[Prevention, Diagnosis, Therapy, and Follow-up of Lung Cancer - Interdisciplinary Guideline of the German Respiratory Society and the German Cancer Society - Abridged Version]. / Prävention, Diagnostik, Therapie und Nachsorge des Lungenkarzinoms.

The current S3 Lung Cancer Guidelines are edited with fundamental changes to the previous edition based on the dynamic influx of information to this field:The recommendations include de novo a mandatory case presentation for all patients with lung cancer in a multidisciplinary tumor board before initiation of treatment, furthermore CT-Screening for asymptomatic patients at risk (after federal approval), recommendations for incidental lung nodule management , molecular testing of all NSCLC independent of subtypes, EGFR-mutations in resectable early stage lung cancer in relapsed or recurrent disease, adjuvant TKI-therapy in the presence of common EGFR-mutations, adjuvant consolidation treatment with checkpoint inhibitors in resected lung cancer with PD-L1 ≥ 50%, obligatory evaluation of PD-L1-status, consolidation treatment with checkpoint inhibition after radiochemotherapy in patients with PD-L1-pos. tumor, adjuvant consolidation treatment with checkpoint inhibition in patients withPD-L1 ≥ 50% stage IIIA and treatment options in PD-L1 ≥ 50% tumors independent of PD-L1status and targeted therapy and treatment option immune chemotherapy in first line SCLC patients.Based on the current dynamic status of information in this field and the turnaround time required to implement new options, a transformation to a "living guideline" was proposed.

Time-Dependent Molecular Motifs of Pulmonary Fibrogenesis in COVID-19.

(1) Background: In COVID-19 survivors there is an increased prevalence of pulmonary fibrosis of which the underlying molecular mechanisms are poorly understood; (2) Methods: In this multicentric study, n = 12 patients who succumbed to COVID-19 due to progressive respiratory failure were assigned to an early and late group (death within ≤7 and >7 days of hospitalization, respectively) and compared to n = 11 healthy controls; mRNA and protein expression as well as biological pathway analysis were performed to gain insights into the evolution of pulmonary fibrogenesis in COVID-19; (3) Results: Median duration of hospitalization until death was 3 (IQR25-75, 3-3.75) and 14 (12.5-14) days in the early and late group, respectively. Fifty-eight out of 770 analyzed genes showed a significantly altered expression signature in COVID-19 compared to controls in a time-dependent manner. The entire study group showed an increased expression of BST2 and IL1R1, independent of hospitalization time. In the early group there was increased activity of inflammation-related genes and pathways, while fibrosis-related genes (particularly PDGFRB) and pathways dominated in the late group; (4) Conclusions: After the first week of hospitalization, there is a shift from pro-inflammatory to fibrogenic activity in severe COVID-19. IL1R1 and PDGFRB may serve as potential therapeutic targets in future studies.

[Detection of BRAF V600E mutation in metastatic colorectal carcinoma : A QuIP round robin test]. / Nachweis der BRAF-V600E-Mutation beim metastasierten kolorektalen Karzinom : Ein QuIP-Ringversuch.

Round robin testing is an important instrument for quality assurance. Increasingly, this also applies to the results of molecular diagnostics in pathology, which directly influence therapy decisions in precision oncology. In metastatic colorectal carcinoma (mCRC), the focus has been on detecting KRAS and NRAS mutations, whose absence allows therapy with EGFR blocking antibodies. Recently, BRAF has been added as another predictive marker, since mCRC patients with BRAF V600E mutation benefit significantly from treatment with encorafenib (a BRAF inhibitor) in combination with cetuximab (anti-EGFR antibody) after systemic therapy. Due to the approval of this treatment in 2020, it is a pre-requisite that BRAF V600E mutation detection in diagnostic pathologies is reliably performed. Therefore, this round robin test with BRAF V600E testing either by immunohistochemistry or molecular methods was performed. The round robin test results demonstrate that molecular BRAF V600E detection is currently clearly superior to immunohistochemical detection.

Dentinogenic Ghost Cell Tumour in Childhood Involving the Temporomandibular Joint: Considerations and Therapy.

Background: Although the uncommon dentinogenic ghost cell tumour (DGCT) is a benign entity, it possesses the ability to cause widespread destruction of the jaws and to recur after bone-preserving therapy. Hence, clear margins should be achieved upon surgery, and reconstruction techniques must often be used to restore osseous defects. However, this can be challenging in cases with involvement of the temporomandibular joint (TMJ), and especially in children. Case report: We present a case of a DGCT in a 12-year-old boy with wide infiltration of the mandible and the TMJ. A two-staged reconstructive approach was performed. Upon primary surgery, tumour-free margins were obtained and mandibular anatomy was restored using an iliac crest graft and an alloplastic condyle implant for temporary TMJ reconstruction. In a second step 5 months later, having received a customized TMJ prosthesis consisting of a fossa and a condyle component, the TMJ was completely replaced for definitive reconstruction. Conclusion: A customized TMJ prosthesis could be a solution for reconstruction of the TMJ in children. However, the further course with respect to growth disturbances must be evaluated upon short-term follow-ups and might require additional corrective interventions.

Detection of PAX8-PPARG fusion transcripts in archival thyroid carcinoma samples by conventional RT-PCR.

The t(2;3)(q13;p25) occurs in a subgroup of follicular-patterned thyroid tumors and leads to a fusion of the genes encoding for the thyroid-specific transcription factor paired box 8 (PAX8) and the peroxisome proliferator-activated receptor gamma (PPARγ). Although initially discovered in follicular carcinomas (FTC), the fusion transcripts were also detected in a small fraction of follicular adenomas and rarely in follicular variants of papillary carcinomas (FV-PTC). In most RT-PCR based studies, fresh or snap-frozen tissue samples were used. The aim of the present study was to develop a method for the detection of chimeric PAX8-PPARG transcripts in formalin-fixed paraffin-embedded (FFPE) thyroid tumor samples by conventional RT-PCR. For this purpose, RNA from FFPE samples of 21 FTC, seven FV-PTC, and one bone metastasis derived from an FTC was subjected to RT-PCR with subsequent gel electrophoretic separation of the products. Fusion transcripts were detected in 2/21 primary FTC (9.5%) and in the bone metastasis, but they were undetectable in all seven FV-PTC under investigation. The RT-PCR approach described herein allows to detect all known variants of PAX8-PPARG fusion transcripts and is applicable to FFPE tissues. Thus, it can be used to screen archival thyroid tumor samples for the gene fusion.

Melanotic Neuroectodermal Tumour of Infancy: Clinical Courses and Therapeutic Options-A Review of Three Cases.

BACKGROUND: Melanotic neuroectodermal tumour of infancy (MNTI) is a rare benign neoplasm. MNTI appears most often during the first year of life, arises predominantly in the maxilla and tends to recur. We discuss possible therapeutic options given in the literature and within our experience in three cases. PATIENTS: In our recent case, we used an intraoral approach to perform resection of the right-sided maxilla. Despite tumour-positive margins, there was no recurrence over the course of one year. In a previous case of MNTI, two recurrences occurred and 6 months after last resection patient received a rib graft for maxillary reconstruction. However, at the age of 7 years, the infant displayed severe maxillary hypoplasia. In a third case of MNTI, the patient was followed up after initial therapy for two decades and underwent multiple reconstruction procedures to achieve successful rehabilitation. CONCLUSION: Surgical treatment of MNTI should respect vital anatomic structures to avoid gross mutilation. The need for extended and repetitive tumour resection in early childhood can lead to growth disturbances and to further multiple reconstruction procedures in adulthood. Because of the rarity of MNTI, an international database is warranted to evaluate therapies and clinical courses over decades.

Expression of Mismatch Repair Proteins in Merkel Cell Carcinoma.

We aimed to assess for the first time the mismatch repair (MMR) protein expression in Merkel cell carcinoma (MCC). Immunohistochemistry was performed for MLH1, MSH2, MSH6, and PMS2 on patients' tumor tissue (n = 56), including neighbored healthy control tissue. In cases with low-level MMR expression (<10th percentile), we performed multiplex PCR in combination with high-resolution capillary electrophoresis in order to confirm microsatellite instability (MSI). Microscopic evaluation revealed a high median expression for all MMR proteins studied (91.6-96.3%). However, six patients (56/10.7%) had low-level MLH1 expression, six (55/10.9%) had low-level MSH2 expression, five (56/8.9%) had low-level MSH6 expression, and six (54/11.1%) had low-level PMS2 expression. Together, we observed nine (56/16.1%) patients who had low-level MMR expression of at least one protein. Of the patients with low-level MMR expression, MSI evaluation was possible in five cases, revealing one case with high-level MSI. In all MMR proteins assessed, low-level expression was significantly (p = 0.0004 to p < 0.0001) associated with a negative Merkel cell polyomavirus (MCPyV) status. However, the expression profiles of the MMR proteins did not correlate with clinical outcome measures such as disease relapse or death (p > 0.05). MCC appears to be a malignancy characterized by low-level MMR rather than completely deficient MMR in a subset of cases, predominantly affecting MCPyV-negative tumors. Future studies will establish whether this subset of MCC patients respond better to immune checkpoint inhibitor therapy.

Graded expression of microRNA-371a-3p in tumor tissues, contralateral testes, and in serum of patients with testicular germ cell tumor.

Background: Serum levels of microRNA-371a-3p represent a specific tumor marker of testicular germ cell tumors (GCTs) but the origin of circulating miR-371a-3p is not finally resolved. The correlation between miR-levels in tissue and serum is unclear. Results: MiR-levels in GCT tissue are 399-fold higher than in contralateral testicular tissue and 5843-fold higher than in non-testicular tissue. MiR tissue levels correlate with corresponding serum levels (r 2 = 0.181). ISH detected miR-371a-3p intracellularly in GCT cells except teratoma. A low expression was also detected in normal testicular germ cells. Conclusions: Circulating miR-371a-3p is specifically derived from GCT tissue. The miR is present in GCT cells except teratoma. A low expression is also found in normal testicular tissue but not in non-testicular tissue. MiR-371a-3p levels in tissue and serum correlate significantly. This study underscores the usefulness of serum miR-371a-3p as tumor marker of GCT. Patients and methods: Expression levels of miR-371a-3p were concurrently measured in tissues of GCT, contralateral testes ( n = 38), and in serum ( n = 36) with real time PCR. For control, 5 healthy testicles and 4 non-testicular tissue samples were examined. MiR-levels were compared using descriptive statistical methods. We also performed in situ hybridization (ISH) of GCT tissue with a probe specific for miR-371a-3p.

Mass Spectrometry Imaging Differentiates Chromophobe Renal Cell Carcinoma and Renal Oncocytoma with High Accuracy.

Background: While subtyping of the majority of malignant chromophobe renal cell carcinoma (cRCC) and benign renal oncocytoma (rO) is possible on morphology alone, additional histochemical, immunohistochemical or molecular investigations are required in a subset of cases. As currently used histochemical and immunohistological stains as well as genetic aberrations show considerable overlap in both tumors, additional techniques are required for differential diagnostics. Mass spectrometry imaging (MSI) combining the detection of multiple peptides with information about their localization in tissue may be a suitable technology to overcome this diagnostic challenge. Patients and Methods: Formalin-fixed paraffin embedded (FFPE) tissue specimens from cRCC (n=71) and rO (n=64) were analyzed by MSI. Data were classified by linear discriminant analysis (LDA), classification and regression trees (CART), k-nearest neighbors (KNN), support vector machine (SVM), and random forest (RF) algorithm with internal cross validation and visualized by t-distributed stochastic neighbor embedding (t-SNE). Most important variables for classification were identified and the classification algorithm was optimized. Results: Applying different machine learning algorithms on all m/z peaks, classification accuracy between cRCC and rO was 85%, 82%, 84%, 77% and 64% for RF, SVM, KNN, CART and LDA. Under the assumption that a reduction of m/z peaks would lead to improved classification accuracy, m/z peaks were ranked based on their variable importance. Reduction to six most important m/z peaks resulted in improved accuracy of 89%, 85%, 85% and 85% for RF, SVM, KNN, and LDA and remained at the level of 77% for CART. t-SNE showed clear separation of cRCC and rO after algorithm improvement. Conclusion: In summary, we acquired MSI data on FFPE tissue specimens of cRCC and rO, performed classification and detected most relevant biomarkers for the differential diagnosis of both diseases. MSI data might be a useful adjunct method in the differential diagnosis of cRCC and rO.

[Response judgement - conventional versus new methods]. / Beurteilung des Therapieerfolgs - konventionelle versus neue Methoden.

New ways of evaluating treatment success among thoracic tumour patients are increasingly being used alongside more conventional methods. These new approaches include tumour regression grading, CAD volumetry (computer-assisted volumetry), determination of the tumour density and tumour perfusion as well as the use of positron emission tomography (PET) using 18F-FDG (fluorodeoxyglucose) or other tracers. Increasingly, endpoints that impact directly on the patient's quality of life and tumour-related symptoms are becoming more relevant factors together with the objectively measurable parameters used for assessing treatment response. This contribution describes the potential value of new methods and end-points from the point of view of a pathologist, radiologist, nuclear medicine specialist, radiotherapist, thoracic surgeon, medical and pneumology oncologist, and general practitioner.

Effect of preoperative chemoradiation in addition to preoperative chemotherapy: a randomised trial in stage III non-small-cell lung cancer.

BACKGROUND: Preoperative chemotherapy improves survival in patients with stage III non-small-cell lung cancer (NSCLC) amenable to resection. We aimed to assess the additional effect of preoperative chemoradiation on tumour resection, pathological response, and survival in these patients. METHODS: Between Oct 1, 1995, and July 1, 2003, patients with stage IIIA-IIIB NSCLC and invasive mediastinal assessment from 26 participating institutions of the German Lung Cancer Cooperative Group (GLCCG) were randomly assigned to one of two treatment groups. The intervention group were scheduled to receive three cycles of cisplatin and etoposide, followed by twice-daily radiation with concurrent carboplatin and vindesine, and then surgical resection (those with positive resection margins or unresectable disease were offered further twice-daily radiotherapy). The control group were scheduled to receive three cycles of cisplatin and etoposide, followed by surgery, and then further radiotherapy. The primary endpoint was median progression-free survival (PFS) in patients eligible for treatment after randomisation. Secondary endpoints in patients eligible for treatment after randomisation were overall survival (OS) and the proportion of patients undergoing surgery. Secondary endpoints in patients with tumour resection were the proportion with negative resection margins, the proportion with complete resection, the proportion with histopathological response, and the proportion with mediastinal downstaging. Additionally, exploratory (not prespecified) post-hoc analyses in terms of PFS and OS were done on patients not amenable to resection and on further subgroups of patients undergoing resection. Analyses were by intention to treat. This trial is registered on the ClinicalTrials.gov website, number NCT 00176137. FINDINGS: 558 patients were randomly assigned. 34 patients did not meet inclusion criteria and were excluded. Of 524 eligible patients, 142 of 264 (54%) in the interventional group and 154 of 260 (59%) in the control group underwent surgery; 98 of 264 (37%) and 84 of 260 (32%) underwent complete resection. In patients with complete resection, the proportion of those with mediastinal downstaging (45 of 98 [46%] and 24 of 84 [29%], p=0.02) and pathological response (59 of 98 [60%] and 17 of 84 [20%], p<0.0001) favoured the interventional group. However, there was no difference in PFS (primary endpoint) between treatment groups-either in eligible patients (median PFS 9.5 months, range 1.0-117.0 [95% CI 8.3-11.2] vs 10.0 months, range 1.0-111.0 [8.9-11.5], 5-year PFS 16% [11-21] vs 14% [10-19], hazard ratio (HR) 0.99 [0.81-1.19], p=0.87), in those undergoing tumour resection, or in patients with complete resection. In both groups, 35% of patients undergoing surgery received a pneumonectomy (50/142 vs 54/154). In patients receiving a pneumonectomy, treatment-related mortality increased in the interventional group compared with the control group (7/50 [14%] vs 3/54 [6%]). INTERPRETATION: In patients with stage III NSCLC amenable to surgery, preoperative chemoradiation in addition to chemotherapy increases pathological response and mediastinal downstaging, but does not improve survival. After induction with chemoradiation, pneumonectomy should be avoided. FUNDING: German Cancer Aid (Bonn, Germany).

Transbronchial biopsy guided by low-dose MDCT: a new approach for assessment of solitary pulmonary nodules.

OBJECTIVE: The objective of our study was to determine whether transbronchial bronchoscopic biopsy of solitary pulmonary nodules under CT guidance using a low-dose protocol can increase diagnostic yield in patients who had undergone unsuccessful conventional bronchoscopic biopsy. SUBJECTS AND METHODS: We included 33 consecutive patients (25 men; mean age +/- SD, 64 +/- 9.6 years) with solitary pulmonary nodules at different sites and with a lesion-to-pleura distance of at least 2 cm who previously underwent conventional bronchoscopy that did not result in histologic diagnosis. All patients were prospectively investigated with transbronchial bronchoscopic biopsy under MDCT guidance. Examinations were performed with the patient in conscious sedation using a low-dose protocol (80 kV, 20 mAs, 5-mm collimation, 10-mm slices). The position of the tip of the biopsy device was confirmed and documented before biopsies were performed. All specimens were examined by standard histopathologic techniques. The effective radiation dose was calculated for every patient. RESULTS: The diagnostic yield was 24 in 33 selected patients (overall accuracy, 72.7%): 13 (54%) had primary lung cancer and 11 (46%) had benign diagnoses. The formal operative characteristics were sensitivity, 59%; specificity, 100%; positive predictive value, 100%; and negative predictive value, 55%. The final diagnoses of the remaining nine patients in whom transbronchial bronchoscopic biopsy was not diagnostic were non-small cell lung cancer (n = 3); small cell lung cancer (n = 3); and alveolar carcinoma, carcinoid tumor, and hemorrhaged bulla (n = 1 each). All nonmalignant diagnoses were confirmed by 6 months radiographic and clinical follow-up. The mean duration of the procedure was 39 +/- 15 minutes, and the average effective dose was 0.7 mSv (range, 0.5-1.1 mSv). One case of pulmonary hemorrhage (3%) occurred after the procedure. CONCLUSION: MDCT-guided transbronchial bronchoscopic biopsy is a promising and safe tool for the diagnostic pathway of solitary pulmonary nodules in previously undiagnosed patients. Image quality was sufficient with low-dose protocols, which resulted in low radiation exposure for patients and personnel.

HER2/neu expression and amplification in non-small cell lung cancer prior to and after neoadjuvant therapy.

BACKGROUND: Expression and amplification of the HER2/neu protooncogene was analyzed in locally advanced NSCLC in a multimodality therapy approach in order to obtain information on the predictive value of HER2/neu for success or failure of neoadjuvant therapy. METHODS: In the scope of a prospective randomized phase III-trial, tumor tissue of pre-therapeutically obtained mediastinal lymph node biopsies (n=105) and corresponding post-surgical resection specimens (n=44) was analyzed by means of immunohistochemistry (DAKO-Hercep-Test) and fluorescence in situ hybridization (FISH). In 58 of 105 patients with metastatic mediastinal lymph node disease the extent of therapy-induced tumor regression could be established. RESULTS: Concerning HER2/neu expression, 16 lymph node biopsies (15.2%) showed 1+, 2+, or 3+ results. Five of these cases revealed amplification in FISH analysis (4.8%). In 44 corresponding resection specimens, Hercep-Test showed 1+, 2+, or 3+ results in 13 tumors (29.5%). Two of these patients revealed HER2/neu amplification in FISH analysis (4.5%). In patients with HER2/neu expressing tumors a trend towards a less extensive therapy-induced tumor regression could be demonstrated. When comparing pre-therapy and post-surgical results, there was a weak trend towards a selection of HER2/neu expressing tumor tissue in the course of neoadjuvant therapy. CONCLUSIONS: Only a limited subcollective of locally advanced NSCLC meets the biological requirements for anti-HER2/neu therapy. HER2/neu positive tumors appeared to be relatively resistant to chemotherapy and radiation treatment, none of these cases having a pathological complete or at least subtotal response in the corresponding resection specimens. This observation requires confirmation in large randomized controlled studies.

Unicentric Castleman's disease of the pancreas with massive central calcification.

Unicentric Castleman's disease of the pancreas is extremely rare, with only six cases described in the worldwide literature. An asymptomatic case of unicentric, hyaline, vascular-type Castlemanos disease (UCD) localized to the tail of the pancreas with central calcification imitating a primary neoplasm of the pancreas is presented. This is the first description of endosonographic and endoscopic retrograde pancreatographic findings of pancreatic UCD. Additionally, computed tomography, histological and serologic findings are reported.

Pathology of tracheal tumors.

Malignant involvement of the trachea predominantly results from direct spread of neighboring tumors to the tracheal wall. Primary tracheal malignancies show a low incidence of approximately 0.1 in every 100,000 persons per year, squamous cell carcinomas and adenoid cystic carcinomas accounting for about two-thirds of adult primary tracheal tumors. The etiology of squamous cell carcinoma and its premalignant lesions is strongly associated with tobacco smoking. Patients with tracheal malignancies show an unfavorable prognosis, with reported 5- and 10-year survival rates of 5% to 15% and 6% to 7%, respectively, for all types of tracheal carcinoma.

Adenoid cystic carcinoma of the skull base mimicking temporomandibular disorder.

BACKGROUND: Temporomandibular disorder (TMD) involves problems of the temporomandibular joint and its adjacent muscular system. Because TMD prevalence is high among Western populations, complaints in these regions are generally attributed to TMD. However, in rare cases, TMD symptoms are mimicked by malignant tumors of the head. CASE REPORT: Upon first presentation, an 18-year-old female complained about typical symptoms of TMD. After an initial splint therapy and physiotherapy, painful symptoms increased significantly. Twelve weeks after initial diagnosis, further diagnostic imaging revealed a tumor formation at the skull base with infiltration of the infratemporal fossa. Histological evaluation confirmed the diagnosis of adenoid cystic carcinoma. Two years after resection of the tumor, lung metastases were detected with no option of curative treatment. CONCLUSION: TMD symptoms, which are refractory to treatment or exhibit significant worsening during therapy, should be regarded as warning signals and as an indication that early further diagnostic imaging is warranted.

Osteonecrosis of the maxilla related to long-standing methamphetamine abuse: a possible new aspect in the etiology of osteonecrosis of the jaw.

BACKGROUND: Osteonecrosis of the jaw (ONJ) related to toxic effects of illicit drugs such as cocaine is not very common and might be overshadowed today by the incidence of bisphosphonate-related osteonecrosis of the jaw. However, we present a case which suggests a close relationship between abuse of the illicit drug methamphetamine (MA) and ONJ. CASE REPORT: A 44-year-old male with extended osteonecrosis of the maxilla admitted chronic abuse and synthesis of MA for at least the previous two decades. Furthermore, he confessed self-extracting teeth since he became addicted to MA. However at presentation, he had been successfully cured of his addiction to MA. A step-by-step surgical treatment was planned using computer-aided design/computer-aided manufacturing techniques. After resection of necrotic bone, a vascularized osteomyocutaneous fibular flap was applied secondarily. DISCUSSION: Two possible mechanisms, alone or in combination, could possibly lead to MA-related ONJ. Self-extraction of teeth as a psychopathologic behavior of self-destruction among MA abusers results in wounds that allow unhindered invasion of microorganisms causing osteomyelitis and ONJ, while on the other hand, the heating of white phosphor releases toxic phosphorous vapor, which could be inhaled and consequently cause ONJ of the maxilla. However, since the worldwide prevalence of MA abuse is remarkably high, a relationship between MA abuse and ONJ will offer a new aspect in the etiology of ONJ and might present a further therapeutic challenge.