Trifluridine/tipiracil in combination with oxaliplatin and either bevacizumab or nivolumab in metastatic colorectal cancer: a dose-expansion, phase I study.

BACKGROUND: In preclinical studies trifluridine/tipiracil (FTD/TPI) plus oxaliplatin (Industriestrasse, Holzkirchen, Germany) sensitised microsatellite stable (MSS) metastatic colorectal cancer (mCRC) to anti-programmed cell death protein-1; the addition of oxaliplatin or bevacizumab (F Hoffmann- la ROCHE AG, Kaiseraugst, Switzerland) enhanced the antitumour effects of FTD/TPI. This study aimed to investigate the safety and efficacy of FTD/TPI plus oxaliplatin and either bevacizumab or nivolumab (Uxbridge business Park, Uxbridge, United Kingdom) in patients with mCRC who had progressed after at least one prior line of treatment. PATIENTS AND METHODS: In 14-day cycles, patients received FTD/TPI 35 mg/m2 (twice daily, days 1-5) plus oxaliplatin 85 mg/m2 (day 1), and, on day 1, either bevacizumab 5 mg/kg (cohort A) or nivolumab 3 mg/kg (cohort B). Patients in Cohort B had confirmed MSS status. RESULTS: In total, 54 patients were enrolled: 37 in cohort A and 17 in cohort B. Recruitment in cohort B was stopped early due to the low response rate (RR) observed at interim analyses of efficacy. The most common adverse events (AEs) in cohort A were neutropenia/decreased neutrophils (75.7%), nausea (59.5%), vomiting (40.5%), diarrhoea (37.8%), peripheral sensory neuropathy (37.8%), fatigue (35.1%) and decreased appetite (35.1%). In cohort B, the most common AEs were neutropenia/decreased neutrophils (70.6%), diarrhoea (58.8%), nausea (47.1%), vomiting (47.1%), fatigue (47.1%), asthenia (41.2%), paraesthesia (41.2%), thrombocytopenia/decreased platelets (35.3%) and decreased appetite (35.3%). Confirmed objective RR was 17.1% in cohort A and 7.1% in cohort B; the corresponding values for median progression-free survival in the two cohorts were 6.3 and 6.0 months. CONCLUSION: FTD/TPI plus oxaliplatin and bevacizumab or nivolumab had an acceptable safety profile and demonstrated antitumour activity in previously treated patients with mCRC.

Alpelisib plus fulvestrant for PIK3CA-mutated, hormone receptor-positive, human epidermal growth factor receptor-2-negative advanced breast cancer: final overall survival results from SOLAR-1.

BACKGROUND: Activation of the phosphatidylinositol-3-kinase (PI3K) pathway via PIK3CA mutations occurs in 28%-46% of hormone receptor-positive (HR+), human epidermal growth factor receptor-2-negative (HER2-) advanced breast cancers (ABCs) and is associated with poor prognosis. The SOLAR-1 trial showed that the addition of alpelisib to fulvestrant treatment provided statistically significant and clinically meaningful progression-free survival (PFS) benefit in PIK3CA-mutated, HR+, HER2- ABC. PATIENTS AND METHODS: Men and postmenopausal women with HR+, HER2- ABC whose disease progressed on or after aromatase inhibitor (AI) were randomized 1 : 1 to receive alpelisib (300 mg/day) plus fulvestrant (500 mg every 28 days and once on day 15) or placebo plus fulvestrant. Overall survival (OS) in the PIK3CA-mutant cohort was evaluated by Kaplan-Meier methodology and a one-sided stratified log-rank test was carried out with an O'Brien-Fleming efficacy boundary of P ≤ 0.0161. RESULTS: In the PIK3CA-mutated cohort (n = 341), median OS [95% confidence interval (CI)] was 39.3 months (34.1-44.9) for alpelisib-fulvestrant and 31.4 months (26.8-41.3) for placebo-fulvestrant [hazard ratio (HR) = 0.86 (95% CI, 0.64-1.15; P = 0.15)]. OS results did not cross the prespecified efficacy boundary. Median OS (95% CI) in patients with lung and/or liver metastases was 37.2 months (28.7-43.6) and 22.8 months (19.0-26.8) in the alpelisib-fulvestrant and placebo-fulvestrant arms, respectively [HR = 0.68 (0.46-1.00)]. Median times to chemotherapy (95% CI) for the alpelisib-fulvestrant and placebo-fulvestrant arms were 23.3 months (15.2-28.4) and 14.8 months (10.5-22.6), respectively [HR = 0.72 (0.54-0.95)]. No new safety signals were observed with longer follow-up. CONCLUSIONS: Although the analysis did not cross the prespecified boundary for statistical significance, there was a 7.9-month numeric improvement in median OS when alpelisib was added to fulvestrant treatment of patients with PIK3CA-mutated, HR+, HER2- ABC. Overall, these results further support the statistically significant prolongation of PFS observed with alpelisib plus fulvestrant in this population, which has a poor prognosis due to a PIK3CA mutation. CLINICALTRIALS. GOV ID: NCT02437318.

Outcome of uterine sarcoma patients treated with pazopanib: A retrospective analysis based on two European Organisation for Research and Treatment of Cancer (EORTC) Soft Tissue and Bone Sarcoma Group (STBSG) clinical trials 62043 and 62072.

BACKGROUND: Uterine sarcomas are a group of mesenchymal tumours comprising several histologies. They have a high recurrence rate following surgery, modest outcome to systemic therapy, and poor overall survival. Pazopanib is a multi-targeted tyrosine kinase inhibitor approved for non-adipocytic advanced soft tissue sarcomas (STS). Here we investigated whether response to pazopanib in patients with uterine sarcomas differs from that of patients with non-uterine sarcomas. PATIENTS AND METHODS: Uterine sarcoma patients were retrieved from all soft tissue sarcoma patients treated with pazopanib in EORTC Phase II (n=10) and Phase III (PALETTE) (n=34) studies. Patient and tumour characteristics, response, progression free and overall survival data were compared. RESULTS: Forty-four patients with uterine sarcoma were treated with pazopanib. The majority of patients had uterine leiomyosarcoma (LMS) (n=39, 88.6%) with high grade tumours (n=37, 84.1%) compared to 54.8% (n=164) in the non-uterine population. The median age was 55years (range 33-79) and median follow up was 2.3years. Uterine patients were heavily pre-treated, 61.3% having ≥2 lines of chemotherapy prior to pazopanib compared to 40.8% in the non-uterine population. Five patients (11%), all LMS, had a partial response (95% CI 3.8-24.6). Median progression free survival (PFS) 3.0months (95% CI 2.5-4.7) in uterine versus 4.5 (95% CI 3.7-5.1) in non-uterine STS. Median overall survival (OS) was 17.5months (95% CI 11.1-19.6), longer than the non-uterine population, 11.1months (95% CI 10.2-12.0) (p=0.352). CONCLUSIONS: Despite heavy pre-treatment, pazopanib shows signs of activity in patients with uterine sarcoma with the similar outcomes to patients with non-uterine STS.

Hypertension (HTN) as a potential biomarker of efficacy in pazopanib-treated patients with advanced non-adipocytic soft tissue sarcoma. A retrospective study based on European Organisation for Research and Treatment of Cancer (EORTC) 62043 and 62072 trials.

BACKGROUND: Reliable biomarkers of pazopanib's efficacy in soft tissue sarcoma (STS) are lacking. Hypertension (HTN) is an on-target effect of vascular endothelial growth factor (VEGF)-receptor inhibitors such as pazopanib. We evaluated the association of pazopanib-induced HTN with antitumour efficacy in patients with metastatic non-adipocytic STS. METHODS: Associations between pazopanib-induced-HTN and antitumour efficacy were retrospectively assessed across 2 prospective studies (European Organisation for Research and Treatment of Cancer (EORTC) study 62043 and 62072) in metastatic STS patients who received pazopanib 800 mg daily. Only patients with baseline blood pressure (BP)<150/90 mmHg, were included. BP was measured monthly. HTN was reported according to National Cancer Institute-Common Toxicity Criteria Adverse Events (NCI-CTC AE) grading (v3.0), and as absolute differences compared to baseline. The effect of HTN developing in patients without baseline anti-hypertensive medication was assessed on progression-free (PFS) and overall survival (OS) using a landmark analysis stratified by study; univariately using the Kaplan-Meier method and a log-rank test, and in a multivariate Cox regression model after adjustment for important prognostic factors. RESULTS: Of the 337 patients eligible for this analysis, 21.7% received anti-hypertensive medication at baseline and had a similar PFS and OS compared to those who did not. In patients without baseline anti-hypertensive medication, 38.6% developed HTN. As the majority of patients developing HTN did so within 5 weeks after initiation of pazopanib (68.6%), this time point was used as landmark. Univariately, there was no effect on PFS or OS from occurrence of HTN within 5 weeks of treatment expressed either in NCI-CTC AE criteria or as maximal differences from baseline in systolic and diastolic BP. Also in multivariate analysis, after adjusting for important prognostic factors, the occurrence of HTN expressed in the different parameters was not associated with PFS and OS. CONCLUSIONS: In this retrospective analysis, pazopanib-induced HTN did not correlate with outcome in pazopanib-treated STS patients. The occurrence of HTN cannot serve as biomarker in this setting.

Application of a new mathematical function for describing chromatographic peaks.

Curve fitting seems to be one of the best methods for the evaluation of chromatographic signals. As it is known, in this case mathematical function is fitted to digitized measured points. The most important task is to find the best mathematical function, which corresponds perfectly to the peak shape, and then to determine the parameters of the equation using a computerized least-squares method of approximation. In this work, a new mathematical function was sought for with the purpose of describing different chromatographic signals and it was fitted to the digitized measured points. The fitted curve is suitable for a quick evaluation of chromatographic information, noise filtering and correction of baseline drift. The fitting of gas chromatographic and high-performance liquid chromatographic signals were completed. The mathematical function, the generated chromatographic curves, the application of the function for describing real signals and the fitting process will be demonstrated in this study.

Bilateral bronchial stenting and esophageal intubation for advanced bronchial carcinoma with esophageal invasion.

Successive bilateral bronchial stenting (Dumon type) and minimally invasive pull-through esophageal intubation for accompanying malignant bronchial and esophageal involvement was undertaken. External radiation and afterloading brachytherapy for localized endobronchial overgrowth was used. A 13-month survival was achieved using mainly out-patient facilities. During such esophageal intubation, bronchoscopic control is mandatory. Extended complex palliation was obtained using this combined treatment, even in the high-risk stage of advanced tracheobronchial carcinoma with associated esophageal stricture.

[Results of limb-saving surgery and prognostic factors in patients with osteosarcoma]. / Végtagmegtartó mútétek eredményei és prognosztikai tényezók osteosarcomás betegeknél.

Ninety six patients with high-grade osteosarcoma of the extremities were treated between 1986 and 1997 in the authors institution. They were divided into three groups: in group I, all of 75 patients with non-metastatic OS received intensive chemotherapy and underwent surgery. In group II, 9 patients already had metastases at the time of referral. In group III, 12 patients received chemotherapy in delayed or suboptimal form. In group I, local recurrences occurred in 7 per cent (3 patients), metastases in 20 per cent of the patients with limb-saving, whereas these numbers were 3 per cent and 38 per cent in the amputation group. The 5-year disease free survival (DFS) was 72% v 69% in the limb-saving and amputation group, respectively. In groups II and III, 5-year DFS was extremely poor, 10 and 20% only. With univariate analysis, factors having a positive influence on the survival were: tumor volume < 60 cm3, wide or radical surgical margin, distal location of osteosarcoma, cartilagineous ground substance less than 20% and response to chemotherapy. The last 4 variables maintained their significance in the multivariate Cox model as well. Age > 30 showed indirect negative influence on the final outcome (enhanced intolerability to the drugs and less co-operability of the patients etc.). This data confirm the competence of the limb-saving surgery at certain indications beside the amputation.

The efficacy of a combination of etoposide, ifosfamide, and cisplatin in the treatment of patients with soft tissue sarcoma.

BACKGROUND: Successful chemotherapy for patients with soft tissue sarcoma (STS) has been limited by a lack of active drugs. The most effective single agents are doxorubicin, dacarbazine, and, more recently, ifosfamide. Previously the most widely used combination has been CYVADIC (cyclophosphamide, vincristine, doxorubicin, and dacarbazine). In one randomized trial, ifosfamide was superior to cyclophosphamide; two nonrandomized studies also reported favorable results. Etoposide monotherapy was successful in 8%; the effectiveness of cisplatin was 5-23%. In view of these findings, the authors treated STS patients with an etoposide, cisplatin, and ifosfamide (VIP) combination. METHODS: The eligibility criteria included histologically confirmed, inoperable, metastatic or locally recurrent STS; a World Health Organization (WHO) performance status of 0-2; a maximum age of 75 years; and progressive, measurable disease. A total of 104 patients were treated from January 1990 to June 1997. The median age of the patients was 42.4 years. The patients were treated with a combination of etoposide (100mg/m(2) for 5 days), ifosfamide (2000 mg/m(2) for 2 days), and cisplatin (20mg/m(2) for 5 days) once a month via a peripheral vein. The treatment response and the toxicity were assessed according to WHO criteria. RESULTS: Of 104 evaluable patients, 47 responded. The overall response rate was 46% (complete response: 10%; partial response: 36%). In 43 patients the disease remained stable (41%). Remission duration was 4.6 months. Toxicity was moderate. The main adverse events were alopecia (100%), nausea and vomiting (73%), and leukopenia (29%). CONCLUSIONS: This new combination is promising for the treatment of patients with advanced STS.

Limb-saving surgery, survival, and prognostic factors for osteosarcoma: the Hungarian experience.

BACKGROUND AND OBJECTIVES: There are many factors thought to have an influence on the prognosis of osteosarcoma that have been reported in the literature. Their significance, however, still remains controversial in most cases. Experience with osteogenic sarcoma (OS) was reviewed in order to evaluate surgical results and survival and to determine the prognostic factors. METHODS: Ninety-six patients with high-grade osteosarcoma of the extremities were treated between 1986 and 1997 in the authors' institution. They were divided into 3 groups: In group I, all 75 patients with nonmetastatic OS received intensive chemotherapy (high-dose methotrexate, doxorubicin, ifosfamide, and cisplatin) and underwent surgery. In group II, 9 patients already had metastases at the time of referral. In group III, 12 patients received chemotherapy in delayed or suboptimal form. Results and Conclusions In group I, there were local recurrences in 3 patients (7%) and metastases in 8 patients (20%) with limb-saving, whereas these numbers were 1 (3%) and 14 (38%) in those who had amputation. The 5-year disease-free survival (DFS) was 72% and 69% in the limb-saving and amputation groups, respectively. In groups II and III, 5-year DFS was extremely poor, 10% and 20% only, underlining the importance of stage and intensity of chemotherapy, respectively. With univariate analysis, sex, duration of symptoms, and radiographic appearance of OS had no prognostic value, whereas tumor volume <60 cm(3), wide or radical surgical margin, distal location of OS, cartilagineous ground substance <20%, and response to chemotherapy were positive prognostic factors. The last 4 variables maintained their significance in the multivariate Cox model as well. Age >30 years showed indirect negative influence on the final outcome through enhanced intolerability to the drugs and less cooperability of the patients. The results on survival with limb-saving surgery were well comparable with those of amputation.

[Congenital broncho-esophageal fistula manifesting in adult age]. / Felnóttkorban manifesztálódó veleszületett broncho-oesophagealis sipoly.

Congenital bronchoesophageal fistula manifesting in adulthood is an infrequent disorder. Presenting a successfully treated case, the authors review the clinicopathological features of the disease regarding the data of literature. The long-standing, non-specific respiratory symptoms recurring in the same pulmonary location call the attention to the fistula, which should be verified by esophagography and endoscopy. The adequate treatment consisting of fistulectomy and resection of the destroyed lung parenchyma lead to prompt recovery.

[Fiberoptic bronchoscopy in intensive care units]. / Bronchofiberoscopia az intenzív osztályokon.

The authors have retrospectively analysed 161 bedside fiberoptic bronchoscopies performed at intensive care units and demonstrate its' main indications, results and influences on the patients' condition. In 35.4% of cases immediate improvement was observed, in 31.6% the examination contributed to choose the proper treatment. Due to the safe method only one serious complication occurred because of bronchoscopy. The results justify-according to the literature-that fiberoptic bronchoscopy is an indispensable method to check airways and for diagnostical and therapeutic interventions of critically ill patients.

[Experience with transbronchial lung biopsy]. / Transbronchialis tüdöbiopsiával szerzett tapasztalataink.

The histological results of transbronchial lung biopsies have been analysed in 109 patients with diffuse or localised lung diseases. This diagnostic procedure is relatively safe, well tolerable and can be carried out in outpatients. In diffuse lung diseases its use can replace the open lung biopsy. The efficacy of this method depends on the availability of biplanar fluoroscopy, the quality of the excisors, the quantity and size of the biopsy material and the technique of the histological handling.

[The role of Nd-YAG in the management of tracheobronchial stenosis]. / Neodymium-YAG laser szerepe a tracheobronchialis szükületek kezelésében.

122 patients with the main airway stenosis were treated with Nd-YAG laser phototherapy. The endobronchial laser treatment was performed either with flexible bronchoscope (64%), or with rigid instrument (36%). This method can result a final recovery of the patients with benign tumors, or inflammatory processes, at the patients with malignant tumors can be achieved an effective palliation. Taking account the generally accepted indications and contraindications of the endobronchial laser phototherapy the number of the complications can be reduced.