Smaller panel, similar results: genomic profiling and molecularly informed therapy in pancreatic cancer.

BACKGROUND: Pancreatic cancer has a dismal prognosis. One reason is resistance to cytotoxic drugs. Molecularly matched therapies might overcome this resistance but the best approach to identify those patients who may benefit is unknown. Therefore, we sought to evaluate a molecularly guided treatment approach. MATERIALS AND METHODS: We retrospectively analyzed the clinical outcome and mutational status of patients with pancreatic cancer who received molecular profiling at the West German Cancer Center Essen from 2016 to 2021. We carried out a 47-gene DNA next-generation sequencing (NGS) panel. Furthermore, we assessed microsatellite instability-high/deficient mismatch repair (MSI-H/dMMR) status and, sequentially and only in case of KRAS wild-type, gene fusions via RNA-based NGS. Patient data and treatment were retrieved from the electronic medical records. RESULTS: Of 190 included patients, 171 had pancreatic ductal adenocarcinoma (90%). One hundred and three patients had stage IV pancreatic cancer at diagnosis (54%). MMR analysis in 94 patients (94/190, 49.5%) identified 3 patients with dMMR (3/94, 3.2%). Notably, we identified 32 patients with KRAS wild-type status (16.8%). To identify driver alterations in these patients, we conducted an RNA-based fusion assay on 13 assessable samples and identified 5 potentially actionable fusions (5/13, 38.5%). Overall, we identified 34 patients with potentially actionable alterations (34/190, 17.9%). Of these 34 patients, 10 patients (10/34, 29.4%) finally received at least one molecularly targeted treatment and 4 patients had an exceptional response (>9 months on treatment). CONCLUSIONS: Here, we show that a small-sized gene panel can suffice to identify relevant therapeutic options for pancreatic cancer patients. Informally comparing with previous large-scale studies, this approach yields a similar detection rate of actionable targets. We propose molecular sequencing of pancreatic cancer as standard of care to identify KRAS wild-type and rare molecular subsets for targeted treatment strategies.

[Vascularized tumor of the retroauricular skin]. / Gefäßreicher Tumor der retroaurikulären Haut.

An 84-year-old female patient with loss of hearing and otorrhoea went to an otolaryngologist. On examination, a polypoid mass in the auditory canal and a retroauricular skin lesion, possibly seborrheic keratosis, were found. Only the skin was submitted for histological examination and showed a cutaneous highly vascular lesion with an associated "zellballen" of clear cells without atypia. The initial diagnosis was that of a cutaneous glomangioma. Immunohistochemical findings favored diagnosis of a paraganglioma. Additional clinical information revealed a large mastoid tumor mass. Therefore, the findings were compatible with an jugulotympanic paraganglioma with infiltration of the overlying skin. This possibility was initially not considered in differential diagnosis, as cutaneous glomangiomas are relatively common (typically located on the hands). Cutaneous paragangliomas, however, are not reported.

[Paratracheal lymph node with suspicion of carcinoma]. / Paratrachealer Knoten mit Karzinomverdacht.

Three paratracheal lymph nodes of a 20-year-old patient were submitted for examination, of which one showed numerous thyrocytes with large void nuclei and was suspected of being metastatic papillary thyroid carcinoma. The simultaneously resected thyroid gland, which was subsequently submitted showed findings consistent with Hashimoto's autoimmune thyroiditis (AIT). In the context of the resected goiter tissue, the suspected lymph node metastasis was identified as a hyperplastic ectopic (so-called parasitic) goiter nodule with thyrocytic changes typically seen in Hashimoto's AIT, such as oxyphilic cell alterations and a high plasma cell content. The re-examination of the suspicious lymph node revealed complete lack of a marginal sinus, thus excluding the diagnosis of a lymph node as well as the diagnosis of thyroid carcinoma metastasis.

Methanogenesis produces strong 13C enrichment in stromatolites of Lagoa Salgada, Brazil: a modern analogue for Palaeo-/Neoproterozoic stromatolites?

Holocene stromatolites characterized by unusually positive inorganic δ(13) CPDB values (i.e. up to +16‰) are present in Lagoa Salgada, a seasonally brackish to hypersaline lagoon near Rio de Janeiro (Brazil). Such positive values cannot be explained by phototrophic fixation of CO2 alone, and they suggest that methanogenesis was a dominating process during the growth of the stromatolites. Indeed, up to 5 mm methane was measured in the porewater. The archaeal membrane lipid archaeol showing δ(13) C values between -15 and 0‰ suggests that archaea are present and producing methane in the modern lagoon sediment. Moreover, (13) C-depleted hopanoids diplopterol and 3ß-methylated C32 17ß(H),21ß(H)-hopanoic acid (both -40‰) are preserved in lagoon sediments and are most likely derived from aerobic methanotrophic bacteria thriving in the methane-enriched water column. Loss of isotopically light methane through the water column would explain the residual (13) C-enriched pool of dissolved inorganic carbon from where the carbonate constituting the stromatolites precipitated. The predominance of methanogenic archaea in the lagoon is most likely a result of sulphate limitation, suppressing the activity of sulphate-reducing bacteria under brackish conditions in a seasonally humid tropical environment. Indeed, sulphate-reduction activity is very low in the modern sediments. In absence of an efficient carbonate-inducing metabolic process, we propose that stromatolite formation in Lagoa Salgada was abiotically induced, while the (13) C-enriched organic and inorganic carbon pools are due to methanogenesis. Unusually, (13) C-enriched stromatolitic deposits also appear in the geological record of prolonged periods in the Palaeo- and Neoproterozoic. Lagoa Salgada represents a possible modern analogue to conditions that may have been widespread in the Proterozoic, at times when low sulphate concentrations in sea water allowed methanogens to prevail over sulphate-reducing bacteria.

[History of dermatopathology]. / Geschichte der Dermatopathologie.

Hebra in Vienna and later Unna in Hamburg are considered to be the protagonists of academic dermatopathology in the German-speaking literature. Whereas the former used a chiefly macroscopic approach to an academic classification, the concepts of the latter were based on microscopic observations. In contrast to pathologists, who in the nineteenth century were dominated by Virchow and his teachings, dermatologists as well as microscopically active gynecologists already applied histological findings for diagnostics and subsequent therapy. Chapters dealing with diseases of the skin in multivolume handbooks of pathology were initially mainly written by dermatologists. The majority of textbooks of dermatopathology were also written by dermatologists. One of the current aims of pathologists is the application of additional methods, e.g. molecular pathology in order to better understand and treat neoplastic diseases, in particular pigmented skin tumors.

Repetitive transgenes in C. elegans accumulate heterochromatic marks and are sequestered at the nuclear envelope in a copy-number- and lamin-dependent manner.

Chromatin is nonrandomly distributed in nuclear space, yet the functional significance of this remains unclear. Here, we make use of transgenes carrying developmentally regulated promoters to study subnuclear gene positioning during the development of Caenorhabditis elegans. We found that small transgenes (copy number ≤50) are randomly distributed in early embryonic nuclei, independent of promoter activity. However, in differentiated tissues, these same transgenes occupied specific subnuclear positions: When promoters are repressed, transgenes are found at the nuclear periphery, whereas active, developmentally regulated promoters are enriched in the nuclear core. The absence of specific transgene positioning in embryonic nuclei does not reflect an absence of proteins that mediate perinuclear sequestration: Embryonic nuclei are able to sequester much larger transgene arrays (copy number 300-500) at the periphery. This size-dependent peripheral positioning of gene arrays in early embryos correlates with the accumulation of heterochromatic marks (H3K9me3 and H3K27me3) on large arrays. Interestingly, depletion of nuclear lamina components caused release of arrays from the nuclear envelope and interfered with their efficient silencing. Our results suggest that developmentally silenced chromatin binds the nuclear lamina in a manner correlated with the deposition of heterochromatic marks. Peripheral sequestration of chromatin may, in turn, support the maintenance of silencing.

[Histological grading of soft tissue sarcomas: stratification of G2-sarcomas in low- or high-grade malignant tumors]. / Graduierung der Weichgewebesarkome Stratifizierung der G2-Sarkome in niederen oder hohen Malignitätsgrad.

Histological grading according to one of the proven systems, e.g. that of the FFCCS, leads to the definition of different prognostic risk groups. Prerequisite is a precise typing of the tumors, if necessary by immunohistochemical and molecular-pathological methods. The therapeutic decision is dependent on the presence either of a low- or high-grade malignant tumor: With low-grade sarcomas surgery has priority, with high grade tumors usually chemo- and/or radiotherapy are indicated. With the latter, also better therapeutic response is reported. Therefore, conversion of a 3-grade into a 2-grade system has to be carried out by including the tumor localization as prognostic parameter. Thereby, the large group of G2-sarcomas with intermediate malignancy can be stratified. Superficial G2-sarcomas are considered to be low grade and deep G2-sarcomas high grade malignant. Immunohistochemical staining of tumor cell nuclei with Ki67/MIB1 allows a more standardized and precise grading. The ultimate aim, not to define risk groups, but to predict the prognosis for individual patients, possibly could be reached someday by molecular diagnostic methods.

[Malignant fibrous histiocytoma: pleomorphic sarcoma NOS or pleomorphic fibrosarcoma]. / Das maligne fibröse Histiozytom. Undifferenziertes pleomorphes Sarkom oder pleomorphes Fibrosarkom?

The entity and nosology of pleomorphic malignant fibrous histiocytoma (MFH) is still ambiguous. The actual WHO-Classification uses pleomorphic malignant fibrous histiocytoma (MFH) and pleomorphic sarcoma NOS (not otherwise specified) synonymously. On the other hand text and illustrations convey the impression, that these tumors also could be pleomorphic lipo-, leio- or rhabdomyosarcomas etc. It would have been more informative to emphasize, that with the above mentioned specific sarcoma types MFH-like appearance may occur. Furthermore it would have been more up to date to consider pleomorphic sarcomas NOS as pleomorphic fibrosarcomas and include them in the chapter of fibroblastic and myofibroblastic tumors. This concept already has been carried out for the former myxoid variant of MFH, nowadays preferentially called myxofibrosarcoma. There is controversial discussion about the clinical significance of exact typing of pleomorphic sarcomas. Problems may also occur due to the lack of standards, which degree of desmin expression signifies leiomyosarcoma or just indicates myofibroblasts in MFH. The requirement of exclusion of other tumor-types before diagnosing pleomorphic fibrosarcoma still remains obligatory. After verification of the diagnosis pleomorphic sarcoma NOS or pleomorphic fibrosarcoma, grading e.g. according to criteria of the FFCCS can be carried out. Most cases of pleomorphic fibrosarcoma will qualify as high grade malignant.

[Injectable silicon--long term sequelae after use in plastic surgery]. / Injizierbares Silikon Folgen der Anwendung in der plastischen Chirurgie. Folgen der Anwendung in der plastischen Chirurgie.

The injection of fluid silicone was formerly an acceptable therapy for recontouring post-traumatic or age-related changes of the face and neck. About 20 years after the use of silicone injections, the number of patients presenting with late complications is increasing. Such complications include migration of the silicone, granuloma formation, chronic cellulitis, skin ulcers and and scarring, all of which are difficult to treat medically or surgically. Recent data in the literature support the notion that fluid silicon is a potential carcinogen. These patients require a careful approach combining the limited surgical possibilities with the support needed to live with such a problem. Using a case report as an example, we discuss the diagnostic and therapeutic problems associated with this phenomenon which is relatively uncommon in Europe.