Survival analysis of carboplatin added to an anthracycline/taxane-based neoadjuvant chemotherapy and HRD score as predictor of response-final results from GeparSixto.

Background: In the neoadjuvant GeparSixto study, adding carboplatin to taxane- and anthracycline-based chemotherapy improved pathological complete response (pCR) rates in patients with triple-negative breast cancer (TNBC). Here, we present survival data and the potential prognostic and predictive role of homologous recombination deficiency (HRD). Patients and methods: Patients were randomized to paclitaxel plus nonpegylated liposomal doxorubicin (Myocet®) (PM) or PM plus carboplatin (PMCb). The secondary study end points disease-free survival (DFS) and overall survival (OS) were analyzed. Median follow-up was 47.3 months. HRD was among the exploratory analyses in GeparSixto and was successfully measured in formalin-fixed, paraffin-embedded tumor samples of 193/315 (61.3%) participants with TNBC. Homologous recombination (HR) deficiency was defined as HRD score ≥42 and/or presence of tumor BRCA mutations (tmBRCA). Results: A significantly better DFS (hazard ratio 0.56, 95% CI 0.34-0.93; P = 0.022) was observed in patients with TNBC when treated with PMCb. The improvement of OS with PMCb was not statistically significant. Additional carboplatin did not improve DFS or OS in patients with HER2-positive tumors. HR deficiency was detected in 136 (70.5%) of 193 triple-negative tumors, of which 82 (60.3%) showed high HRD score without tmBRCA. HR deficiency independently predicted pCR (ypT0 ypN0) [odds ratio (OR) 2.60, 95% CI 1.26-5.37, P = 0.008]. Adding carboplatin to PM significantly increased the pCR rate from 33.9% to 63.5% in HR deficient tumors (P = 0.001), but only marginally in HR nondeficient tumors (from 20.0% to 29.6%, P = 0.540; test for interaction P = 0.327). pCR rates with carboplatin were also higher (63.2%) than without carboplatin (31.7%; OR 3.69, 1.46-9.37, P = 0.005) in patients with high HRD score but no tmBRCA. DFS rates were improved with addition of carboplatin, both in HR nondeficient (hazard ratio 0.44, 0.17-1.17, P = 0.086) and HR deficient tumors (hazard ratio 0.49, 0.23-1.04, P = 0.059). Conclusions: The addition of carboplatin to neoadjuvant PM improved DFS significantly in TNBC. Long-term survival analyses support the neoadjuvant use of carboplatin in TNBC. HR deficiency in TNBC and HRD score in non-tmBRCA TNBC are predictors of response. HRD does not predict for carboplatin benefit.

Expression of Cyclin D1 protein in residual tumor after neoadjuvant chemotherapy for breast cancer.

PURPOSE: Hormone receptor (HR)-positive breast cancer (BC) shows a poor response to neoadjuvant chemotherapy (NACT). New treatment targets like the Cyclin D1-CDK4/CDK6 complex are promising adjuvant/post-neoadjuvant therapeutic strategies. Evaluating Cyclin D1 overexpression in residual tumor could recognize those patients that benefit most from such post-neoadjuvant treatment. In this study, we determined Cyclin D1 expression in residual BC after NACT. Secondary aims were to correlate Cyclin D1 expression levels with clinicopathological parameters and to assess its prognostic value after NACT. METHODS: We retrospectively assessed the nuclear expression of Cyclin D1 on tissue microarrays with residual tumor from 284 patients treated in the neoadjuvant GeparTrio (n = 186) and GeparQuattro (n = 98) trials. Evaluation was performed with a standardized immunoreactive score (IRS) after selecting a cut-off value. RESULTS: A high expression level (IRS ≥ 6) of Cyclin D1 was found in 37.3% of the assessed specimens. An increased Cyclin D1 expression was observed in HR-positive tumors, compared to HR-negative tumors (p = 0.02). Low Cyclin D1 levels correlated with clinical tumor stage 1-3 (p = 0.03). Among patients with HR-positive/Her2-negative tumors and high Cyclin D1 expression, a better disease-free survival (DFS) was graphically suggested, but not significant (p = 0.21). CONCLUSION: Our study demonstrates a measurable nuclear expression of Cyclin D1 in post-neoadjuvant residual tumor tissue of HR-positive BC. Cyclin D1 expression was not prognostic for DFS after NACT. Our results and defined cut-off suggest that the marker can be used to stratify tumors according to protein expression levels. Based on this, a prospective evaluation is currently performed in the ongoing Penelope-B trial.

Higher rate of severe toxicities in obese patients receiving dose-dense (dd) chemotherapy according to unadjusted body surface area: results of the prospectively randomized GAIN study.

BACKGROUND: In routine clinical practice, chemotherapy doses are frequently capped at a body surface area (BSA) of 2.0 m2 or adjusted to an ideal weight for obese patients due to safety reasons. MATERIALS AND METHODS: Between August 2004 and July 2008, a total of 3023 patients were enrolled in the GAIN study, a randomized phase III adjuvant trial, comparing two types of dose-dense (dd) regimen [epirubicin, docetaxel and cyclophosphamide (iddETC) versus epirubicin and cyclophosphamide (EC) followed by docetaxel (T) plus capecitabine (X)]. We retrospectively evaluated a total of 555 patients with a BMI of ≥30 for safety and outcome. RESULTS: Eighteen percent of all patients were obese: 31% of those received chemotherapy according to an unadjusted BSA. For the remaining patients, BSA was adjusted to ideal weight or was capped at 2.0 m2. A total of 15% of obese patients receiving full (unadjusted) dose of chemotherapy versus 6% of obese patients with an adjusted BSA experienced febrile neutropenia (P = 0.003) and 9% versus 3% high-grade thrombopenia (P = 0.002). Overall, 17% versus 10% had a thromboembolic event (P = 0.017), which was high grade in 13% versus 6%, respectively (P = 0.019), and 3% versus 0.3% high-grade hot flushes (P = 0.013). Dizziness (5% versus 11%; P = 0.016), diarrhea (19% versus 27%; P = 0.033) and an increase in serum creatinine (7% versus 14%; P = 0.019) were higher in the adjusted group. However, no differences in disease-free survival (DFS) and overall survival (OS) were observed between non-obese patients, obese patients receiving full-dose chemotherapy or according to an adjusted BSA [5-year DFS 81% (confidence interval 79% to 83%) versus 82% (75% to 87%) versus 81% (76% to 84%); P = 0.761; 5-year OS 90% (88% to 91%) versus 86% (80% to 91%) versus 88% (84% to 91%); P = 0.143]. CONCLUSION: Obese patients receiving dd chemotherapy according to their real BSA have a higher risk of developing severe toxicities without influencing survival. Therefore, a dose adjustment of intense dd chemotherapy should be carried out to avoid life-threatening complications.

Cytophotometric investigations of DNA-content in transitional cell tumors of the bladder. Comparison of results with clinical follow up.

Forty-nine patients with transitional cell tumors of the urinary bladder were followed up clinically for a period of at least 36 months (average time 61.4 months). Initial tumors were examined by means of DNA-Feulgencytophotometry. Histologic grading was performed according to Bergkvist et al. (1965). Clinical behavior clearly demonstrates the validity of the grading schedule used and shows the significance of DNA-Feulgencytophotometry for the standardization of bladder tumors and for the comparability of diagnostic and therapeutic results. Determination of the individual prognosis of low-malignancy tumors and the differentiation of histologic borderline cases does not appear to be possible by means of DNA-Feulgencytophotometry.

[Transluminal dilatation of innominate stenosis in aortic arch syndrome]. / Transluminale Dilatation einer Anonymastenose bei Aortenbogensyndrom.

Successful percutaneous transluminal dilatation of an anonyma stenosis is reported. The patient was a 40 year-old male with the aortic arch syndrome. Five years before an occlusion of the central carotid artery, as well as anonyma and left subclavian stenoses were treated by means of vascular grafts. On recurrence of the neurological symptoms, reocclusion of the right graft to the anonyma artery and subtotal stenosis of the left carotid bifurcation was noted. The anonyma stenosis was dilated by means of PTD. Haemodynamic success was demonstrated by Doppler sonography.

[Two cases of primary sclerosing cholangitis (author's transl)]. / Zur Problematik der primär sklerosierenden Cholangitis.

Two patients with symptoms of progressive obstructive jaundice, a history of vague pains in the right upper quadrant and laboratory evidence of biliary obstruction underwent laparotomy. A stone-free, but extremely thick-walled gallbladder was found in both patients. Intraoperative cholangiography showed diffusely-stenosed extrahepatic bile ducts suggestive of chronic inflammatory changes in the biliary system. The correct diagnosis was made only on histological examination, which revealed primary sclerosing cholangitis with secondary cholestatic changes of the liver. Postoperative treatment included long-time corticosteroid therapy. Both patients have remained jaundice-free for periods of one and two years, respectively, to date, but the eventual prognosis is poor. The diagnosis, which can be made only surgically, therapy and prognosis are discussed.

[Tissue concentrations of sulfametrol-trimethoprim in the human prostate (author's transl)]. / Zur Bestimmung der Gewebskonzentration von Sulfametrol-Trimethoprim in der menschlichen Prostata.

Ten patients with normal liver and kidney functions were admitted to a urology department for prostatectomy because of benign prostatic hypertrophy. They received a twice daily administration of 2 tablets of sulfametrole/trimethoprim (Lidaprim) for 4 days; the last dose of 2 tablets was given 4 hours before surgery. Having been enucleated by the suprapubic route, the prostatic glands were examined both histologically and chemico-analytically. The concentrations of the chemotherapeutically active substances were determined in the plasma and in the prostatic tissues. The prostatic tissue concentration of sulfametrole was 24,0 +/- 8,6 mg/kg and that of trimethoprim 7,1 +/- 2,2 mg/kg.

[Cytobiopsy as the best present method of intraoperative diagnosis of tumors of the pancreas]. / La citobiopsia come attuale miglior metodo nella diagnosi intraoperatoria dei tumori del pancreas.

A report has been made over six years experience with a fine needle aspiration biopsy, from authors who have developed a cytological intraoperative quick diagnosis of pancreas tumours. 116 patients have been treated up to this time. This method has proved to be important for the diagnosis of small pancreas tumours, while especially in such cases the indication to pancreas resection is used only in case of malignant tumours. In relation to other normal histological freezer microtome, the cytological method of fine needle biopsy has the advantage of being completely without complication. One can make as many punctures as needed and exactly this is what assues accurate diagnosis. In 90 cases with certain diagnosis, 65 correct conclusions and 12 suspect conclusions of tumour were obtained, and only five cases were erroneously judged negative; in eight cases the poor material did not allow a diagnosis. Therefore, wide application of cytobiopsy can be recommended.

[Cancer of the female sex organs in Baranja: 1985-1990]. / Obolijevanje od raka zenskih spolnih organa u Baranji: razdoblje od 1985. do 1990. godine.

Over a 6-year-period (January 1, 1985 to December 31, 1990) 86 women with cancer of genital organs were detected in the region of Baranya. According to the census of the year 1981, 27416 women have lived in Baranya, and in the above mentioned period 23533 examinations were done at the Women Welfare Clinic of the Health Centre Beli Manastir. In the period from 1985 to 1989, the average frequency of cervical cancer was 63.1%, uterine corpus cancer followed with 19.7%, ovarian and tubal with 13.1%, vulvar with 2.6% and vaginal with 1.3%. In the period from January 1 to December 31, 1990, cervical cancer accounted for 45.4% of all cancer cases, corpus cancer for 27.2%, ovarian and tubal cancer for 18.1%, without detection of any vulvar or vaginal cancer cases. In the observed period mean annual incidence of genital cancer was 52.9 per 100,000. According to organ sites mean annual incidence of cervical cancer was 32.1, corpus cancer 10.9, ovarian and tubal cancer 7.3, vulvar 1.2 and vaginal cancer 0.7 per 100,000. During the six year period cervical cancer incidence was reduced from 43.8 in 1985 to 18.2 per 100,000 in 1990. Corpus cancer incidence in 1985 was 14.6 as compared to 10.9 in 1990. Ovarian and tubal cancer incidence in 1985 and 1990 was 10.9 and 7.3, respectively. In the observed period preinvasive lesions of genital organs were discovered in 208 women, 201 (96.6%) of whom had cervical lesions--mean incidence here is 122.2 per 100,000. The overall proportion of preinvasive to invasive cervical lesions in the observed period was 79.1% to 20.9%.(ABSTRACT TRUNCATED AT 250 WORDS)

[Pregnant with possibilities]. / Embarazada con posibilidades.

AIDS: It may be possible for an inexpensive dose of vitamin A to reduce HIV transmission from mother to fetus. Last year, Dr. Richard Semba of Johns Hopkins University did a study involving vitamin A and pregnant HIV-positive African women in Malawi. The women taking vitamin A had a significantly lower percentage of HIV transmission to their infants. These women also had a lower mortality rate. In the United States, several university studies have shown that HIV-positive persons with diets high in vitamins, including vitamin A, have lower mortality rates. To prevent toxic reactions to high levels of vitamin A, use beta carotene, a form of the vitamin, and eat a diet rich in fruits and vegetables. The government recommends that pregnant HIV-positive women use AZT to prevent HIV transmission to the fetus. The government has overlooked the benefits of vitamin A.^ieng