Pressurized intraperitoneal aerosol chemotherapy (PIPAC) in patients with peritoneal surface malignancies (PSM): a prospective single-center registry study.

PURPOSE: Pressurized intraperitoneal aerosol chemotherapy (PIPAC) is a new, palliative approach for patients with peritoneal surface malignancies (PSMs). Its main goals are to control symptoms and ascites. For this experimental procedure, treatment efficacy and patient safety need to be closely monitored. METHODS: We performed a prospective registry study for patients with PSMs. Cisplatin (C) (7.5 mg/m2 body surface) and doxorubicin (D) (1.5 mg/m2) were administered laparoscopically via PIPAC. RESULTS: Between November 2015 and June 2020, we recorded data from 108 patients and 230 scheduled procedures. Tumor burden, patient fitness, quality of life, operating time and in-hospital stay remained stable over consecutive procedures. We recorded 21 non-access situations and 14 intraoperative complications (11 intestinal injuries, and three aspirations while inducing anesthesia). Three or more previous abdominal surgeries or cytoreductive surgery (CRS) with intraperitoneal hyperthermic chemoperfusion (HIPEC) were risk factors for non-access and intestinal injuries (χ2, p ≤ 0.01). Five Grade IV and three Grade V postoperative complications according to the Clavien-Dindo Classification (CDC) occurred. Median overall survival was 264 days (interquartile range 108-586). Therapies were primarily discontinued because of death (34%), progressive (26%), or regressive (16%) disease. CONCLUSION: PIPAC is effective in stabilizing PSMs and retaining quality of life in selected patients. Earlier abdominal surgeries and CRS with HIPEC should be considered when determining the indication for PIPAC. Randomized controlled studies are needed to evaluate PIPAC's therapeutic benefits compared to systemic chemotherapy (sCHT) alone. TRIAL REGISTRATION: NCT03100708 (April 2017).

[Scope of activities and research in pathology laboratories from 1920 to 1940]. / Tätigkeitsfelder und Forschungslandschaft der Pathologie in den Jahren 1920 bis 1940.

The ideal of a pathology institute consisted of a large autopsy department and a wide collection of specimens for the training of students and clinically active doctors. Additional departments supporting the autopsy department were a chemical and bacteriological laboratory. Other departments were experimental laboratories for biology, immunology, and cell research as well as an animal facility.The main pillar of the training was the understanding of the concept of disease and the development of disease. In this context, the final state of a disease was usually presented in the context of the autopsy. The special contribution of Rudolf Virchow was the additional consideration of cellular changes using microscopic preparations.In contrast, in England and America, clinical care on patients was carried out within the institutes in addition to autopsies. For this purpose, some institutes had their own wards with patient beds. The areas of research were accordingly different. The analysis of journal articles from 1920 to 1940 in two German-language journals, Virchows Archive and Naunyn-Schmiedebergs Archiv für experimentelle Pathologie und Pharmakologie (today: Naunyn-Schmiedeberg's Archives of Pharmacology), and two English-language journals, Journal ofPathology and Bacteriology and American Journal of Pathology, showed different scopes and numbers of publications.On the basis of these publications, it was found that the German journals published a huge variety of diseases, especially series of identical tumors and often the first description of the disease. The British Journal of Pathology published mainly infectious topics and numerous animal experiments. The American journal covered a very broad spectrum of publications, including many on clinically relevant histological techniques.

[Cervical cancer : Update on morphology]. / Zervixkarzinom : Aktuelles zur Morphologie.

The World Health Organization (WHO) classification from 2014 differentiates between different subtypes of mucinous adenocarcinoma of the uterine cervix. A gastric subtype was recently described that showed no association with high-risk human papillomavirus (HPV) infections, has a poor prognosis, is mainly diagnosed in women of Asian origin and can occur in patients with Peutz-Jeghers syndrome. Although no clear grading system has been recommended in the WHO classification, it is likely that grading of adenocarcinomas of the uterine cervix will partly be based on the different patterns of invasion. Deep stromal infiltration of macroinvasive carcinomas is defined as an infiltration of >66 % of the cervical stroma. In the near future a maximum tumor size of 2 cm could act as a discriminator for planning of less radical surgery. Parameters of the histopathological report that are relevant for the prognostic assessment as well as the choice of adjuvant treatment and function as quality indicators during certification are described. The histological type of an adenocarcinoma alone is of no predictive or prognostic relevance for patients undergoing primary surgical treatment, neoadjuvant chemotherapy, combined chemo-radiotherapy or treatment with angiogenesis inhibitors. Currently, molecular parameters and biomarkers are of no relevance.

[Nomenclature of squamous cell precursor lesions of the lower female genital tract : Current aspects]. / Nomenklatur der plattenepithelialen Präkanzerosen des unteren weiblichen Genitales : Aktuelle Aspekte.

The majority of precancerous lesions of the lower female genital tract (intraepithelial neoplasia, IN) are caused by human papillomavirus (HPV) infections resulting in cellular atypia and in turn an altered tissue architecture. Depending on the pathogenesis, a distinction is made between vulvar intraepithelial neoplasia (VIN) classified as classical VIN associated with high-risk HPV infections (u-VIN) and differentiated VIN (d-VIN), which is associated with lichen sclerosus et atrophicus and p53 alterations. In the current World Health Organization (WHO) classification a novel grading system for squamous cell precancerous lesions of the lower female genital tract has been proposed, differentiating low grade squamous intraepithelial lesions (L-SIL) including condyloma and HPV-associated alterations plus VIN 1, vaginal intraepithelial neoplasia (VaIN 1) and cervical intraepithelial neoplasia (CIN 1) from high grade squamous intraepithelial lesions (H-SIL) with VIN 2 and 3, VaIN 2 and 3 as well as CIN 2 and 3. The use of p16 immunohistochemistry can assist the differentiation. The new binary classification, however, contradicts the German cytological nomenclature (Munich nomenclature III), which differentiated three grades of dysplasia in order to avoid overtreatment of patients with moderate IN. The individual nomenclatures are compared to each other. It is recommended to report the grade of precancerous lesions in addition to the SIL classification of the WHO.

[Grading of gynecological tumors : Current aspects]. / Grading gynäkologischer Tumoren : Aktuelle Aspekte.

Histopathological assessment of the tumor grade and cell type is central to the management and prognosis of various gynecological malignancies. Conventional grading systems for squamous carcinomas and adenocarcinomas of the vulva, vagina and cervix are poorly defined. For endometrioid tumors of the female genital tract as well as for mucinous endometrial, ovarian and seromucinous ovarian carcinomas, the 3­tiered FIGO grading system is recommended. For uterine neuroendocrine tumors the grading system of the gastrointestinal counterparts has been adopted. Uterine leiomyosarcomas are not graded. Endometrial stromal sarcomas are divided into low and high grades, based on cellular morphology, immunohistochemical and molecular findings. A chemotherapy response score was established for chemotherapeutically treated high-grade serous pelvic cancer. For non-epithelial ovarian malignancies, only Sertoli-Leydig cell tumors and immature teratomas are graded. At this time molecular profiling has no impact on the grading of tumors of the female genital tract.

[What Surgeons Need to Know About the Histopathological Processing of a Specimen]. / Was soll der Chirurg vom histopathologischen Präparate-Processing wissen?

A multitude of factors influence the state of tissue samples on their way from the biopsy site in the body to the pathologist's microscope. Some of these factors can be influenced by surgeons, while others are dealt with in pathology departments, but surgeons should know potential pitfalls and caveats and their influence on the pathohistological diagnosis. These factors influence diagnoses made on conventional stains, but even more so the results of immunohistochemical stains and molecular pathology examinations. Therefore, the work-up of tissue samples should be standardised. This is of utmost importance for biobank tissue samples, especially those for which a tissue treatment protocol is recommended.

[Glomuvenous malformations]. / Glomuvenöse Malformationen.

SYMPTOMS: A patient presented suffering from neural pain in the medial foot for a period of over 20 years. DIAGNOSIS: Diagnostic showed a widely spread soft-tissue tumor consisting of confluent glomuvenous malformations that was responsible for the immense pain syndrome.The solitary or multiform-appearing knots are not compressible and manifest as the characteristic syndromes of regional pain, sensitivity to coldness, or local pressure pain. Alternatively, the patient could also be completely symptom-free. TREATMENT: Because of the dimension of the tumor and the degree of suffering, a radical resection with simultaneous microsurgical reconstruction was carried out. Twelve weeks postoperatively, healing of the flap stabilized, the foot is fully weight-bearing, and the patient is pain-free.

ADM3, TFF3 and LGALS3 are discriminative molecular markers in fine-needle aspiration biopsies of benign and malignant thyroid tumours.

BACKGROUND: Previously, we reported a six-marker gene set, which allowed a molecular discrimination of benign and malignant thyroid tumours. Now, we evaluated these markers in fine-needle aspiration biopsies (FNAB) in a prospective, independent series of thyroid tumours with proven histological outcome. METHODS: Quantitative RT-PCR was performed (ADM3, HGD1, LGALS3, PLAB, TFF3, TG) in the needle wash-out of 156 FNAB of follicular adenoma (FA), adenomatous nodules, follicular and papillary thyroid cancers (TC) and normal thyroid tissues (NT). RESULTS: Significant expression differences were found for TFF3, HGD1, ADM3 and LGALS3 in FNAB of TC compared with benign thyroid nodules and NT. Using two-marker gene sets, a specific FNAB distinction of benign and malignant tumours was achieved with negative predictive values (NPV) up to 0.78 and positive predictive values (PPV) up to 0.84. Two FNAB marker gene combinations (ADM3/TFF3; ADM3/ACTB) allowed the distinction of FA and malignant follicular neoplasia with NPV up to 0.94 and PPV up to 0.86. CONCLUSION: We demonstrate that molecular FNAB diagnosis of benign and malignant thyroid tumours including follicular neoplasia is possible with recently identified marker gene combinations. We propose multi-centre FNAB studies on these markers to bring this promising diagnostic tool closer to clinical practice.

[Current TNM/FIGO classification for cervical and endometrial cancer as well as malignant mixed müllerian tumors. Facts and background]. / Aktuelle TNM/FIGO-Stadieneinteilung für das Zervix- und Endometriumkarzinom sowie maligne Müller-Mischtumoren. Fakten und Hintergründe.

Numerous recent studies of endometrial and cervical carcinomas as well as malignant mixed müllerian tumors (MMMT) of the uterus have made a revision of the FIGO/TNM classification necessary, effective as of January 1st, 2010. There will be a new subclassification of carcinoma of the uterine cervix with proximal vaginal infiltration, using the same cut-off for the tumor extension as used for stage FIGOIB/T1b (≤/>4 cm), resulting in stage FIGO IIA1/T2a1 and FIGO IIA2/T2a2. In endometrial carcinoma, the previous FIGO IA/pT1a and FIGO IB/pT1b will be merged to FIGO IA/pT1a. The former category FIGO IC/T1c will be changed into FIGO IB/T1b. The category FIGO IC/pT1c will not longer been used. Additionally, there will be no separate classification for the involvement of the endocervical glands by endometrial carcinoma. This feature will be incorporated in stage FIGO I/T1 disease. The new category FIGO II/T2 will be defined as endocervical stromal involvement. There will be a new category, termed T3c/IIIC, which includes regional lymph node involvement. Stage T3c1/IIIC1 will be defined as pelvic lymph node involvement and stage T3c2/IIIC2 para-aortal lymph node involvement with or without pelvic lymph node disease. In the TNM system, regional lymph node involvement can alternatively be classified as N1. The MMMT will be staged like endometrial carcinoma.

Distinct regulation of intrinsic apoptosis in benign and malignant thyroid tumours.

Aberrations in the control of apoptosis represent a central feature of thyroid carcinogenesis. However, little is known about the regulation of components of the intrinsic apoptosis pathway in the thyroid. Using a real-time PCR approach we investigated the mRNA expression levels of Caspase3, Caspase3 s, xIAP, Bad, and beta-actin in a panel of 79 thyroid tumours. Additionally, we assessed the activation status of Caspase3 by immunohistochemistry. In the present study, we provide first evidence for a deregulation of the intrinsic apoptosis pathway on the transcriptional and post-transcriptional level. Thus, malignant thyroid tumours revealed a significant downregulation of the proapoptotic Bad. In contrast Caspase3 s, an alternative splice variant of Caspase3 with anti-apoptotic characteristics, was upregulated in follicular and anaplastic cancers. Moreover, papillary thyroid tumours revealed a significant upregulation of Caspase3 mRNA. On the post-translational level, thyroid malignancies featured an impairment in the activation of Caspase3, since activated Caspase3 accumulated exclusively in the cytoplasm of thyroid cancer cells, whereas follicular adenoma and normal thyroid tissues showed no cytoplasmatic but nuclear Caspase3 distribution. Further knowledge on apoptosis-deregulation during thyroid carcinogenesis might confer diagnostic and therapeutic benefits in the management of thyroid cancer.

Somatostatin receptor subtype expression in human thyroid tumours.

Somatostatin receptors (SSTR) are expressed in various endocrine tumours. The expression of SSTR at the tumour cell surface confers the possibility for diagnostic imaging and therapy of tumours using radiolabeled somatostatin analogues. The majority of currently available somatostatin analogues show a higher binding affinity for the SSTR2 subtype. To date, the precise expression pattern of the SSTR subtypes 1-5 in thyroid epithelial tumours remains to be determined. We investigated the mRNA expression of SSTR1-5 in benign and malignant epithelial thyroid tumours [20 cold thyroid nodules (CTNs), 20 toxic thyroid nodules (TTNs), 20 papillary, 20 follicular, and 5 anaplastic carcinomas (PTCs, FTCs, ATCs, respectively)] and compared them to normal surrounding thyroid tissues. Four out of five SSTR subtypes were detected in malignant thyroid tumours, benign neoplasia, and normal surrounding tissue with a predominant expression of SSTR2 and SSTR5, and a weak expression of SSTR1 and SSTR3. Weak SSTR4 mRNA expression was detected in some PTCs. Compared to normal thyroid tissue, SSTR2 was significantly upregulated in PTC and ATC. In addition significant upregulation of SSTR3 was found in PTC. SSTR5 mRNA expression was increased in PTC and FTC and significantly decreased in CTN and TTN compared to normal thyroid tissue. SSTR2 is the predominant subtype in thyroid epithelial tumours with a high expression pattern, in particular, in PTC . Perspectively, the expression of distinct SSTR in thyroid epithelial tumours might represent a promising avenue for diagnostics and therapy of advanced thyroid cancer with somatostatin analogues.

[Pathoanatomical preparation and reporting of specimens from precancerous lesions and carcinomas of the vulva]. / Pathologisch-anatomische Aufarbeitung und Befundung von Präparaten bei Präkanzerosen und Karzinomen der Vulva.

On the basis of varying morphology and pathogenesis, two types of vulvar intraepithelial neoplasias (VIN) have been defined: the common type (approximately 98%), classic VIN, is characterised by strong association to high-risk HPV infection (up to 90%), occurrence at younger age (median age 30-40 years) and multifocality. The differentiated (or simplex) type is rare (1%-2%) and is associated with older age (median age 65 years) and p53 alterations. It is usually diagnosed in combination with vulvar (keratinizing) squamous cell carcinoma. The classification currently preferred by the WHO in which VIN are classified into VIN 1-3 is to be replaced due to new data and according to a proposal by the International Society for the Study of Vulvovaginal Diseases (ISSVD) which eliminates VIN 1 and combines VIN 2 and 3 to VIN of common or, depending on histopathology, differentiated type. Prognostically relevant factors in vulvar cancer include stage of disease, inguinal lymph node involvement, size of metastatic deposits and presence of extracapsular extension, depth of invasion and distance of the tumor from resection margins. Tumor grade and the presence of lymphovascular space involvement are controversially discussed.