR mutations (very rare single point mutations, compound mutations, exon 18 deletions, exon 19 insertions). RESULTS: Our study comprises the largest thus far reported real-world cohort of very rare EGFR single point and compound mutations treated with different systemic treatments. We validated higher efficacy of EGFR-TKI in comparison to chemotherapy in group 1 (uncommon), while most exon 20 insertions (group 2) were not EGFR-TKI responsive. In addition, we found TKI sensitivity of very rare point mutations (group 3) and of complex EGFR mutations containing exon 19 deletions or L858R mutations independent of the combination partner. Notably, treatment responses in group 3 (very rare) were highly heterogeneous. Co-occurring TP53 mutations exerted a non-significant trend for a detrimental effect on outcome in EGFR-TKI-treated patients in groups 2 and 3 but not in group 1. CONCLUSIONS: Based on our findings, we propose a novel nNGM classification of atypical EGFR mutations.

MRI grading for the prediction of prostate cancer aggressiveness.

OBJECTIVES: T o evaluate the value of multiparametric MRI (mpMRI) for the prediction of prostate cancer (PCA) aggressiveness. METHODS: In this single center cohort study, consecutive patients with histologically confirmed PCA were retrospectively enrolled. Four different ISUP grade groups (1, 2, 3, 4-5) were defined and fifty patients per group were included. Several clinical (age, PSA, PSAD, percentage of PCA infiltration) and mpMRI parameters (ADC value, signal increase on high b-value images, diameter, extraprostatic extension [EPE], cross-zonal growth) were evaluated and correlated within the four groups. Based on combined descriptors, MRI grading groups (mG1-mG3) were defined to predict PCA aggressiveness. RESULTS: In total, 200 patients (mean age 68 years, median PSA value 8.1 ng/ml) were analyzed. Between the four groups, statistically significant differences could be shown for age, PSA, PSAD, and for MRI parameters cross-zonal growth, high b-value signal increase, EPE, and ADC (p < 0.01). All examined parameters revealed a significant correlation with the histopathologic biopsy ISUP grade groups (p < 0.01), except PCA diameter (p = 0.09). A mixed linear model demonstrated the strongest prediction of the respective ISUP grade group for the MRI grading system (p < 0.01) compared to single parameters. CONCLUSIONS: MpMRI yields relevant pre-biopsy information about PCA aggressiveness. A combination of quantitative and qualitative parameters (MRI grading groups) provided the best prediction of the biopsy ISUP grade group and may improve clinical pathway and treatment planning, adding useful information beyond PI-RADS assessment category. Due to the high prevalence of higher grade PCA in patients within mG3, an early re-biopsy seems indicated in cases of negative or post-biopsy low-grade PCA. KEY POINTS: • MpMRI yields relevant pre-biopsy information about prostate cancer aggressiveness. • MRI grading in addition to PI-RADS classification seems to be helpful for a size independent early prediction of clinically significant PCA. • MRI grading groups may help urologists in clinical pathway and treatment planning, especially when to consider an early re-biopsy.

Mesopancreatic excision for pancreatic ductal adenocarcinoma improves local disease control and survival.

BACKGROUND: Survival in ductal adenocarcinoma of the pancreatic head (hPDAC) is poor. After implementation of the circumferential resection margin (CRM) into standard histopathological evaluation, the margin negative resection rate has drastically dropped. However, the impact of surgical radicality on survival and the influence of malignant infiltration of the mesopancreatic fat remains unclear. At our institution, a standardized dissection of the mesopancreatic lamina and peri-pancreatic vessels are obligatory components of radical pancreatoduodenectomy. The aim of our study was to histopathologically analyze mesopancreatic tumor infiltration and the influence of CRM-evaluated resection margin on relapse-free and overall survival. METHOD: Clinicopathological and survival parameters of 264 consecutive patients who underwent surgery for hPDAC were evaluated. RESULTS: The rate of R0 resection R0(CRM-) was 48.5%, after the implementation of CRM. Mesopancreatic fat infiltration was evident in 78.4% of all consecutively treated patients. Patients with mesopancreatic fat infiltration were prone to lymphatic metastases (N1 and N2) and had a higher rate of positive resection margin (R1/R0(CRM+)). In multivariate analysis, only R0 resection was shown to be an independent prognostic parameter. Local recurrence was diagnosed in only 21.1% and was significantly lower in patients with R0(CRM-) resected hPDACs (10.9%, p < 0.001). CONCLUSION: Mesopancreatic excision is justified, since mesopancreatic fat invasion was evident in the majority of our patients. It is associated with a significantly improved local tumor control as well as longer relapse-free and overall survival.

[Metastasis of pancreatic tumors]. / Metastasierung von Pankreastumoren.

With a 5-year survival rate that has remained stagnant at 6 % for decades, pancreatic ductal adenocarcinoma (PDAC) is still one of the most fatal malignancies. Despite intensive research, currently available therapy options are less than adequate. As more than half of the patients already show distant metastases at the time of diagnosis, metastatic disease should be a primary focus in the development of new therapeutic strategies. New findings from basic research provide various interesting approaches: molecular profiling of the primary tumor seems to be a possible method to gain knowledge about the prognosis, metastatic potential and therapy response of each individual case of PDAC. Certain subpopulations of cancer stem cells also seem to be of importance in metastasis of PDAC and could become potential therapeutic targets in the future. Interactions between tumor cells and their microenvironment are another crucial factor in the metastasis of pancreatic cancer and present various new starting points for potential therapies. As the number of cell types and signaling pathways that are found to play a role in PDAC metastasis continue to grow, the next big challenge will be to translate these findings into viable clinical applications.

[Classification and malignant potential of pancreatic cystic tumors]. / Klassifikation und malignes Potenzial der zystischen Pankreastumoren.

Cystic lesions of the pancreas are increasingly diagnosed with a reported prevalence of 10 % in 70-year-old individuals. Despite their broad spectrum, most resected cystic lesions can be attributed to one of the following entities: intraductal papillary mucinous neoplasms (IPMN), mucinous cystic neoplasms (MCN), serous cystic neoplasms (SCN), neuroendocrine cystic tumors (NECT), and solid pseudopapillary neoplasms (SPN). Among them, IPMN and MCN represent precursors of ductal adenocarcinoma, NECT and SPN are low-grade, potentially malignant lesions, and SCN are usually benign. Due to the not negligible morbidity and mortality rates in pancreatic surgery, even in highly specialized centers, an interdisciplinary preoperative stratification of pancreatic cystic lesions into high- and low-risk tumors is necessary in order to accurately select those cases that need to undergo immediate resection. The role of the pathologist is fundamental in both the preoperative assessment and in the postoperative classification, which determines prognosis, further treatment, and follow-up.

[Update of the S3 guidelines for pancreatic cancer. What is new for pathologists?]. / Update der S3-Leitlinie für das Pankreaskarzinom. Was ist neu für Pathologen?

The S3 guidelines for pancreatic cancer were revised in 2013. Besides the oncological and palliative therapy modalities and surgical therapy, the guidelines for pathologists in topic 3 were updated. The modifications essentially concern the histopathological assessment of surgical specimens and in particular the circumferential resection margin and the R classification. In addition, the current recommendations were amended by recommendations concerning the pathohistological records, which should include the lymph node ratio in the future.

[Autoimmune pancreatitis--treatment and pitfalls in diagnostics]. / Autoimmune Pankreatitis--Behandlung und Problematik der Diagnosestellung.

BACKGROUND: Autoimmune pancreatitis (AIP) was first classified as a defined disease entity in 1995. It accounts for approximately 2 % of cases of chronic pancreatitis (western world prevalence 36-41/100,000 inhabitants) and AIP is diagnosed in 2.4 % of pancreas resection specimens. OBJECTIVES: Presentation of strategies for diagnosis and treatment with focus on differentiation of AIP and pancreatic carcinoma. METHODS: Selective literature research in PubMed regarding pathogenesis, diagnosis and treatment of AIP. RESULTS: Key characteristics of AIP are recurrent jaundice due to obstructed bile ducts, histological evidence of fibrosis, a lymphoplasmocytic or granulocytic infiltrate and the response to steroid therapy. There are two distinctive forms of AIP: type I or lymphoplasmocytic sclerosing pancreatitis and type II or idiopathic duct centric pancreatitis. The IgG4 positive AIP type I belongs to the group of IgG4-related systemic diseases. Diagnosis of AIP is established according to the international consensus diagnostic criteria (ICDC) or HISORt (mnemonic standing for histology, imaging, serology, other organ involvement and response to therapy) criteria. Differentiation from pancreatic adenocarcinoma can be challenging. The standard treatment consists of corticosteroids and in some cases azathioprine can be added. In refractory disease rituximab is a further option. Treatment is indicated in patients with jaundice, systemic manifestation or persistent pain. CONCLUSION: Although AIP is increasingly being identified, the differentiation from pancreatic adenocarcinoma still remains difficult and in cases of a suspicion of neoplasia, resection should be favored. It can successfully be treated conservatively with steroids and rituximab.

MRI in-bore biopsy following MRI/US fusion-guided biopsy in patients with persistent suspicion of clinically significant prostate cancer.

PURPOSE: Patients with suspicion of clinically significant prostate cancer (csPC) on multiparametric prostate MRI (mpMRI) but negative or inconclusive MRI/US fusion-guided biopsy (FB) can be challenging in clinical practice. To assess the utility of MRI in-bore biopsy (IB) in patients with discordant imaging and histopathological findings after FB. METHODS: Consecutive patients with Prostate Imaging Reporting and Data System (PI-RADS) category 4 or 5 on mpMRI at 3T after FB without histologically confirmed csPC who underwent IB between 01/2014 and 05/2022, were retrospectively included. The primary objective was to assess the detection rate of csPC. Secondary objectives were to analyze clinical parameters, MRI parameters, and lesion localization. RESULTS: In the final cohort of 51 patients, the IB resulted in an overall detection rate of 71% for PC and 47% for csPC. Furthermore, in 55% of cases with initial low-grade PC, the Gleason score was upgraded after IB. CsPC was often detected apical and/or anterior. The detection rate for PC was 58% in PI-RADS category 4 and 94% in PI-RADS category 5 (csPC 39% and 61%, respectively). Patients with csPC had statistically significant smaller prostate volumes, a higher PI-RADS category, a higher prostate-specific antigen density (PSAD), and were older. CONCLUSIONS: For a relevant proportion of patients with PI-RADS category 4 or 5 and negative or inconclusive findings on previous FB, but with persistent suspicion of csPC, a subsequent IB verified the presence of csPC. Therefore, IB can be a backup in cases of uncertainty.

[Intraductal papillary neoplasms of the bile duct (IPNB). Diagnostic criteria, carcinogenesis and differential diagnostics]. / Intraduktale papilläre Neoplasien der Gallenwege (IPNB). Diagnosekriterien, Karzinogenese und Differenzialdiagnosen.

Intraductal papillary neoplasms of the bile duct (IPNB) are rare precursor lesions of intrahepatic and extrahepatic cholangiocarcinoma that follow an adenoma-carcinoma sequence. According to the histomorphology and the distinct immunohistochemical mucin pattern, four different subtypes are recognized: pancreatobiliary, intestinal, gastric and oncocytic. Differential diagnoses include micropapillary lesions (biliary intraepithelial neoplasms), papillary cystic lesions (intraductal tubulopapillary neoplasms) and cystic lesions (mucinous cystic neoplasms).

Multiparametric MRI characteristics of prostatitis and atrophy in the peripheral zone in men without prostate cancer.

PURPOSE: To analyse multiparametric magnetic resonance imaging (mpMRI) characteristics and appearance of histopathologically proven non-cancerous intraprostatic findings focussing on quantity of prostatitis and atrophy in the peripheral zone. METHOD: In this retrospective analysis consecutive patients with mpMRI followed by MRI/TRUS-fusion biopsy comprising targeted (TB) and systematic biopsy (SB) cores without prostate cancer (PC) at histopathology were included. Subgroup analysis was performed in younger men (≤50 years). The proportions of prostatitis and atrophy were quantified for each biopsy core based on histopathology. MRI findings in the peripheral zone (PZ) and index lesions (IL, most suspicious/representative lesion) were characterized regarding changes in T2w, ADC value, and enhancement of dynamic contrast enhancement (DCE) and correlated with quantity of prostatitis and atrophy. RESULTS: Seventy-two patients were analysed. The median baseline characteristics were PSA 5.4 ng/ml (4.0-7.9), PI-RADS classification 3 (2-4), prostate volume 43 ml (33-57), and PSA density 0.13 ng/ml2 (0.10-0.19). Prostatitis was found in 44 % (n = 32) and atrophy in 65 % (n = 47) of cases. The quantity of atrophy demonstrated a significant correlation to T2w changes, ADC increase and DCE enhancement (p = 0.05, p = 0.05, p = 0.01), whereas quantity of prostatitis did not show any significant correlation to the MRI changes (p = 0.68, p = 0.58, p = 0.95). Quantity of prostatitis and atrophy increased with PI-RADS classification. Younger men had lower PSA (4.4 vs. 7.8 ml/ng; p < 0.001), smaller prostate volume (40 vs. 59 ml; p = 0.001), and lower PI-RADS classification (2-3 vs. 3-4; p = 0.005) and prostatitis and atrophy were less frequently observed (p ≤ 0.01, p = 0.03). CONCLUSIONS: Quantity of atrophy and prostatitis had different influence on MRI characteristics and increased within higher PI-RADS classification. Younger men had diffuse hypointense changes at T2w images, but less quantity of prostatitis and atrophy.

High STEAP1 expression is associated with improved outcome of Ewing's sarcoma patients.

BACKGROUND: Ewing's sarcoma (ES) is the second most common bone or soft-tissue sarcoma in childhood and adolescence and features a high propensity to metastasize. The six-transmembrane epithelial antigen of the prostate 1 (STEAP1) is a membrane-bound mesenchymal stem cell marker highly expressed in ES. Here, we investigated the role of STEAP1 as an immunohistological marker for outcome prediction in patients with ES. PATIENTS AND METHODS: Membranous STEAP1 immunoreactivity was analyzed using immunohistochemistry in 114 primary pre-chemotherapy ES of patients diagnosed from 1983 to 2010 and compared with clinical parameters and patient outcome. Median follow-up was 3.85 years (range 0.43-17.51). RESULTS: A total of 62.3% of the ES samples displayed detectable STEAP1 expression with predominant localization of the protein at the plasma membrane. High membranous STEAP1 immunoreactivity was found in 53.5%, which correlated with better overall survival (P=0.021). Accordingly, no or low membranous STEAP1 expression was identified as an independent risk factor in multivariate analysis (hazard ratio 2.65, P=0.036). CONCLUSION: High membranous STEAP1 expression predicts improved outcome and may help to define a specific subgroup of ES patients, who might benefit from adapted therapy regimens.

[New insights into the origin of pancreatic cancer. Role of atypical flat lesions in pancreatic carcinogenesis]. / Neue Einblicke in die Entstehung des Pankreaskarzinoms. Die Rolle der atypischen flachen Läsionen in der Karzinogenese.

The identification and characterization of precursor lesions is fundamental to develop screening programs for early diagnosis and treatment, aiming at reducing cancer-related mortality. Pancreatic ductal adenocarcinoma (PDAC) is an aggressive disease that becomes clinical apparent only in advanced stages. In order to enable screening procedures for early detection of PDAC, an exact characterization of precursor lesions is of utmost importance. Pancreatic intraepithelial neoplasias (PanIN) are the most frequent and best characterized precursors of PDAC and are lesions with a ductal phenotype thus indicating a ductal cell origin of PDAC. However, evidence from genetically engineered mouse models suggests that tubular complexes (TC) originating through a process of acinar-ductal metaplasia (ADM) form atypical flat lesions (AFL) that may represent an alternative pathway of pancreatic carcinogenesis. Based on a thorough morphological and genetic analysis of murine TC, AFL and PanIN and their human counterparts, a new dual model of pancreatic carcinogenesis is proposed taking into account the role of AFL as possible new precursors of PDAC.

Pre-operative magnetic resonance imaging can predict prostate cancer with risk for positive surgical margins.

PURPOSE: Analysis of patients with pre-operative 3 T multiparametric prostate MRI (mpMRI) to determine reliable MRI-based risk predictors of patients at risk for positive surgical margins (PSM) in robotic assisted radical prostatectomy (RPE). METHODS: Consecutive patients with 3 T mpMRI and subsequent RPE from 01/2015 to 12/2018 were retrospectively included. Patients were compared regarding clinical and MRI related parameters such as length of capsular tumor contact (LCC) and distance to the membranous urethra (UD). RESULTS: Forty-nine of 179 patients (27%) had PSM in 70 different localizations, with the majority located at the capsule (57%, 40/70), mostly apical and/or posterior. The second most often PSM occurred at the apical urethra (22%, 15/70). PCA was visible on mpMRI at the localization of PSM in 93% at the capsule and in 80% at the urethra. PSA, PI-RADS classification, extraprostatic extension (EPE), and seminal vesicles infiltration (SVI) on MRI were significantly higher / more frequent in patients with PSM. LCC (AUC 0.710), EPE (AUC 0.693), and UD (1-AUC 0.673) predicted PSM (overall). An UD of ≤ 3.5 mm showed the highest accuracy of 95% (J = 0.946) for PSM at the urethra and a LCC of ≥ 22.5 mm with 77% (J = 0.378) for PSM at the capsule. CONCLUSION: PSM occurred mostly in the apex and/or posteriorly at the capsule or at the apical urethra. LCC was the best MRI predictor for PSM at the capsule and UD for tumors with PSM at the apical urethra. Using these MRI parameters readers might pre-operatively determine PCA localizations at risk for PSM.

Comparison of 3 T mpMRI and pelvic CT examinations for detection of lymph node metastases in patients with prostate cancer.

PURPOSE: This study investigates preoperative lymph node metastases (LNM) detection accuracy by MRI and CT in patients with prostate cancer (PCA). METHODS: All patients with preoperative MRI, CT or both and subsequent radical prostatectomy (RPE) and lymphadenectomy (LA) were included in this retrospective cohort study. Prostate specific antigen (PSA), PI-RADS, ISUP grade group, clinical and pathological tumor (T) stage was compared between negative and positive nodal (N) stage. LNM were assessed with size and localization and weather they were preoperatively detected or not. In patients with preoperative CT and MRI, the results were compared intermodally. The reference standard was the histopathological results after RPE and LA. RESULTS: A total of 228 patients were analysed including 24 patients with confirmed LNM (N1; 11%). PSA (median 9.7 vs. 14 ng/ml), PI-RADS (median 4 vs. 5), ISUP (median 2 vs. 4), and cT/pT-stage (median T2 vs. T3) was significantly higher in patients with LNM. No LNM were found in patients with ISUP-1-PCA. MRI was able to detect 67% of patients with LNM. Lymph node metastases presented on MRI predominantly small, round-shaped, located parailiacally with a minimum SAD of 4 mm (vs. CT SAD of 8 mm). In comparison, MRI was superior to CT in the detection of LNM (sensitivity 81% vs. 33%; specificity 99% vs. 97). CONCLUSION: LNM were very rare in patients with PSA < 10 ng/ml, PI-RADS ≤ 4, and ≤ cT2. MRI could detect LNM up to 4 mm with a moderate sensitivity and high specificity. Thus, MRI might optimise the preoperative diagnostic and therapy planning of patients with PCA, whereas CT was clearly limited for N-stage assessment.