Impact of encorafenib on survival of patients with BRAFV600E-mutant metastatic colorectal cancer in a real-world setting.

PURPOSE: Patients with BRAFV600E-mutant metastatic colorectal cancer (mCRC) have a dismal prognosis. The best strategies in these patients remain elusive. Against this background, we report the clinical course of patients with BRAFV600E-mutant mCRC to retrieve the best treatment strategy. PATIENTS AND METHODS: Clinico-pathological data were extracted from the electronic health records. Kaplan-Meier method was used to estimate overall (OS) and progression-free survival (PFS). Objective response rate (ORR) was assessed according to RECIST 1.1. RESULTS: In total, 51 patients were enrolled. FOLFOXIRI was administered to 12 patients; 29 patients received FOLFOX or FOLFIRI as first-line treatment. Median OS was 17.6 months. Median PFS with FOLFOXIRI (13.0 months) was significantly prolonged (HR 0.325) as compared to FOLFOX/FOLFIRI (4.3 months). However, this failed to translate into an OS benefit (p = 0.433). Interestingly, addition of a monoclonal antibody to chemotherapy associated with superior OS (HR 0.523). A total of 64.7% patients received further-line therapy, which included a BRAF inhibitor in 17 patients. Targeted therapy associated with very favourable OS (25.1 months). CONCLUSION: Patients with BRAFV600E-mutated mCRC benefit from the addition of an antibody to first-line chemotherapy. Further-line treatment including a BRAF inhibitor has a dramatic impact on survival.

[First diagnosis of celiac disease in a 67-year old female patient]. / Erstdiagnose einer einheimischen Sprue bei einer 67-jährigen Patientin.

HISTORY AND CLINICAL FINDINGS: A 67 year old female patient presented herself to our emergency room with paraesthesia in both hands, chronic diarrhea and continuous weight loss. From the past medical history, only an autoimmune hypothyroidism was known. On initial, examination leading features were carpopedal spasms and a pulse deficit. Her general condition, especially the nutritional status was low. INVESTIGATIONS: Serum levels of potassium (2.2 mmol/l) and calcium (1.45 mmol/l) were low, as well as the levels of total protein (5.1 g/dl) and albumin (2.94 g/dl). Clotting time was prolonged (Quick 51%). The ECG showed a ventricular bigeminus and a prolonged QT-period (120% rel). Endoscopy and biopsy showed a total villous atrophy suggesting celiac disease as probable cause. This was emphasized by the high antibody levels against gliadin (1:80) and endomyosin (1:40). Furthermore, the Human Leukocyte Antigen molecules HLA-B8 and HLA-DR3 showed increased expression. TREATMENT AND COURSE: After normalizing the electrolyte imbalance intravenously the neurological symptoms disappeared as well as the arrhythmia. The QT-period went back to normal. Under initial drip feeding and a strict gluten-free diet the general condition improved quickly and the diarrhea stopped. A follow-up investigation 3 months later showed the woman in a good condition having gained 10 kg weight and an improvement in histological findings, so that diagnosis of celiac disease could be proved. CONCLUSIONS: The possibility of ventricular arrhythmia and a prolonged QT-period in the ECG should be taken into account for patients diagnosed with celiac disease, especially in case of electrolyte imbalance. In these cases addition to a strict gluten free diet a rapid correction of the electrolyte imbalance is necessary because of the risk of sudden cardiac death. Furthermore associated disorders like autoimmune diseases expressing the same HLA-antigens (HLA-B8 and HLA-DR3) must be considered. Combined incidence of celiac disease and autoimmune hypothyroidism is well documented. For patients with celiac disease we therefore recommend a routine testing of thyroid hormone levels.

[The intraductal components and microinvasive foci in ductal breast carcinoma on the mammogram]. / Intraduktale Anteile und Mikroinvasionsherde beim duktalen Mammakarzinom im Mammogramm.

Intraductal component is a risk factor for local recurrences of ductal carcinomas after breast-conserving therapy. Up to the present, only microcalcifications have been recognised as a mammographic sign of the intraductal component. The authors examined 67 ductal carcinomas; in addition to microcalcifications they paid attention to spicula at the margin of the tumors. These have been examined histologically and it has been shown that in 91% of the cases the spicula contain more or less marked intraductal carcinomatous tissue. Even in 23 cases (34.3%) the spicula consisted entirely of intraductal components. Microcalcifications in this respect are of less diagnostic importance. In 29 cases there were additional invasive foci which were not evident macroscopically and in four cases intramammary lymph node metastases were discovered radiologically only. The slice-specimen radiography carried out by the authors provides additional help in evaluating of accurate pathologic margins of "lumpectomy".

[Fulminant liver failure in tuberculostatic therapy. A contribution to clinical aspects and pharmacokinetics]. / Fulminantes Leberversagen unter tuberkulostatischer Therapie. Ein Beitrag zur Klinik und Pharmakokinetik.

A 23-year old female patient on a prolonged regimen of tuberculostatic chemotherapy finally developed fulminant hepatic failure shortly after addition of hormonal contraception. The pathophysiology of this almost fatal drug reaction is described as a pharmacokinetic interaction: the inherent hepatotoxicity of prothionamide-the drug finally prescribed during convalescence-was significantly potentiated by the Cyt-P-450-inducing effect of the progestagen component of the hormonal contraceptive. Potentiation of hepatotoxicity in connection with tuberculostatic regimes containing rifampicin is well known and this pharmacokinetic phenomenon also pertains to the combination with other Cyt-P-450-inducing drugs such as, for instance, anticonvulsants. However, since the maximum of rifampicin-related Cyt-P-450-inducing effect is limited to the initial 2-3 weeks of therapy, the hepatotoxic risk triggered by this rifampicin-related induction may decline during continuation of therapy. This, unfortunately, does not pertain to the other Cyt-P-450-inducers, whose inductive effect is not time-limited. Progressive severe hepatic damage may follow from such interaction as demonstrated in this case report.

[Histopathology of collagen fibers of the tympanic membrane]. / Zur Histopathologie der kollagenen Fasern des Trommelfells.

The lamina propria of the human tympanic membrane consists mainly of collagen fibres, but vessels and nerves can also be found as solitary elastic fibres. The pathologic alterations of the collagen fibres were examined by 47 biopsies of the tympanic membrane. These biopsies were taken in various middle ear diseases, and pathological changes were found in every case, ranging from clotting to chondral metaplasia; in one case a metaplasia into osseous tissue was found. No relationship was seen between the otoscopic findings and the severity of the pathological changes.

[Plasma cell granuloma of the lung]. / Das Plasmazellgranulom der Lunge.

Plasma cell granuloma is a rare, benign and usually solitary round tumour of the lung. Although uncommon, it is found relatively more frequently among children and adolescents. The lack of symptoms and absence of characteristic features make diagnosis difficult. In adults, the differentiation from bronchial carcinomas is particularly difficult because of their radiological similarity. Consequently, thoracotomy and excision of the tumour is the treatment of choice.

Hepatic involvement in hairy cell leukemia: diagnosis by tartrate-resistant acid phosphatase enzyme histochemistry on formalin fixed and paraffin-embedded liver biopsy specimens.

The leukemic infiltrate in the liver in hairy cell leukemia may be easily overlooked in conventional histological slides and an exact classification may not always be possible. In order to facilitate the identification of tricholeukocytes , it is suggested to perform the tartrate-resistant acid phosphatase stain on routinely formalin fixed and paraffin-embedded liver biopsy specimens. Thereby it will be in most cases possible to demonstrate sufficiently enough enzyme activity to establish unequivocally the diagnosis of hairy cell leukemia.

Germinal testicular tumors in childhood. Report of observations and literature review.

1,124 case observations, published from 1955 to 1981, and 45 of our own cases of childhood testicular tumor are evaluated. The age distribution, histology (WHO classification), stage and prognosis are compared to 1,062 adult cases. Diagnostic procedures are itemized. Priorities in the therapeutic approach and the effectiveness of various methods, depending on stage and histology, and toxic side effects and other complications are documented. In children, 29% of childhood testicular tumors are non-germinal, as compared to 8% in adults. 49% are yolk sac tumors. The age distribution differs depending on histology. Metastases occur less frequently (9%) than in adults (61%). Dissemination is predominantly hematogenic. Prognosis is best in teratoma which is cured by orchiectomy. Yolk sac tumor limited to the testicle, in infants less than 2 years old, is sufficiently treated with orchiectomy alone. Older children require adjuvant chemotherapy. Overall, chemotherapy was indicated in 15% of the evaluated cases of childhood testicular malignoma.

[Pelvic bone angiomas]. / Pelvine Knochenangiome.

Three patients were seen with angiomas of the pelvic bones; the radiological and clinical features are described and the literature reviewed. The patients had been observed for four to six years. The differential diagnosis includes infiltrating mesenchymal neoplasms and the histologically similar, but rare, Gorham-Stout syndrome. Recommended treatment is irradiation, which is effective up to a point.

[Vessel damage caused by the administration of intra-arterial methotrexate? Fluorescence angiography and histologic findings]. / Gefässschäden bei intraarterieller Methotrexatapplikation? Fluoreszenzangiographische und histologische Befunde.

During a 7 days course of intraarterial methotrexate therapy in patients with certain head and neck tumours, we could demonstrate changes in the blood supply of the tympanic membranes as well as in the tumours themselves by the fluorescence angiography technique. Chemotherapy generally was followed by an operation, the material of which histologically showed varying degrees of vascular occlusions, which we ascribe to the high concentration of methotrexate. The drug given into the external carotid artery reached not only the tumour-supplying vessels but also more peripheral branches such as the arteries of the tympanic membrane. This could explain the observed vascular changes. We conclude that the high concentration of methotrexate achieved by intraarterial therapy may cause vascular occlusions. Therefore, this kind of chemotherapy should be used for a limited time only, because later the penetration of the drug may be inhibited.

[Regressive change in the rat prostate after castration. A study using histology, morphometrics and autoradiography with special reference to apoptosis (author's transl)]. / Die Regression der Rattenprostata nach Kastration. Histologische, morphometrische und zellkinetische Untersuchungen unter Berücksichtigung der Apoptose.

The individual processes involved in involution of the prostate gland following androgen withdrawal are incompletely understood. The rat prostate was used to investigate cell loss (numeric atrophy), decrease in cell size (simple or cellular atrophy) and altered cell proliferation. The prostate gland was studied at various times after castration using histological, nuclear morphometric and 3-H-thymidine autoradiographic methods, as well as by measuring weight. Cell loss was determined by the proportion of apoptosis-bodies. Following castration a decreased formation of secretions and reduction in interstitial tissue fluid were observed, as well as reduced cell proliferation, which did not affect the weight, as the normal cell proliferation in all lobes of the prostate is extremely small. The nuclear size fell to 30%. The apoptosis index, i.e. cell loss, was considerable and reached a maximum in the coagulating glands on day 2, and in the other prostate lobes between day 4 and 8. After this time cell loss corresponded to that of control animals. Cell loss measured by apoptosis has proved to be reliable parameter of hormone-dependent regression of the prostate. The responsiveness of prostate carcinomas to hormone treatment can be tested possibly using alteration in the apoptosis index already some days after withdrawal of androgens.

[Histological and cell kinetic studies of the growth of rat prostate of various ages]. / Histologische und proliferationskinetische Untersuchungen zum Wachstum der Rattenprostata in verschiedenen Lebensaltern.

Histologic and cell-kinetic investigations were performed on the developing prostate of growing rats. The ages ranged from 1 day to 15 months. The most intensive cell proliferation is observed within the first 2 weeks after birth. Thereafter, the cell proliferation decreases continually as the cellular differentiation of the prostatic glandular epithelium increases to form well-differentiated secretory cells. The second peak of cell proliferation occurs with the beginning of sexual maturation and an elevated testosterone production. But the rapid increase of prostatic weight at that time is mainly caused by an increased formation of secretory and interstitial tissue fluids. The different lobes of the adult prostate all exhibit the same cellular proliferation pattern. The prostate belongs to the organs with stable growth pattern and an only small cellular turnover. Mitotic figures are extremely rare under normal conditions. But this low cellular proliferative activity may be easily changed, in contrast to other organs with stable tissue and steady-state growth, i.e., liver and kidney, in dependence of hormone levels.

[Experimental investigations on cell loss and cell proliferation of the rat prostate after castration and androgen administration (author's transl)]. / Experimentelle Untersuchungen zum Zellverlust und zur Zellneubildung der Rattenprostata nach Kastration und Androgenzufuhr.

The rat prostate was used to investigate cell loss (numeric atrophy) and altered cell proliferation after castration. Cell loss was determined by the proportion of apoptotic bodies. The apoptotic index was considerable and reached a maximum in the coagulating gland on day 2 and in the other prostate lobes between days 4 and 8. Thereafter, cell loss was reduced and finally corresponded to that of control animals. Cell proliferation decreased and soon ceased at all. Androgen administration caused cell increase in all prostate lobes. Following a latent period of 35--40 h, the 3H-labeling index increased with a maximum on day 3. Values then fell and were minimal above control values. Rhythmically interrupted administration of testosterone resulted in a decreased ability to stimulate cell proliferation. This androgen-induced cell proliferation is a useful model for testing cell proliferation of the prostate. The combined determination of cell loss and the cell proliferation, therefore, may be important for the clinical examination of the hormonal responsiveness of prostatic carcinomas.

[Pathology of liver lesions in malignant non-Hodgkin lymphomas (author's transl)]. / Morphologie des Leberbefalls bei malignen non-Hodgkin-Lymphomen.

The Kiel classification of lymphomas based on cytological criteria can be applied to tumor cell types found in liver infiltrates as well. Lymphomas with low degree of malignancy are delineated distinctly against the normal parenchyma; the borderline is slightly blurred only in the centroblastic-centrocytic subtype. Generally, the portal fields in these cases are round-shaped, expanded, and filled with lymphoid cells. Lymphomas with a high degree of malignancy are characterized on the contrary by portal fields with very irregular borderlines; in some cases there is a certain similarity to piece meal necrosis. There is an increased incidence of mitoses in the malignant tissue. Bile ducts are often disrupted. Hair cell leukemia can be differentiated in paraffin sections too, if tartrate-resistent acid phosphotase is present.