Final results of the IFCT-0803 study, a phase II study of cetuximab, pemetrexed, cisplatin, and concurrent radiotherapy in patients with locally advanced, unresectable, stage III, non-squamous, non-small-cell lung cancer.

PURPOSE: Roughly 20% of patients with non-small-cell lung cancer exhibit locally advanced, unresectable, stage III disease. Concurrent platinum-based chemoradiotherapy is the backbone treatment, which is followed by maintenance immunotherapy, yet with poor long-term prognosis. This phase II trial (IFCT-0803) sought to evaluate whether adding cetuximab to cisplatin and pemetrexed chemoradiotherapy would improve its efficacy in these patients. MATERIALS AND METHODS: Eligible patients received weekly cetuximab (loading dose 400mg/m2 day 1; subsequent weekly 250mg/m2 doses until two weeks postradiotherapy). Chemotherapy comprised cisplatin (75mg/m2) and pemetrexed (500mg/m2), both delivered on day 1 of a 21-day cycle of maximally four. Irradiation with maximally 66Gy started on day 22. Disease control rate at week 16 was the primary endpoint. RESULTS: One hundred and six patients were included (99 eligible patients). Compliance exceeded 95% for day 1 of chemotherapy cycles 1 to 4, with 76% patients receiving the 12 planned cetuximab doses. Maximal grade 3 toxicity occurred in 63% patients, and maximal grade 4 in 9.6%. The primary endpoint involving the first 95 eligible patients comprised two (2.1%) complete responses, 57 (60.0%) partial responses, and 27 (28.4%) stable diseases. This 90.5% disease control rate (95% confidence interval [95% CI]: 84.6%-96.4%) was achieved at week 16. After median 63.0-month follow-up, one-year and two-year survival rates were 75.8% and 59.5%. Median overall survival was 35.8months (95% CI: 23.5-NR), and median progression-free survival 14.4months (95% CI: 11.2-18.8), with one-year and two-year progression-free survival rates of 57.6% and 34.3%. CONCLUSION: These survival rates compare favourably with published data, thus justifying further development of cetuximab-based induction chemoradiotherapy.

[Primary non-small-cell lung cancer: analysis of 419 T1 (

T1 tumors have the best prognosis among primary non-small-cell lung cancers, basically because surgery is generally possible. Among 5.667 patients with primary lung cancer included in the KBP-2000-CPHG study, we examined the characteristics of 419 T1 tumors, i.e. 9.2% of the non-small-cell cancers. Compared with the group of patients with non-T1 tumors, patients with T1 tumors were younger (p=0.0007). They had an equivalent percentage of squamous-cell tumors but more adenocarcinomas (40.3% versus 35.5%, p=0.05). TNM staging showed that 27.6% of the T1 tumors were metastatic at diagnosis (stage IV) with 12.4% T1N0M1 nad 15.2% T1N1-3M1. For the M0 tumors, 52.2% were T1N0 (stage IA) and 20.1% were T1N1-3. Squamous-cell tumors were significantly more frequent among the T1M1 tumors (p=0.07). More than one quarter (27.6%) of the T1 tumors were in stage IV, pointing out the importance of the initial work-up. This findings suggests we should revisit strategies in order to take into account new diagnostic possibilities. Likewise for the therapeutic strategy. Combinations using chemotherapy, surgery and radiotherapy should be better defined for this group of tumors.

[Lung volume reduction surgery in emphysema]. / Chirurgie de réduction de volume dans l'emphysème.

Lung volume reduction surgery in emphysema has, as an objective, the reduction of dyspnoea and an increase in the exercise tolerance in patients with respiratory insufficiency suffering from diffuse emphysema. In principle the resection of the most diseased areas of emphysema leads to improvement in the mechanical properties of the emphysematous lung and correct pulmonary hyperinflation. The respiratory function benefits both objective and subjective, produced by surgery are real but transitory and inconstant depending in particular on the evolutionary profile of the emphysematous disease. The indications should be further refined and an objective comparison of different surgical techniques has not been achieved. The impact on the quality of life for these patients is unknown.

Progressive obstructive lung disease associated with microscopic polyangiitis.

Small airway involvement and progressive severe airflow obstruction are unexpected features in patients with microscopic polyangiitis. We report the case of a patient with microscopic polyangiitis and circulating anti-neutrophil cytoplasmic antibodies (ANCA), who developed pulmonary hyperinflation and airflow obstruction over a 7-yr period. Systemic manifestations of this vasculitis improved under corticosteriods and cyclophosphamid therapy, a treatment that did not influence either the very high level of anti-myeloperoxidase antibodies or the ventilatory impairment. Small airway involvement was suspected on the basis of pathologic small airway lesions and a mild emphysematous pattern on computed tomography (CT) scan, which was out of proportion with the severity of the obstructive lung disease.

[Pulmonary emphysema: surgical indications]. / Emphysème pulmonaire: indications chirurgicales.

Surgery for pulmonary emphysema, with the exception of lung transplantation, is limited at present to resection of the emphysematous areas. The resection of a unique bulla within an otherwise healthy parenchyma can be indicated in case of complications but rarely in asymptomatic patients. When the bullae are large (i.e. volume greater than one-third of the hemithorax) in a patient suffering from diffuse emphysema, bullectomy is the ideal indication. Mortality varies from 0 to 10%, essentially due to infection or acute respiratory failure. In most patients, the subjective improvement in terms of dyspnea and the objective improvement as measured by spirometry remains significative up to 5 years after surgery. Inversely, surgical resection is classically considered to be contraindicated in patients with small poorly-limited bullae. Recent data would however question this idea since subjective and objective improvement after reduction of the lung volume is still present 1 year after surgery in most patients, even those with severe obstruction. The mechanism is probably related to increased elastic recoil. Even if only temporary improvement can be achieved for a few years, the persisting course of emphysema would suggest that volume reduction should always be entertained as an alternative before lung transplantation.

Refractory hypoxemia during liver cirrhosis. Hepatopulmonary syndrome or "primary" pulmonary hypertension?

We report an uncommon mechanism of severe hypoxemia in two cirrhotic patients under long-term beta-blocker therapy. Our patients presented with profound hypoxemia refractory to oxygen therapy, normal lung radiography and pulmonary function tests, and evidence of right-to-left anatomic shunt. Although these features are highly suggestive of hepatopulmonary syndrome, pulmonary hypertension was present, and a right-to-left shunt through a patent foramen ovale was demonstrated by contrast-enhanced echocardiography. No cause of pulmonary hypertension other than portal hypertension was identified. Pulmonary hypertension and intracardiac right-to-left shunt eventually regressed after discontinuation of beta-blocker therapy. We conclude that "primary" pulmonary hypertension associated with portal hypertension may because of severe hypoxemia during liver cirrhosis. Differential diagnosis of hepatopulmonary syndrome relies upon contrast-enhanced echocardiography and may be of critical importance because of possible therapeutic implications.

Clinical significance of the pulmonary vasodilator response during short-term infusion of prostacyclin in primary pulmonary hypertension.

BACKGROUND: The short-term vasodilator response to prostacyclin (PGI2) in patients with primary pulmonary hypertension (PPH) is not only unpredictable but also extremely variable in magnitude. In this retrospective study, we attempted to evaluate in a nonselected population of patients with PPH the degree of vasodilatation achieved during short-term infusion of PGI2 and to investigate whether patients with PPH differed in terms of baseline characteristics and prognoses, according to the level of vasodilatation achieved during initial testing with PGI2. METHODS AND RESULTS: Between 1984 and 1992, 91 consecutive patients with PPH underwent catheterization of the right side of the heart with a short-term vasodilator trial with PGI2 (5 to 10 ng.kg-1.min-1). According to the level of vasodilatation achieved during PGI2 infusion, patients were divided into three groups: nonresponding (NR, n = 40), moderately responding (MR, n = 42), and highly responding (HR, n = 9) patients. All three groups were defined by a decrease in total pulmonary resistance index (TPRi) of < 20%, between 20% and 50%, and > 50%, respectively, relative to control values. Prolonged oral vasodilator therapy was subsequently started only in MR and HR patients. All patients had long-term oral anticoagulant therapy. The survival rate at 2 years (transplant recipients excluded) was significantly higher in HR patients compared with NR and MR patients (62% versus 38% and 47% survivors, respectively; P < .05). Comparisons between groups showed no significant differences in baseline hemodynamics or clinical characteristics except for a longer time between onset of symptoms and diagnosis (ie, first catheterization) of PPH in HR patients than in NR and MR patients (71 +/- 61 versus 35 +/- 34 and 21 +/- 21 months, respectively; P < .05). CONCLUSIONS: In this study, patients with PPH exhibiting a decrease in TPRi > 50% during short-term PGI2 challenge at the time of diagnosis had longer disease evolutions and better prognoses than patients with a lower vasodilator response.

Mucosal T-lymphocytes in central airways of lung transplant recipients.

The immunohistochemical profile of mucosal lymphocytes was investigated in the central airways of lung transplant recipients. Bronchial and transbronchial biopsies (BB and TBB, respectively) and bronchoalveolar lavage for culture of bacteria and viruses were performed during a fibroscopic procedure in patients without evidence of chronic rejection, 3 to 10 mo after surgery. Analysis was restricted to samples without concurrent airway infection: 23 pairs of BB and TBB from 18 transplant recipients were analyzed. An immunohistochemical technique was used to identify and score mucosal cells that reacted with monoclonal antibodies against CD4, CD8, CD45-Ro (memory T-cells), and HLA-DR molecules. The same procedure was applied in nine nonsmoking control subjects (NS group). Data from transplant recipients were allocated to R+ (n = 11) or R- groups (n = 12), depending on the presence or absence of histologic evidence of acute rejection on TBB. A statistically significant depletion of every immunoreactive cell subset was observed in the R+ and the R- groups, but not in the NS group. Conversely, no significant difference for either score of immunoreactive cells were found between R+ and R- groups. The immunosuppressive regimen is suspected to play to play a major role in this depletion of bronchial mucosal T-cells. The acute lung rejection process does not appear to affect concurrently the immunohistochemical profile of immunoreactive cells in the bronchial mucosa.

Pulmonary reimplantation response in single-lung transplantation.

We studied the characteristics of the pulmonary reimplantation response (PRR) in single-lung transplantation (SLT), and detailed the occurrence, evolution, prognosis and risk factors of this complication. Forty single-lung transplant recipients were studied. Twenty four patients developed hypoxaemia and allograft infiltrates consistent with the PRR. In 40% of the cases hypoxaemia was severe, precluding weaning and requiring prolonged mechanical ventilation with high fractional inspiratory oxygen (FIO2). The mean duration of ventilation was 7 days (range 1-19 days). Clearing of the chest radiographs was progressive, with complete resolution between 6 and 21 days. In all cases, the pulmonary arterial wedge pressure was normal (6 +/- 2 mmHg) suggesting low pressure oedema. Sampling of the pulmonary oedema fluid revealed that the ratio of protein concentration in oedema fluid to that in serum exceeded 0.5. In patients with severe PRR (40% of cases) clinical, radiographic and haemodynamic abnormalities were identical to adult respiratory distress syndrome (ARDS), but the prognosis was more favourable with no death directly related to PRR in our patients. The mean duration of graft ischaemia of the oedematous grafts (241 +/- 103 min) was significantly longer than that of nonoedematous grafts (155 +/- 71 min). These date suggest that prolongation of graft ischaemia increased the incidence of PRR.

[Single-lung transplant in chronic obstructive disease]. / Greffes monopulmonaires chez les obstructifs chroniques.

The feasibility and the good immediate acceptability of unilateral lung transplants in the patients with obstructive respiratory problems have recently been demonstrated and since the initial reports, some hundreds of lung transplants have been performed in various parts of the world for this indication. Nevertheless, few results of respiratory function are currently available in the medium term. We report these in a series of 20 patients with severe obstruction who were given single lung transplants. The actual probability of survival for 1 and 2 years was 75 and 70% respectively with 4 peri-operative deaths and 2 later deaths. In the 16 survivors of more than 6 months, in relation to the pre-operative values, a significant improvement was observed 3 months after the graft in the FEV1 which rose from 17 +/- 6 to 53 +/- 13% of the predicted values. The PaO2 rose from 52 +/- 10 to 81 +/- 3 mmHg. The distance covered on the six minute walking test went from 99 +/- 84 m before the graft to 587 +/- 147 m 6 months after the operation. In addition to the improved distance, the lung function was stable in a group of patients as the months went by, although there was a fall in the respiratory function in others with the appearance of the syndrome of bronchiolitis obliterans or in 2 patients with bronchial complications. The four patients with severe deterioration in the graft function were re-transplanted with a good clinical result in three of them, the fourth dying in the immediate post-operative period. We conclude that single lung transplant represents an effective treatment both in the short and medium term in patients with chronic airflow obstruction.

[Severe acute asthma in adults]. / Asthme aigu grave de l'adulte.

Despite a better understanding of the physiopathology of asthma and the availability of potent drugs, severe acute asthma is still a frequent cause of death (1500 to 2000 patients die each year of asthma in France). Among the different clinical presentations, hyperacute attack with an attack duration (period from onset of attack to mechanical ventilation or to fatality) of less than 3 hours has to be individualized. The agents of choice in the treatment of acute life-threatening asthma are oxygen, beta-adrenergic sympathomimetic amines given intravenously or by nebulization, and corticosteroids. Theophylline is not any more the first choice of treatment but should not be rejected. Anticholinergics given by nebulization in combination with sympathomimetic agents are effective. Beside these treatment, hydratation and antibiotics are important adjunctive treatment. Mechanical ventilation is rarely necessary but has to be instituted either in emergency in case of near fatal asthma or electively because of deterioration of clinical status and blood gases, despite full medical treatment.