18F-FDG PET/CT Evaluation of Crizotinib and Lorlatinib Therapy in Metastatic ROS-1-Positive Non-Small Cell Lung Cancer.

ROS-1-positive non-small cell lung cancers (NSCLCs) are rare (approximately 1% of all NSCLCs) and require a first-line treatment by crizotinib. Crizotinib resistance is frequent within the first 12 months of treatment. Lorlatinib is a novel tyrosine kinase inhibitor of ROS-1 recently indicated for metastatic or locally advanced crizotinib-resistant NSCLC. We report the use of lorlatinib as second-line with a complete tumoral response after only 3 months of treatment. This case shows the major role of F-FDG PET/CT in treatment evaluation and monitoring targeted therapy in metastatic NSCLC.

Low-level laser therapy in treatment of chemoradiotherapy-induced mucositis in head and neck cancer: results of a randomised, triple blind, multicentre phase III trial.

BACKGROUND: Low-level laser therapy (LLLT) also called Photobiomodulation therapy (PBMT) could reduce oral mucositis (OM) incidence and severity in head and neck cancer patients treated by chemoradiotherapy, however randomised data about efficacy and safety are missing with curative dose 4 J/cm2. METHODS: This phase III trial was conducted in patients with oral cavity, or oro/hypopharyngeal cancers (stage III or IV). Patients were treated by lasertherapy on OM lesions grade ≥ 2 (4 J/cm2 or placebo), during chemoradiotherapy and until recovery. Severity of OM (incidence and duration of grades ≥3) was used as primary endpoint and blindly assessed. RESULTS: Among 97 randomised patients, 83 patients (85.6%) could be assessed finally (erroneous inclusions, chemoradiotherapy interruptions) and 32 patients had no lasertherapy because of unreachable OM lesions. Randomisation and population characteristics (sex ratio, age, chemoradiotherapy procedures, toxicities incidence) were still comparable between the two LLLT/PBMT groups. An acute OM (grade ≥ 3) was observed in 41 patients (49.4%): 23 patients (54.8%) of the active laser group versus 18 (43.9%) in the control group (modified intend to treat, p = 0.32). Median time before occurrence of OM ≥ grade 3 in half of the patients was 8 weeks in active laser group (vs. 9 weeks in control group). However, 95% of patients exhibited a very good tolerance of LLLT/PBMT. CONCLUSIONS: This study assessed LLLT/PBMT according to the Multinational Association of Supportive care in Cancer recommendations but lacked power. LLLT/PBMT was well tolerated with a good safety profile, which promotes its use in clinical routine for severe OM treatment. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01772706 . TITLE: Laser Mucite ORL: Effectiveness of Laser Therapy for Mucositis Induced by a Radio-chemotherapy in Head and Neck Cancer (LaserMucite). Study Start Date: October 2008. Primary Completion Date: October 2016. Responsible Party: Institut de Cancérologie de l'Ouest - Paul Papin. Principal Investigator: Eric Jadaud, M.D., Institut de Cancérologie de l'Ouest - Paul Papin. FUNDING: French Ministry of Health, French national funding scheme (PHRC 2008).

Biosimilar filgrastim treatment patterns and prevention of febrile neutropenia: a prospective multicentre study in France in patients with solid tumours (the ZOHé study).

BACKGROUND: The ZOHé study was a prospective, non-interventional, multicentre study in France to assess the use of biosimilar filgrastim Zarzio® (Sandoz filgrastim) in routine clinical practice in patients at risk of neutropenia-inducing chemotherapy (CT). METHODS: Patients ≥ 18 years undergoing CT for a malignant disease and with a first prescription for Zarzio® were enrolled in two cohorts according to tumour type: solid tumour or haematological malignancy; results from the solid tumour cohort are reported here. Analyses primarily described the prescription and use of Zarzio® in current practice, and also included identification of factors linked to prescription for primary prophylaxis and comparison of Zarzio® use in relation to European Organisation for Research and Treatment of Cancer (EORTC) guidelines. RESULTS: Responses were obtained from 125 physicians and 1179 patients with solid tumours, allowing robust statistical analysis of the data. Use of Zarzio® in clinical practice was relatively standardised and followed label indication. The patient profile was in line with EORTC guidelines for granulocyte colony-stimulating factor (G-CSF) febrile neutropenia (FN) prophylaxis, and the majority of patients had ≥ 1 EORTC factor(s) for increased risk of febrile neutropenia. Some patients (10.8%) received Zarzio® despite receiving CT regimens categorised in guidelines as low (< 10%) FN risk ('over prophylaxis'). Nearly half of patients' CT regimens did not have a recommended FN risk category. Zarzio® was commonly initiated as primary prophylaxis; initiation in Cycle ≥ 2 of the current line of CT was associated more with a history of neutropenia. The safety profile of Zarzio® was confirmed. CONCLUSIONS: Use of Zarzio® in routine clinical practice is generally in line with EORTC guidelines for prophylaxis of CT-induced neutropenia. Patient-related risk factors appear to be a stronger driver of clinicians' decision to initiate Zarzio® than CT risk category for FN. The intrinsic risk of FN associated with a specific CT protocol is often miscategorised by physicians. In contrast to earlier reports of underuse of G-CSF prophylaxis, over prophylaxis is observed in a small subgroup of patients with FN risk of < 10%.

Anti-tumour effect of low molecular weight heparin in localised lung cancer: a phase III clinical trial.

The anti-tumour and anti-metastatic properties of heparins have not been tested in patients with early stage cancer. Whether adjuvant low molecular weight heparin (LMWH) tinzaparin impacts the survival of patients with resected non-small cell lung cancer (NSCLC) was investigated.Patients with completely resected stage I, II or IIIA NSCLC were randomly allocated to receive subcutaneous tinzaparin 100 IU·kg-1 once a day for 12 weeks or no treatment in addition to standard of care. The trial was open-label with blinded central adjudication of study outcomes. The primary outcome was overall survival.In 549 patients randomised to tinzaparin (n=269) or control (n=280), mean±sd age was 61.6±8.9 years, 190 (34.6%) patients had stage II-III disease, and 220 (40.1%) patients received adjuvant chemotherapy. Median follow-up was 5.7 years. There was no significant difference in overall survival between groups (hazard ratio (HR) 1.24, 95% CI 0.92-1.68; p=0.17). There was no difference in the cumulative incidence of recurrence between groups (subdistribution HR 0.94, 95% CI 0.68-1.30; p=0.70).Adjuvant tinzaparin had no detectable impact on overall and recurrence-free survival of patients with completely resected stage I-IIIA NSCLC. These results do not support further clinical evaluation of LMWHs as anti-tumour agents.

NutriCancer: A French observational multicentre cross-sectional study of malnutrition in elderly patients with cancer.

OBJECTIVES: To compare the prevalence of malnutrition and nutritional management between elderly (≥70years old) and younger patients (<70years) with cancer. PATIENTS AND METHODS: This is a post-hoc analysis of NutriCancer 2012 study; a one-day cross-sectional nationwide survey conducted to assess malnutrition in adult patients with cancer in France. Patients diagnosed with cancer at the study date in both inpatient and outpatient settings were included. Data collection was performed by means of questionnaires completed by the physician, the patient and the caregiver. RESULTS: This post-hoc analysis compared 578 elderly patients (27.6%) vs. 1517 younger patients (72.4%). There were significant differences in cancer localization between the groups particularly in gastrointestinal cancer (27% in younger patients vs. 42% in elderly), breast cancer (17% vs 8% in elderly) and oropharyngeal (15% vs. 9% in elderly). Weight loss was significantly more reported in the elderly than in younger patients (73.6% vs. 67.6%, p=0.009). Elderly patients were more frequently malnourished than younger patients (44.9% vs. 36.7%, p=0.0006). Food intake was comparable between the groups; however, physicians overestimated the food intake, particularly in the elderly. The malnutrition management was more frequently proposed in elderly, as dietary advice and oral nutritional supplements, than in younger patients; however, enteral nutrition was significantly less undertaken in the elderly. CONCLUSION: Malnutrition is prevalent in elderly patients with cancer, and more frequent than in younger patients. There is a need for an early integration of the nutritional counselling in patients with cancer, and particularly in the elderly.

18F-FDG PET/CT Evaluation of Ceritinib Therapy in Metastatic ALK-Positive Non-small Cell Lung Cancer.

Anaplastic lymphoma kinase (ALK)-positive non-small cell lung cancers (NSCLC) account for 3% to 7% of all NSCLC and require a standard treatment by crizotinib. However, crizotinib resistance is frequent within the first 12 months of treatment. Ceritinib is a novel tyrosine kinase inhibitor of ALK recently introduced in France for metastatic or locally advanced crizotinib-resistant ALK NSCLC. We report the first use of ceritinib in our institution with a spectacular tumoral response after only 3 months of treatment. This case demonstrates the major role of F-FDG PET/CT for monitoring the effectiveness of this new treatment.

Incidental gastrointestinal 18F-Fluorodeoxyglucose uptake associated with lung cancer.

BACKGROUND: F-Fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT) is increasingly used for the initial staging and restaging of lung cancer. Incidental gastrointestinal findings are often observed on (18)F-FDG PET/CT. The objective of this study was to assess incidental 18F-FDG uptake by the gastrointestinal tract (GIT) in patients with lung cancer. METHODS: Two hundred thirty consecutive 18F-FDG PET/CT examinations performed for lung cancer over a 3-year period were retrospectively reviewed for the presence of incidental FDG uptake in the GIT. The charts of patients with positive FDG uptake were then reviewed and analysed to determine the GIT uptake sites, the standardized uptake value (SUV) max and the final clinical diagnosis. RESULTS: Fifty-two patients (52/230, 23%) demonstrated incidental FDG uptake in the GIT. Thirty-three patients (63.5%) had diffuse uptake (oesophagus, n = 2, colon, n = 31) and 19 patients (36.5%) had focal uptake (oesophagus, n = 1, small bowel, n = 1, ascending colon, n = 5, descending colon, n = 4, sigmoid, n = 4, rectum, n = 3, and anal margin, n = 1). Twelve of the 52 patients with GIT uptake were further investigated, revealing, a diagnosis of malignancy in 4 patients with focal FDG uptake. No significant differences in mean SUVmax were observed between patients with malignant and benign GIT diseases. CONCLUSION: This study demonstrates a high incidence of FDG uptake in the GIT associated with lung cancer. Focal GIT uptake was frequently associated with malignant disease. These results suggest that further GIT investigations should be performed in patients with focal GIT uptake.

Education and home based training for intermittent claudication: functional effects and quality of life.

BACKGROUND: Supervised exercise programs increase physical performance in patients with peripheral artery disease (PAD). However, there are a limited number of programs, and to date they have failed to provide evidence of long-term adherence to exercise or any meaningful effect on Quality of Life (QoL). We created a program of therapeutic education and a personalized program of reconditioning exercise for patients with PAD. METHODS: Patients with an ankle-brachial index (ABI) below 0.9 in at least one limb, and an absolute claudication distance (ACD) ≤500 meters, were included in the study. Quality of Life (QoL) as measured by SF-36, cardiovascular risk factors and functional parameters were evaluated at 0, 3, 6 and 12 months. RESULTS: Forty-six patients completed the program. Cardiovascular risks were controlled and stabilized over time. SF-36 scores improved significantly and remained stable. Initial and absolute claudication distance (ICD and ACD) as well as other functional parameters improved significantly (6 months: +138 m or +203% ICD and +139 m or +84% ACD). Ten patients (22%) did not show improvement in ICD or ACD within the first 3 months, but their SF-36 score did increase at subsequent visits. Interestingly, these patients had a significantly lower ACD at baseline. CONCLUSIONS: This study measured beneficial effects of an educational therapeutic program for patients with PAD. The results demonstrate a significant improvement in functional and QoL parameters during the first 3 months of coaching, and long-term persistence of the results even when patients were no longer coached.

Delay of airway epithelial wound repair in COPD is associated with airflow obstruction severity.

BACKGROUND: Airway epithelium integrity is essential to maintain its role of mechanical and functional barrier. Recurrent epithelial injuries require a complex mechanism of repair to restore its integrity. In chronic obstructive pulmonary disease (COPD), an abnormal airway epithelial repair may participate in airway remodeling. The objective was to determine if airway epithelial wound repair of airway epithelium is abnormal in COPD. METHODS: Patients scheduled for lung resection were prospectively recruited. Demographic, clinical data and pulmonary function tests results were recorded. Emphysema was visually scored and histological remodeling features were noted. Primary bronchial epithelial cells (BEC) were extracted and cultured for wound closure assay. We determined the mean speed of wound closure (MSWC) and cell proliferation index, matrix metalloprotease (MMP)-2, MMP-9 and cytokines levels in supernatants of BEC 18 hours after cell wounding. In a subset of patients, bronchiolar epithelial cells were also cultured for wound closure assay for MSWC analyze. RESULTS: 13 COPD and 7 non COPD patients were included. The severity of airflow obstruction and the severity of emphysema were associated with a lower MSWC in BEC (p = 0.01, 95% CI [0.15-0.80]; p = 0.04, 95% CI [-0.77;-0.03] respectively). Cell proliferation index was decreased in COPD patients (19 ± 6% in COPD vs 27 ± 3% in non COPD, p = 0.04). The severity of COPD was associated with a lower level of MMP-2 (7.8 ± 2 10(5) AU in COPD GOLD D vs 12.8 ± 0.13 10(5) AU in COPD GOLD A, p = 0.04) and a lower level of IL-4 (p = 0.03, 95% CI [0.09;0.87]). Moreover, higher levels of IL-4 and IL-2 were associated with a higher MSWC (p = 0.01, 95% CI [0.17;0.89] and p = 0.02, 95% CI [0.09;0.87] respectively). Clinical characteristics and smoking history were not associated with MSWC, cell proliferation index or MMP and cytokines levels. Finally, we showed an association of the MSWC of bronchial and corresponding bronchiolar epithelial cells obtained from the same patients (p = 0.02, 95% CI [0.12;0.89]). CONCLUSION: Our results showed an abnormal bronchial epithelial wound closure process in severe COPD. Further studies are needed to elucidate the contribution and the regulation of this mechanism in the complex pathophysiology of COPD.

Validation of a new bedside echoscopic heart examination resulting in an improvement in echo-lab workflow.

BACKGROUND: In daily cardiology practice, porters are usually required to transfer inpatients who need an echocardiogram to the echocardiographic department (echo-lab). AIMS: To assess echo-lab personnel workflow and patient transfer delay by comparing the use of a new, ultraportable, echoscopic, pocket-sized device at the bedside with patient transfer to the echo-lab for conventional transthoracic echocardiography, in patients needing pericardial control after cardiac invasive procedures. METHODS: After validation of echoscopic capabilities for pericardial effusion, left ventricular function and mitral regurgitation grade compared with conventional echocardiography, we evaluated echo-lab personnel workflow and time to perform bedside echoscopy for pericardial control evaluation after invasive cardiac procedures. This strategy was compared with conventional evaluation at the echo-lab, in terms of personnel workflow, and patients' transfer, waiting and examination times. RESULTS: Concordance between echoscopy and conventional echocardiography for evaluation of pericardial effusion was good (0.97; kappa value 0.86). For left ventricular systolic function and mitral regurgitation evaluations, concordances were 0.96 (kappa value 0.90) and 0.96 (kappa value 0.86), respectively. In the second part of the study, the mean total time required in the bedside echoscopy group was 20.3±5.4 mins vs. 66.0±16.4 mins in the conventional echo-lab group (p<0.001). The echo-lab strategy needed porters in 100% of cases; 69% of patients needed a wheelchair. CONCLUSION: The use of miniaturized echoscopic tools for pericardial control after invasive cardiac procedures was feasible and accurate, allowing improvement in echo-lab workflow and avoiding patient waiting time and transfer.

Detection of drug-resistance genes using single bronchoscopy biopsy specimens.

Expression of three major resistance genes MDR1, MRP1 and LRP was investigated in small cell lung cancer, non-small cell lung cancer and metastasis. Single biopsies of bronchoscopy from 73 patients were performed to investigate expression of these three resistance genes by reverse transcriptase-polymerase chain reaction. Relations between gene expression and patient age, smoking status, histology, and chemotherapy were evaluated. A more frequent expression of MDR1 (77 versus 66%), MRP1 (91 versus 72%) and LRP (77 versus 63%) genes was detected in the malignant biopsies than in the non-malignant, respectively. In the metastasis biopsies, expression of these genes was markedly increased. No significant difference was observed between specimens before and after chemotherapy. Biopsies from progressing cancer showed higher MDR1, MRP1 and LRP gene expression. In conclusion, these data reveal a major role of MRP1 in intrinsic resistance and the high gene expression of MDR1 and MRP1 in relapsed diseases.

Estimates of work-related cancers in workers exposed to carcinogens.

AIM: To evaluate the proportion of work-related cancers. METHODS: A descriptive study of incident cases of cancer during 3 years in a French county. All people with cancer having a current or past working history were included in the studied population which was recruited from local hospitals. A working history was obtained from each subject by interview. The different organ cancers were linked using well-defined criteria, to specific occupational carcinogenic exposures. The results obtained were compared to international data on work-related cancer incidences. RESULTS: A total of 2009 cases were included and 3.18% (64) met the criteria for work-related cancer as defined. Asbestos and polycyclic hydrocarbons were the main occupational carcinogens identified. Construction and fabricated metal products sectors were linked to almost two-thirds of work-related cancers. The percentage of the studied population with attributable risk for occupational cancer was relatively close to international data (mean 4%) and organ cancer distribution percentages did not vary significantly from international published validated data. CONCLUSION: Work-related cancers tend to be concentrated in relatively small groups of people among whom the risk of developing the disease may be quite large. The detection of occupational hazards should therefore have a higher priority in any programme of cancer prevention. Well-defined criteria to identify specifically cancers with an occupational origin should be specified by the scientific international community.

Nicotine induces chromatin changes and c-Jun up-regulation in HL-60 leukemia cells.

Although nicotine has been implicated as a potential factor in the pathogenesis of human cancer, its mechanisms of action regarding cancer development remain largely unknown. HL-60 cells were used to investigate the effects of a short-term treatment with nicotine at concentrations found in the blood of smokers. The findings show that nicotine induces chromatin decondensation, histone H3 acetylation and up-regulation of the c-Jun transcription factor mRNA. This increase is inhibited by mecamylamine, a nicotinic receptor antagonist, suggesting that nicotine alters cellular function directly via nicotinic acetylcholine receptors and may then play a role in cell physiology and tumor promotion.

A randomized trial between two neoadjuvant chemotherapy protocols: CDDP + 5-FU versus CDDP + VP16 in advanced cancer of the head and neck.

We investigated a phase III randomized trial to compare efficacy and tolerance of CDDP + 5-FU to CDDP + VP16, both given intravenously in patients with unresectable advanced head and neck cancer. The 197 eligible patients were paired off successively on the basis of tumor sites and UICC stage. Comparisons were made through sequential closed plans. In 179 patients, tumor beds and cervical lymph nodes were irradiated, and 20 patients underwent salvage surgical procedures. Cisplatin plus 5-fluorouracil showed a response (CR + PR) rate of 15% greater than that observed with cisplatin plus etoposide (alpha=0.05, power 70%). Complete responses played a major role in the CDDP + 5-FU regimen. Furthermore, we noted a higher cervical node regression with this chemotherapy combination. Because radiotherapy was administered after chemotherapy, we could not analyze the mean duration response for each protocol. No significant difference in survival existed between the two groups. Myelosuppression was the most frequent sign of toxicity observed, especially with the CDDP + VP16 regimen. Mucositis was rare with allopurinol protection. In the CDDP + 5-FU group, one patient had grade 4 cardiac dysfunction, and 3 patients exhibited unconsciousness that may be related to cerebral vascular damage. Thirteen patients died, with 8 cases related to septic shock (5 CPPP + VP16 and 3 CDDP + 5-FU). Cisplatin plus 5-FU chemotherapy showed a satisfactory efficacy and acceptable toxicity profile compared with CDDP + VP16, with caution to patients with a cardiac or vascular history. Although we could not show a benefit in survival with the CDDP + 5-FU protocol, this trial supports literature data and confirms that this regimen may be proposed as a first-line therapy in advanced cancer of the head and neck.

Prevalence of Chlamydia pneumoniae infection in squamous cell carcinoma of the head and neck.

On the basis of epidemiological data, an association between Chlamydia pneumoniae (Cp) infection and head and neck cancer might be suggested. The aim of the present study was to detect Cp-DNA within tumour tissue specimens by a two-step polymerase chain reaction. Investigation was planned on the Fleming's procedure for early termination when initial results were extreme. So, after ten consecutive patients, only one tumour contained Cp-DNA. Hence the prevalence could be regarded as inferior to 60% (2a=b=0.08), the threshold under which a direct role of Cp in head and neck cancer development does not seem to be likely.

Endobronchial brachytherapy in combination with external beam irradiation in obstructing malignant bronchial tumors.

Endobronchial brachytherapy is commonly used in the palliative management of malignant airway obstructions. In the present study, we describe the results of brachytherapy (mean dose of 18 Gy), used in combination with external beam irradiation (mean dose of 50 Gy) in 30 patients who had primary bronchogenic carcinoma of the lung. The extent of airway obstruction was determined according to symptoms and by bronchoscopy. We found symptoms improved in nearly 37% of patients and 21 of 30 patients (70%), evaluated with bronchoscopy, showed a response when evaluated 3 to 6 months after brachytherapy. This endobronchial technique appeared to be a well-tolerated procedure with a low rate of acute toxicity. The immediate complication rate was 13%, during the follow-up 3 deaths were related to treatment, of which 2 were fatal haemoptysis (12 and 18 months after irradiation). We conclude that the combination of endobronchial brachytherapy with external beam irradiation may be useful and needs further comparisons with other irradiation procedures.

Role of beta 1- and beta 2-adrenoceptor subtypes in preconditioning against myocardial dysfunction after ischemia and reperfusion.

Using an isolated nonworking rat heart model, this study investigated the role of beta-adrenergic preconditioning (beta-PC) to attenuate myocardial dysfunction after an ischemia/reperfusion injury. After a 20-min stabilization period, the noradrenaline depleted hearts were perfused for 5 min with isoproterenol (ISO) before 40-min global ischemia (I) followed by 30-min reperfusion (R). ISO 0.02 microM provided significant protection versus unconditioned in vivo reserpinized IR control, causing a decrease of creatine kinase (CK) release (mIU/min/g wet weight) on reperfusion in coronary effluent, a preservation of the mean coronary flow (MCF) and preservation of left ventricular function assessed by the rate-pressure product (RPP). These beneficial effects were similar to those of ischemic preconditioning (I-PC) in both nonreserpinized and reserpinized rats. Propranolol (1 microM) and atenolol (10 microM) completely suppressed the ISO preconditioning. In contrast, ICI 118551 (2 microM) a highly selective beta -blocker, did not blunt the salutary effects of ISO on CK release and MCF preservation. These results indicate that ISO pretreatment provides a significant cardioprotection against prolonged ischemic myocardial injury. Although endogenous catecholamines are not necessary for I-PC in isolated rat hearts, cardioprotection provided by beta-adrenergic stimulation is quite similar to I-PC. This significant cardioprotection is mediated less by beta -adrenoceptor than by beta -adrenoceptor activation, which seems to play a crucial role in the beta-PC mechanism.

New approach to pre-therapeutic prognosis in advanced squamous cell carcinoma of the head and neck.

The Bleomycin (BLM)-induced apoptosis in peripheral blood mononuclear cells (PBMC), from patients with advanced squamous cell carcinoma of the head and neck (SCCHN), cultured in vitro with PHA, was tested as a predictive indicator of the survival time. The rates of the PBMC BLM-induced apoptosis and of the cycling-PBMCs, measured respectively after Giemsa- and Feulgen-staining were determined in 25 patients before induction chemotherapy. By using the Cox model, the survival probability was significantly and independently increased for a high percentage of PBMC BLM-induced apoptosis and a high rate of cycling PBMCs. (Chi-2(2): 10; p=0.007). Six patients, in whom both PBMC variables were simultaneouly greater than the median values, showed a median survival time as long as 60 months versus 10 months for the other 19. Conclusively, the PBMC susceptibility to BLM-induced apoptosis as well as the PBMC capability for cycling may be regarded as independent pretherapeutic prognosis factors for patients with advanced SCCHN.