Prognostic value of histopathologic traits independent of stromal tumor-infiltrating lymphocyte levels in chemotherapy-naïve patients with triple-negative breast cancer.

BACKGROUND: In the absence of prognostic biomarkers, most patients with early-stage triple-negative breast cancer (eTNBC) are treated with combination chemotherapy. The identification of biomarkers to select patients for whom treatment de-escalation or escalation could be considered remains an unmet need. We evaluated the prognostic value of histopathologic traits in a unique cohort of young, (neo)adjuvant chemotherapy-naïve patients with early-stage (stage I or II), node-negative TNBC and long-term follow-up, in relation to stromal tumor-infiltrating lymphocytes (sTILs) for which the prognostic value was recently reported. MATERIALS AND METHODS: We studied all 485 patients with node-negative eTNBC from the population-based PARADIGM cohort which selected women aged <40 years diagnosed between 1989 and 2000. None of the patients had received (neo)adjuvant chemotherapy according to standard practice at the time. Associations between histopathologic traits and breast cancer-specific survival (BCSS) were analyzed with Cox proportional hazard models. RESULTS: With a median follow-up of 20.0 years, an independent prognostic value for BCSS was observed for lymphovascular invasion (LVI) [adjusted (adj.) hazard ratio (HR) 2.35, 95% confidence interval (CI) 1.49-3.69], fibrotic focus (adj. HR 1.61, 95% CI 1.09-2.37) and sTILs (per 10% increment adj. HR 0.75, 95% CI 0.69-0.82). In the sTILs <30% subgroup, the presence of LVI resulted in a higher cumulative incidence of breast cancer death (at 20 years, 58%; 95% CI 41% to 72%) compared with when LVI was absent (at 20 years, 32%; 95% CI 26% to 39%). In the ≥75% sTILs subgroup, the presence of LVI might be associated with poor survival (HR 11.45, 95% CI 0.71-182.36, two deaths). We confirm the lack of prognostic value of androgen receptor expression and human epidermal growth factor receptor 2 -low status. CONCLUSIONS: sTILs, LVI and fibrotic focus provide independent prognostic information in young women with node-negative eTNBC. Our results are of importance for the selection of patients for de-escalation and escalation trials.

The small GTPase, Rap1, mediates CD31-induced integrin adhesion.

Integrin-mediated leukocyte adhesion is a critical aspect of leukocyte function that is tightly regulated by diverse stimuli, including chemokines, antigen receptors, and adhesion receptors. How cellular signals from CD31 and other adhesion amplifiers are integrated with those from classical mitogenic stimuli to regulate leukocyte function remains poorly understood. Here, we show that the cytoplasmic tail of CD31, an important integrin adhesion amplifier, propagates signals that induce T cell adhesion via beta1 (VLA-4) and beta2 (LFA-1) integrins. We identify the small GTPase, Rap1, as a critical mediator of this effect. Importantly, CD31 selectively activated the small Ras-related GTPase, Rap1, but not Ras, R-Ras, or Rap2. An activated Rap1 mutant stimulated T lymphocyte adhesion to intercellular adhesion molecule (ICAM) and vascular cell adhesion molecule (VCAM), as did the Rap1 guanine nucleotide exchange factor C3G and a catalytically inactive mutant of RapGAP. Conversely, negative regulators of Rap1 signaling blocked CD31-dependent adhesion. These findings identify a novel important role for Rap1 in regulating ligand-induced cell adhesion and suggest that Rap1 may play a more general role in coordinating adhesion-dependent signals during leukocyte migration and extravasation. Our findings also suggest an alternative mechanism, distinct from interference with Ras-proximal signaling, by which Rap1 might mediate transformation reversion.

Malignant transformation of benign gliomas during interstitial irradiation.

Interstitial curietherapy with 125-Iodine is an effective therapeutic option in the treatment of low grade gliomas. Four cases with astrocytoma grade II are presented, where tumour growth characteristics have changed to anaplasia during interstitial irradiation after a primary period of tumour regression. Anaplastic transformation could be due to a radiation effect or an insufficient therapeutic influence of interstitial irradiation on natural tumour progression of glioma growth due to genetic events.

[Radiotherapy of cervix and uterus carcinomas (Marburg results of 1960 to 1975)]. / Beitrag zur Strahlentherapie der Kollum- und Korpuskarzinome (Marburger Ergebnisse 1960 bis 1975).

The authors present the therapy results and complications of 479 patients with carcinomas of the cervix and 241 patients with carcinomas of the body of the uterus. The five-year survival rate of the patients with carcinomas of the cervix is 57%. The first five years after diagnosis were survived by 79.6% of the patients in stage I, 57.3% of the patients in stage II, 31.1% of the patients in stage III, and 5.9% of the patients in stage IV. 60% of these patients were only submitted to percutaneous and intracavitary irradiation, and 40% were irradiated after operation. The five-year survival rate of the patients with carcinoma of the body was 74.3%. This rate was 80.8% in stage I, 77.5% in stage II, 57.5% in stage III, and 30% in stage IV. The operation frequency was relatively high with 74%, only 26% of these patients were only treated by radiotherapy. The percutaneous radiotherapy was performed exclusively under high voltage conditions, preponderantly according to the method of Marburg which allows a homogenous, small-field irradiation of the small pelvis with a dose until 45 Gy, but which deliberately does not expose to radiation the para-aortal lymph nodes. In the years of 1966 to 1971, a comparison with the method established in Düsseldorf was made. This method is working with two big U-shaped stationary fields including the para-aortal lymph nodes. The central part of the pelvis is collimated when percutaneous irradiation is applied, and the intracavitary treatment is applied with a higher dose, correspondingly. The present analysis of the treatment results of both methods does not show any significant difference as to the survival time. The incidence of fistulas, however, a severe late complication, which is 2.4% for the method of Marburg, is markedly lower than that of 8.6% for the other method. Prognostic factors and therapeutic aspects are discussed in detail.

[ECG-changes following postoperative irradiation of patients with mammary carcinoma (author's transl)]. / EKG-Veränderungen nach postoperativer Bestrahlung von Mammakarzinom-Patientinnen.

Systematic ECG-analyses and determinations of serum creatin-kinase were performed in 32 patients with mammary carcinoma of the left, prior to and immediately after postoperative radiation therapy. Treatment was done with a gammatron, during this, the average load to the anterior cardiac wall amounted to 3600 rd. Eleven cases exhibited coronary-negative T-waves in at least two chest leads after treatment, seven other cases had flat negative or isoelectric T-waves. Two patients additionally revealed prolongation of the relative QT-period by more than 115%. These changes are interpreted as a sign of radiation-induced myopericarditis. Pericardial effusions did not appear during the follow-up period, furthermore no modifications of creatin-kinase activity. Clinical injury to the patients developed in no case.

[Results of radiotherapy of bronchial carcinoma (author's transl)]. / Ergebnisse der Strahlenbehandlung des Bronchialkarzinoms

In a joint retrospective study by 17 radiotherapy clinics in German-speaking countries the results of treatment of bronchial carcinoma after radiotherapy were analysed in 7503 cases. The age peak was between the 60th and 70th year. Squamous-cell carcinoma was the most frequent histological type, followed by anaplastic carcinoma, with adenocarcinoma being rare. There was a high proportion of histologically not clearly identified cases (27% in central and 35% in peripheral carcinomas). Survival rate at one year was 31% for central (3662 patients) and peripheral (961 patients) tumours, but only 2% at five years. Prognostically there was no difference between histological types and kind of radiotherapy or technique, but total dose affected survival rate. At a total dose of less than 5000 rd the survival rate at five years was minimal. The prognosis of combined surgical and radiotherapeutic measures was slightly better than with a radiotherapy alone, but results were unpredictable for the individual case. It is concluded that radiotherapy aiming at cure should be used in imoperable bronchial carcinoma if the tumour state and general condition of the patient appear to make a cure possible. But if this is not the case, radiotherapy should be used only palliatively, i.e. only to ameliorate symptoms.

[Varying standard concentrations as a cause of divergent serum digoxin estimations using radioimmune-essays (author's transl)]. / Unterschiedliche Standardkonzentrationen als Ursache für divergierende Serumdigoxinbestimmungen mit Radioimmunoassays

1. The results of various commercial radio-immune essays for digoxin differ and cannot readily be compared. 2. For each RIA it is therefore necessary to determine one's own therapeutic and toxic levels in relation to the clinical requirements. 3. When quoting data, it is necessary to define the method of RIA with its therapeutic and toxic levels. 4. A cause for the high digoxin estimations of 2 RIA's carried out by the same firm has been identified as being due to the low concentration of the standard preparation. 5. The introduction of a defined and obligatory digoxin standard is recommended.