Spectroscopy along Flerovium Decay Chains: Discovery of

A nuclear spectroscopy experiment was conducted to study α-decay chains stemming from isotopes of flerovium (element Z=114). An upgraded TASISpec decay station was placed behind the gas-filled separator TASCA at the GSI Helmholtzzentrum für Schwerionenforschung in Darmstadt, Germany. The fusion-evaporation reactions ^{48}Ca+^{242}Pu and ^{48}Ca+^{244}Pu provided a total of 32 flerovium-candidate decay chains, of which two and eleven were firmly assigned to ^{286}Fl and ^{288}Fl, respectively. A prompt coincidence between a 9.60(1)-MeV α particle event and a 0.36(1)-MeV conversion electron marked the first observation of an excited state in an even-even isotope of the heaviest man-made elements, namely ^{282}Cn. Spectroscopy of ^{288}Fl decay chains fixed Q_{α}=10.06(1) MeV. In one case, a Q_{α}=9.46(1)-MeV decay from ^{284}Cn into ^{280}Ds was observed, with ^{280}Ds fissioning after only 518 µs. The impact of these findings, aggregated with existing data on decay chains of ^{286,288}Fl, on the size of an anticipated shell gap at proton number Z=114 is discussed in light of predictions from two beyond-mean-field calculations, which take into account triaxial deformation.

A randomized study of KRAS-guided maintenance therapy with bevacizumab, erlotinib or metronomic capecitabine after first-line induction treatment of metastatic colorectal cancer: the Nordic ACT2 trial.

BACKGROUND: Maintenance treatment (mt) with bevacizumab (bev) ± erlotinib (erlo) has modest effect after induction chemotherapy in metastatic colorectal cancer (mCRC). We hypothesized the efficacy of erlo to be dependent on KRAS mutational status and investigated this by exploring mt strategies with bev ± erlo and low-dose capecitabine (cap). PATIENTS AND METHODS: Included patients had mCRC scheduled for first-line therapy, Eastern Cooperative Oncology Group (ECOG) 0-1 and no major comorbidities. Treatment with XELOX/FOLFOX or XELIRI/FOLFIRI + bev was given for 18 weeks. After induction, patients without progression were eligible for randomization to mt; KRAS wild-type (wt) patients were randomized to bev ± erlo (arms wt-BE, N = 36 versus wt-B, N = 35), KRAS mutated (mut) patients were randomized to bev or metronomic cap (arms mut-B, N = 34 versus mut-C, N = 33). Primary end point was progression-free survival (PFS) rate (PFSr) at 3 months after start of mt. A pooled analysis of KRAS wt patients from the previous ACT study was performed. RESULTS: We included 233 patients. Median age was 64 years, 62% male, 68% ECOG 0, 52% with primary tumor in situ. A total of 138 patients started mt after randomization. PFSr was 64.7% versus 63.6% in wt-B versus wt-BE, P = 1.000; and 75% versus 66.7% in mut-B versus mut-C, P = 0.579, with no significant difference in median PFS and overall survival (OS). In the pooled cohort, median PFS was 3.7 months in wt-B (N = 64) and 5.7 months in wt-BE (N = 62) (hazard ratios 1.03, 95% confidence interval 0.70-1.50, P = 0.867). The frequency of any grade 3/4 toxicities during mt was: 28%/58%/18%/15% (wt-B/wt-BE/mut-B/mut-C). CONCLUSIONS: Addition of erlo to bev as mt in KRAS wt mCRC did not significantly improve PFS or OS, but it did increase toxicity. KRAS status does not seem to influence the outcome of treatment with erlotinib. Metronomic cap warrants further investigation in mt strategies, given our explorative results. CLINICALTRIALSGOV: NCT01229813.

A randomized phase III multicenter trial comparing irinotecan in combination with the Nordic bolus 5-FU and folinic acid schedule or the bolus/infused de Gramont schedule (Lv5FU2) in patients with metastatic colorectal cancer.

BACKGROUND: To compare irinotecan with the Nordic 5-fluorouracil (5-FU) and folinic acid (FA) bolus schedule [irinotecan 180 mg/m(2) on day 1, 5-FU 500 mg/m(2) and FA 60 mg/m(2) on day 1 and 2 (FLIRI)] or the Lv5FU2 schedule [irinotecan 180 mg/m(2) on day 1, FA 200 mg/m(2), 5-FU bolus 400 mg/m(2) and infused 5-FU 600 mg/m(2) on day 1 and 2 (Lv5FU2-IRI)] due to uncertainties about how to administrate 5-FU with irinotecan. PATIENTS AND METHODS: Patients (n = 567) with metastatic colorectal cancer were randomly assigned to receive FLIRI or Lv5FU2-IRI. Primary end point was progression-free survival (PFS). RESULTS: Patient characteristics were well balanced. PFS did not differ between groups (median 9 months, P = 0.22). Overall survival (OS) was also similar (median 19 months, P = 0.9). Fewer objective responses were seen in the FLIRI group (35% versus 49%, P = 0.001) but the metastatic resection rate did not differ (4% versus 6%, P = 0.3). Grade 3/4 neutropenia (11% versus 5%, P = 0.01) and grade 2 alopecia (18% versus 9%, P = 0.002) were more common in the FLIRI group. The 60-day mortality was 2.4% versus 2.1%. CONCLUSIONS: Irinotecan with the bolus Nordic schedule (FLIRI) is a convenient treatment with PFS and OS comparable to irinotecan with the Lv5FU2 schedule. Neutropenia and alopecia are more prevalent, but both regimens are equally well tolerated.

Phase II studies on docetaxel alone every third week, or weekly in combination with gemcitabine in patients with primary locally advanced, metastatic, or recurrent esophageal cancer.

BACKGROUND: The purpose of these studies was to compare efficacy and toxicity of docetaxel alone with the combination of gemcitabine and docetaxel for treatment of metastatic esophageal carcinoma. PATIENTS AND METHODS: These studies enrolled patients with histopathologically verified squamous cell carcinoma or adenocarcinoma of the esophagus or cardia. Between March 1997 and June 1999, 52 patients were enrolled in the initial Phase II study (Study 1). They were scheduled for treatment with docetaxel 100 mg/m2 every third week as a 1-h infusion. The second Phase II study between September 2000 and March 2003 included 65 patients (Study II). They were given docetaxel 30 mg/m2, administered as a 30-min i.v. infusion weekly for four times, followed by 2 weeks of rest, and gemcitabine starting with a dose of 750 mg/m2 (if well-tolerated 1,000 mg/m2) on days 1 and 15, followed by 3 weeks of rest. A new cycle began on day 36. Patients were premedicated with betamethasone 8 mg p.o. on the evening before, and 8 mg i.v. 30-60 min before the docetaxel infusion. Response was confirmed by computed tomography and assessed at 12 and 24 weeks. Toxicity was assessed according to WHO scales. RESULTS: In study I, 38 out of the 52 enrolled patients were valuable. Two patients experienced complete remission (CR) (5%), 10 patients partial remission (PR) (26%), nine patients stable disease (SD) (24%), and 17 patients showed progressive disease (PD) (45%). Toxicity mainly involved leukopenia, which in some cases required hospitalization and treatment with antibiotics. In Study II, 46 out of the 65 enrolled patients (70%) were assessable. Out of these, three patients (7%) had CR, eight patients (17%) had PR, 10 patients (22%) had SD, and 25 (54%) PD. Overall response was 24% while an additional 22% showed stable disease. Toxicity mainly consisted of leucopenia and pain. CONCLUSION: Docetaxel as a single agent is active in esophageal cancer, both in treatment naive and in previously treated patients with recurrent disease. The overall response rate was 31%, with a good-safety profile. The addition of gemcitabine is well tolerated, but adds no efficacy. Weekly administration of docetaxel may be less effective. It demonstrates moderate efficacy and the doses used provide an acceptable safety profile.

Megestrol acetate in advanced, progressive, hormone-insensitive cancer. Effects on the quality of life: a placebo-controlled, randomised, multicentre trial.

A randomised double-blind placebo-controlled multicentre trial was performed to investigate the effects of megestrol acetate (MA) on the quality of life (QoL), appetite, weight and survival of patients with advanced, incurable, hormone-insensitive cancer. QoL was assessed at the start of treatment and at 4, 8 and 12 weeks, using the EORTC-QLQ-C30 instrument. 255 patients were randomised to 320 mg of MA daily or placebo for 12 weeks. 244 patients were assessable at baseline, 190 at 4 weeks (placebo 94; MA 96), 150 at 8 weeks (placebo 69; MA 81) and 112 at 12 weeks (placebo 55; MA 57). A beneficial effect of MA on appetite loss was observed at week 4 (P < 0.0001) and possibly at week 8 (P = 0.058). Further weight loss during treatment was significant only in the placebo group. In the first 8 weeks, changes in mean global QoL were small and similar in both groups. By 12 weeks the decrease in mean global QoL was more pronounced in the MA group (P = 0.028), which was related to a deterioration in physical function, while psychosocial function was not affected. Survival was not affected by MA, and side-effects were mild. The results show that MA has a beneficial effect on appetite and that it may retard weight loss with no adverse impact on survival and with mild toxicity. However, MA does not appear to improve global QoL as measured by the EORTC QLQ-C30.

Adverse cardiac effects during induction chemotherapy treatment with cis-platin and 5-fluorouracil.

Survival for patients with advanced head and neck carcinoma and esophageal carcinoma is poor with radiotherapy and/or surgery. Obviously, there is a need for effective chemotherapy. In the present study, cis-platin (80-120 mg/m2BSA) and 5-FU (1000 mg/m2BSA daily as a continuous infusion during 5 days) were given to 76 patients before radiotherapy and surgery. The aim of the study was to clarify the incidence and severity of adverse cardiac effects to this treatment. Before treatment all patients had a cardiac evaluation and during treatment serial ECG recordings were performed. In the pre-treatment evaluation, signs of cardiovascular disease were found in 33 patients (43%). During treatment, adverse cardiac effects were observed in 14 patients (18%). The mean age of these patients was the same as for the entire group, 64 years. The incidence of cardiotoxicity was not higher in patients with signs of cardiovascular disease than in those without in the pre-treatment evaluation. The most common signs of cardiotoxicity were chest pain, ST-T wave changes and atrial fibrillation. This was followed by ventricular fibrillation in one patient and sudden death in another. It is concluded that patients on 5-FU treatment should be under close supervision and that the treatment should be discontinued if chest pain or tachyarrhythmia is observed.

Reaction of the vascular system in the trachea of the rabbit exposed to fractionated irradiation with and without the addition of misonidazole.

As the radiation field used in the radiation therapy of malignancies in the thoracic cavity often exposes the trachea to ionizing irradiation, it is important to ascertain the effects of radiation on this tissue either as a single therapy or in combination with radiosensitizers. In the study reported here the vascular area in the subepithelial layer of the trachea has been calculated in 160 rabbits treated in four ways: (1) 10 rabbits received no treatment and served as controls; (2) 50 rabbits were given 100 mg misonidazole daily on consecutive days, with the individual total dose ranging from 100 to 1000 mg; (3) 50 rabbits were treated with misonidazole in the same way, but were also exposed to radiation (2 Gy/F) at 15-30 min later; (4) 50 rabbits received only fractionated radiation (2 Gy/F). The total radiation dose in the irradiated animals ranged from 2 to 20 Gy. In the treated groups, an oedema was observed in both the ciliary cell layer and in the subepithelial area. In the group given only irradiation, this oedema was dose-dependent, but no such dose-dependency was observed in the two groups treated with misonidazole. The vascular area in the groups treated with misonidazole was significantly increased as compared with the group given only irradiation and the control group; this was valid both with and without correction for the oedema. There was a significant correlation between the oedema and the vascular area in the groups treated with misonidazole, which was not found in the group irradiated without the drug.

Scanning electron microscopy and transmission electron microscopy of the ciliated cells of the trachea of the rabbit treated with misonidazole alone and in combination with ionizing radiation.

The trachea is often located in the treatment volume when irradiating malignant tumours in the thorax. In order to evaluate possible synergism between misonidazole and irradiation on this tissue, the following studies were made. Fifty rabbits were treated with daily injections of 100 mg misonidazole given i.p. on consecutive days from 1 to 10 days. Morphological investigations of the trachea were made with scanning electron microscopy (SEM), transmission electron microscopy (TEM) and light microscopy (LM). Physiological examinations were performed with recording of the ciliary beat frequency. The results were compared with those from a group of 100 rabbits given misonidazole in a similar manner and exposed to irradiation (2 Gy) 15-30 min after each injection. Ten rabbits were used as controls. The results are compared to the effect of fractionated irradiation alone with 2 Gy/day. Fractionated irradiation of the ciliary epithelium in the trachea of the rabbit has shown dose-dependent physiological and morphological effects. Misonidazole potentiates these effects of radiation with a more pronounced change of the ciliary beat frequency and an increased metabolic activity as could be visualized on TEM. The combination of drug and irradiation also induced a hyperplasia of the ciliary epithelium. Misonidazole itself had no effect on the ciliary beat frequency, but caused a hypoplasia of the ciliary epithelium.

The prognostic value of body protein in patients with lung cancer.

Lung cancer is a major cause of death in many countries. To improve the results of treatment, more individualized therapy is necessary; for this, it is necessary to identify new prognostic factors. In 21 patients with lung cancer (17 with non-small-cell lung cancer and 4 with small-cell lung cancer) that had received radiation treatment, the amount of body protein was estimated with in vivo neutron activation analysis. Patients in whom body protein decreased had recurrences of the disease earlier and a poorer survival than patients whose body protein increased. A clear relationship was seen between changes in the body's protein content and recurrence-free survival. To better evaluate the prognostic value of body protein content in patients with lung cancer, a larger number of patients and a longer follow-up period are needed.

Small cell carcinoma of the oesophagus: a clinical and immunohistopathological review.

Primary small cell carcinoma of the oesophagus (SCCO), histologically indistinguishable from its counterpart of the lung, is a rare tumour. Less than 100 cases are reported. A review of 558 consecutive patients with oesophageal carcinomas referred to our department revealed seven cases. These were studied and compared to a survey of 80 cases collected from 24 reports. The present results, as well as the survey, indicate a poor prognosis with rapid and widespread dissemination, and that death is attributed to distant metastases rather than local failure. Freedom from local symptoms was achieved in all seven patients, regardless of therapy modalities employed. A complete response of the primary lesion was observed in three patients after chemo- and subsequent radiotherapy. According to these findings the most suitable treatment approach seems to be the same as for small cell carcinoma of the lung. A detailed immunohistochemical analysis revealed more characteristics similar to small cell carcinoma of the lung than that of the skin, viz 'Merkel cell carcinoma'.

Malignant melanoma of the nasal cavity and nasopharynx treated with cisplatin and accelerated hyperfractionated radiation.

Primary malignant melanoma of the nasal cavity and paranasal sinuses is an uncommon disease, accounting for only 0.5-2% of all malignant melanomas. The primary treatment has been surgery. The frequency of local recurrence is high and recurrence is also the major determinant of treatment failure. Here we report on six patients with locally advanced disease, four of whom were too advanced for surgery, who were treated with accelerated hyperfractionated radiation in combination with cis-platinum. Three of four patients treated for local recurrent disease achieved a local cure and died of disseminated disease after 9-21 months. One patient given preoperative cisplatin and radiation is still alive with no evidence of disease 34 months after the completion of treatment. The present protocol may be a useful approach to obtain local control with the possibility of long-term cure.

Pilocarpine treatment of xerostomia in head and neck patients.

We studied the effect of pilocarpine hydrochloride, a parasympathicomimetic agent, on major salivary gland output and subjective responses in 40 patients with salivary hypofunction. Pilocarpine increased salivary output or gave significant symptomatic relief in 21 of the 40 patients. The women fared better than the men. Side effects were uncommon, were generally mild, and caused no treatment interruption. These results indicate that pilocarpine is effective in relieving the signs and symptoms of postradiation xerostomia.

Effects of compression bandaging with or without manual lymph drainage treatment in patients with postoperative arm lymphedema.

We examined the effects of low stretch compression bandaging (CB) alone or in combination with manual lymph drainage (MLD) in 38 female patients with arm lymphedema after treatment for breast cancer. After CB therapy for 2 weeks (Part I), the patients were allocated to either CB or CB + MLD for 1 week (Part II). Arm volume and subjective assessments of pain, heaviness and tension were measured. The mean lymphedema volume reduction for the total group during Part I was 188 ml (p < 0.001), a mean reduction of 26% (p < 0.001). During Part II the volume reduction in the CB + MLD group was 47 ml (p < 0.001) and in CB group 20 ml. These differences were not significant (p = 0.07). A percentage reduction of 11% (p < 0.001) in the CB + MLD group and 4% in the CB group was significantly different (p = 0.04). In both the CB and the CB + MLD group, a decrease of feeling of heaviness (p < 0.006 and p < 0.001, respectively) and tension (p < 0.001 for both) in the arm was found, but only the CB + MLD group showed decreased pain (p < 0.03). Low stretch compression bandaging is an effective treatment giving volume reduction of slight or moderate arm lymphedema in women treated for breast cancer. Manual lymph drainage adds a positive effect.

Factors associated with the development of arm lymphedema following breast cancer treatment: a match pair case-control study.

We examined factors that may influence the development of arm lymphedema following breast cancer treatment including the specific mode of therapy, patient occupation and life style. Medical record data and a questionnaire were used to collect information after surgery concerning such issues as wound seroma, infection, adjuvant treatment, vessel string (phlebitis), body mass index, smoking habits and stress. Occupational workload was assessed after surgery whereas housework, exercise, hobbies and body weight were assessed both before and after surgery. Seventy-one breast cancer treated women with arm lymphedema lasting more than 6 months but less than 2 years were matched to women similarly treated for breast cancer but without arm lymphedema (controls). The matching factors included axillary node status, time after axillary dissection, and age. In the lymphedema group, there was a higher body mass index at time of surgery (p=0.03) as well at time of study (p=0.04). No differences were found in occupational workload (n=38) or housework, but the lymphedema group reduced their spare time activities including exercise after surgery compared with the controls (p<0.01). In conclusion, women treated for breast cancer with axillary node dissection with or without adjuvant radiotherapy could maintain their level of physical activity and occupational workload after treatment without an added risk of developing arm lymphedema. On the other hand, a higher BMI before and after operation increases the lymphedema risk.

Electron microscopy of squamous cell carcinoma of the head and neck.

Squamous cell carcinoma of the head and neck carries a bad prognosis. In order to achieve cure, the most important thing to attain is local tumour control. The main therapy available is external radiotherapy, which can be supplemented when necessary, with interstitial radiotherapy, chemotherapy and surgery. In this paper we have evaluated specimens, taken before therapy, from 35 patients with squamous cell carcinoma of the head and neck. Scanning electron microscopy (SEM) and transmission electron microscopy (TEM) analyses were made. With SEM, the parameters analysed were the amount and appearance of microvilli, filaments, and blood vessels. From TEM, scoring was made of the filaments, desmosomes, nuclei, nucleoli, mitochondria, and blood vessels. Scoring of the samples showed a difference between the group with recurrent disease (n = 10, Group 1) and the group with local tumor control (n = 25, Group 2) in regard to both blood vessels and intracellular filaments. No differences of the nuclei, nucleoli, or the mitochondria were observed.

Antithrombotic treatment in protection against thrombogenic effects of 5-fluorouracil on vascular endothelium: a scanning microscopy evaluation.

Cardiotoxicity is a serious side effect of treatment of malignant diseases with 5-fluorouracil (5-FU). The underlying pathophysiologic mechanism remains unclear but clinical data suggest that the endothelium of coronary arteries may be involved. Experimental studies indicate that the endothelium is especially susceptible to 5-FU and support the hypothesis that a thrombogenic effect of 5-FU, secondary to its direct toxic effect on the endothelium, is one of the pathophysiologic mechanisms behind 5-FU-induced cardiotoxicity. In the present study we evaluate the role of antithrombotic treatment with dalteparin as protection against the thrombogenic effect of 5-FU on the vascular endothelium in a rabbit model. The effects on the vascular endothelium of 5-FU, dalteparin, and the combination of these two substances were evaluated with scanning electron microscopy 1, 3, 7, 14, and 30 days after treatment and compared with a control group. Very severe damage to the endothelium was seen in 5-FU-treated animals, often leading to intima disruption and denudation of underlying structures, with accompanying platelet accumulation and fibrin formation. The most extensive damage was observed on Day 3 after treatment. The cytotoxic effect of 5-FU was partly reversible. The combination of 5-FU and dalteparin gave lower scores on Day 3 because of less evidence of thrombotic events. However, the reversibility of the endothelial damage was poorer in this group, as well as in the group that received dalteparin alone. The findings support the hypothesis that antithrombotic treatment with dalteparin can protect against the thrombogenic effect of 5-FU, secondary to its direct toxic effect on the vascular endothelium. However, the study indicates that dalteparin per se has a toxic effect on the endothelium that is different from that of 5-FU.

Body protein as a prognostic instrument for cancer patients?

Many cancer patients are affected by loss of appetite, weight loss and fatigue in the course of disease. These symptoms reduce the patients' quality of life, increase morbidity, and lessen tolerance to anti-tumor treatment. In some cases the symptoms are partly caused by various treatment modalities. The aim of this study was to investigate if radiotherapy affects the body weight and body protein of patients, and if changes in body protein have any clinical significance.