Metabolic tumor volume predicts outcome in patients with advanced stage follicular lymphoma from the RELEVANCE trial.

BACKGROUND: We investigated the prognostic value of baseline positron emission tomography (PET) parameters for patients with treatment-naïve follicular lymphoma (FL) in the phase III RELEVANCE trial, comparing the immunomodulatory combination of lenalidomide and rituximab (R2) versus R-chemotherapy (R-chemo), with both regimens followed by R maintenance therapy. PATIENTS AND METHODS: Baseline characteristics of the entire PET-evaluable population (n = 406/1032) were well balanced between treatment arms. The maximal standard uptake value (SUVmax) and the standardized maximal distance between tow lesions (SDmax) were extracted, the standardized distance between two lesions the furthest apart, were extracted. The total metabolic tumor volume (TMTV) was computed using the 41% SUVmax method. RESULTS: With a median follow-up of 6.5 years, the 6-year progression-free survival (PFS) was 57.8%, the median TMTV was 284 cm3, SUVmax was 11.3 and SDmax was 0.32 m-1, with no significant difference between arms. High TMTV (>510 cm3) and FLIPI were associated with an inferior PFS (P = 0.013 and P = 0.006, respectively), whereas SUVmax and SDmax were not (P = 0.08 and P = 0.12, respectively). In multivariable analysis, follicular lymphoma international prognostic index (FLIPI) and TMTV remained significantly associated with PFS (P = 0.0119 and P = 0.0379, respectively). These two adverse factors combined stratified the overall population into three risk groups: patients with no risk factors (40%), with one factor (44%), or with both (16%), with a 6-year PFS of 67.7%, 54.5%, and 41.0%, respectively. No significant interaction between treatment arms and TMTV or FLIPI (P = 0.31 or P = 0.59, respectively) was observed. The high-risk group (high TMTV and FLIPI 3-5) had a similar PFS in both arms (P = 0.45) with a median PFS of 68.4% in the R-chemo arm versus 71.4% in the R2 arm. CONCLUSIONS: Baseline TMTV is predictive of PFS, independently of FLIPI, in patients with advanced FL even in the context of antibody maintenance.

Risk stratification in diffuse large B-cell lymphoma using lesion dissemination and metabolic tumor burden calculated from baseline PET/CT†.

BACKGROUND: We analyzed the prognostic value of a new baseline positron emission tomography (PET) parameter reflecting the spread of the disease, the largest distance between two lesions (Dmax). We tested its complementarity to metabolic tumor volume (MTV) in a large cohort of diffuse large B-cell lymphoma (DLBCL) patients from the REMARC trial (NCT01122472). PATIENTS AND METHODS: MTVs were defined using the 41% maximum standardized uptake value threshold. From the three-dimensional coordinates, the centroid of each lesion was automatically obtained and considered as the lesion location. The distances between all pairs were calculated. Dmax was obtained for each patient and normalized with the body surface area [standardized Dmax (SDmax)]. RESULTS: From the REMARC trial, 290 patients aged 60-80 years were included: 91% had an advanced stage and 71% International Prognostic Index (IPI) ≥3. High versus low SDmax significantly impacted progression-free survival (PFS) (P < 0.0001) and overall survival (OS) (P = 0.0027). Patients with SDmax > 0.32 m-1 (n = 82) had a 4-year PFS and OS of 46% and 71%, respectively, against 77% and 87%, respectively, for patients with low SDmax. High SDmax and high MTV were independent prognostic factors of PFS (P = 0.0001 and P = 0.0010, respectively) and OS (P = 0.0028 and P = 0.0004, respectively). Combining MTV and SDmax yielded three risk groups with no (n = 109), one (n = 122) or two (n = 59) factors (P < 0.0001 for both PFS and OS). The 4-year PFS were 90%, 63%, 41%, respectively, and the 4-year OS were 95%, 79%, 66%, respectively. In addition, patients with at least two of the three factors including high SDmax, high MTV, Eastern Cooperative Oncology Group (ECOG) ≥2 had a higher number of central nervous system relapse (P = 0.017). CONCLUSIONS: SDmax is a simple feature that captures lymphoma dissemination, independent from MTV. These two PET metrics, SDmax and MTV, are complementary to characterize the disease, reflecting the tumor burden and its spread. This score appeared promising for DLBCL baseline risk stratification.

FDG-PET-driven consolidation strategy in diffuse large B-cell lymphoma: final results of a randomized phase 2 study.

Dose-dense induction and up-front consolidation with autologous stem cell transplantation (ASCT) remain controversial issues when treating patients with high-risk diffuse large B-cell lymphoma. GELA designed a randomized phase 2 trial evaluating the efficacy of either rituximab, doxorubicin, cyclophosphamide, vindesine, bleomycin, prednisone (R-ACVBP) or rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone (R-CHOP14) induction and a positron emission tomography (PET)-driven ASCT or standard immunochemotherapy (SIC) consolidation in age-adjusted international prognosis index 2 (aaIPI2)-aaIPI3 patients. PET was performed at baseline, after 2 (PET2) and 4 (PET4) induction cycles, and centrally assessed using international harmonization project (IHP) criteria. PET2-/PET4- patients were assigned SIC, PET2+/PET4- patients were assigned ASCT, and PET4+ patients were treated with the investigator's choice. The primary end-point was the 2007 international working group complete response (CR) rate after induction. Change in maximum standard uptake value (ΔSUVmax) after PET assessment was explored. Two hundred eleven patients were randomly assigned to R-ACVBP (n = 109) or R-CHOP14 (n = 102). PET4-/CR rates were 53%/47% with R-ACVBP and 41%/39% with R-CHOP14 (CR 95% confidence interval [CI], 38%-67% and 28%-54%, respectively; P = .076). Consolidation in the R-ACVBP and R-CHOP14 groups was SIC in 26% and 23% of patients and ASCT in 28% and 18% of patients, respectively. PET4 positivity was higher with R-CHOP14 vs R-ACVBP (54% vs 41%; P = .08), leading to more salvage therapy (37% vs 26%; P = .07) and lower event-free survival (EFS; 4-year EFS, 31% vs 43%; P < .01), but progression-free survival (PFS) and overall survival (OS) were similar in both groups. PET2-/PET4- and PET2+/PET4- patients had similar outcomes. Using ΔSUVmax, 79% of the patients were PET2-/PET4- ΔSUVmaxPET0-4 >70% was associated with better outcome (4-year PFS, 84% vs 35%; 4-year OS, 91% vs 57%; P < .0001), whatever the consolidation. Superiority of R-ACVBP over R-CHOP14 was not established, as IHP criteria did not properly reflect disease control. ΔSUVmax may help better select patients needing an alternative to SIC, including ASCT.

International Working Group consensus response evaluation criteria in lymphoma (RECIL 2017).

In recent years, the number of approved and investigational agents that can be safely administered for the treatment of lymphoma patients for a prolonged period of time has substantially increased. Many of these novel agents are evaluated in early-phase clinical trials in patients with a wide range of malignancies, including solid tumors and lymphoma. Furthermore, with the advances in genome sequencing, new "basket" clinical trial designs have emerged that select patients based on the presence of specific genetic alterations across different types of solid tumors and lymphoma. The standard response criteria currently in use for lymphoma are the Lugano Criteria which are based on [18F]2-fluoro-2-deoxy-D-glucose positron emission tomography or bidimensional tumor measurements on computerized tomography scans. These differ from the RECIST criteria used in solid tumors, which use unidimensional measurements. The RECIL group hypothesized that single-dimension measurement could be used to assess response to therapy in lymphoma patients, producing results similar to the standard criteria. We tested this hypothesis by analyzing 47 828 imaging measurements from 2983 individual adult and pediatric lymphoma patients enrolled on 10 multicenter clinical trials and developed new lymphoma response criteria (RECIL 2017). We demonstrate that assessment of tumor burden in lymphoma clinical trials can use the sum of longest diameters of a maximum of three target lesions. Furthermore, we introduced a new provisional category of a minor response. We also clarified response assessment in patients receiving novel immune therapy and targeted agents that generate unique imaging situations.

Prognostic value of baseline total metabolic tumor volume (TMTV0) measured on FDG-PET/CT in patients with peripheral T-cell lymphoma (PTCL).

BACKGROUND: Most peripheral T-cell lymphoma (PTCL) patients have a poor outcome and the identification of prognostic factors at diagnosis is needed. PATIENTS AND METHODS: The prognostic impact of total metabolic tumor volume (TMTV0), measured on baseline [(18)F]2-fluoro-2-deoxy-d-glucose positron emission tomography/computed tomography, was evaluated in a retrospective study including 108 PTCL patients (27 PTCL not otherwise specified, 43 angioimmunoblastic T-cell lymphomas and 38 anaplastic large-cell lymphomas). All received anthracycline-based chemotherapy. TMTV0 was computed with the 41% maximum standardized uptake value threshold method and an optimal cut-off point for binary outcomes was determined and compared with others prognostic factors. RESULTS: With a median follow-up of 23 months, 2-year progression-free survival (PFS) was 49% and 2-year overall survival (OS) was 67%. High TMTV0 was significantly associated with a worse prognosis. At 2 years, PFS was 26% in patients with a high TMTV0 (>230 cm(3), n = 53) versus 71% for those with a low TMTV0, [P < 0.0001, hazard ratio (HR) = 4], whereas OS was 50% versus 80%, respectively, (P = 0.0005, HR = 3.1). In multivariate analysis, TMTV0 was the only significant independent parameter for both PFS and OS. TMTV0, combined with PIT, discriminated even better than TMTV0 alone, patients with an adverse outcome (TMTV0 >230 cm(3) and PIT >1, n = 33,) from those with good prognosis (TMTV0 ≤230 cm(3) and PIT ≤1, n = 40): 19% versus 73% 2-year PFS (P < 0.0001) and 43% versus 81% 2-year OS, respectively (P = 0.0002). Thirty-one patients (other TMTV0-PIT combinations) had an intermediate outcome, 50% 2-year PFS and 68% 2-year OS. CONCLUSION: TMTV0 appears as an independent predictor of PTCL outcome. Combined with PIT, it could identify different risk categories at diagnosis and warrants further validation as a prognostic marker.

[Impact of positron emission tomography on clinical management of potentially resectable non-small-cell lung cancer: a French prospective multicenter study]. / Impact de la tomographie par émission de positons au 18-FDG dans la prise en charge des patients porteurs d'un cancer bronchique non à petites cellules a priori opérable. Etude prospective multicentrique française.

BACKGROUND: Whole-body (18)F-deoxyglucose positron emission tomography (FDG-PET) has the potential to improve the management of non-small-cell lung cancer (NSCLC). We prospectively evaluated the impact of combining FDG-PET with conventional staging methods, including computed tomography (CT), on the staging and management of patients with potentially resectable NSCLC. METHODS: Ninety-four consecutive patients with newly diagnosed/suspected NSCLC were enrolled. Each patient was first staged by using conventional methods, and then by FDG-PET. FDG-PET results were forwarded in a sealed envelope and divulged at the weekly staff meeting on staging and treatment, only after "Decision 1", based on conventional staging, had been reached by consensus; reevaluation taking FDG-PET into account yielded "Decision 2". The validity of these latter decisions was analyzed retrospectively. RESULTS: Eighty-nine patients were eligible. Relative to standard imaging, FDG-PET led to clinical staging changes in 26 (29.2%) patients. The stage was lowered in eight cases (9%) and raised in 18 cases (20.2%). "Decision 2" differed from "Decision 1" in 19 patients, modifying the surgical procedure in four cases, indicating other investigations to confirm FDG-PET evidence of metastases in 12 cases, or modifying the medical treatment in three cases. These modifications were retrospectively justified in 9/19 cases, and consisted of 2/4 modifications of the surgical procedure (one hilar and one adrenal metastasis not confirmed histologically), 4/12 further investigations (axillary and liver biopsies, mediastinoscopy, occult colon cancer) and three indications for palliative treatment, in patients who all died within 3 months after FDG-PET. CONCLUSIONS: Based on FDG-PET, management was modified in 19/89 (21.3%) patients, but these changes were justified in only 9/89 patients (10.1%). FDG-PET can detect asymptomatic local and distant metastases and improves the preoperative assessment of NSCLC, thereby avoiding unnecessary surgery. However, histological verification is required because of the risk of false-positive results.

Whole-body diffusion-weighted imaging in lymphoma.

The current evidence regarding the usefulness of whole-body diffusion-weighted magnetic resonance imaging (DWI) in lymphoma is reviewed. DWI is capable of combining anatomical and functional information and is becoming a valuable tool in oncology, in particular for staging purposes. DWI may prove to be a useful biomarker in clinical decision making for patients with lymphoma. Large-scaled prospective studies are needed to confirm these preliminary results.

Response assessment after an inductive CHOP or CHOP-like regimen with or without rituximab in 103 patients with diffuse large B-cell lymphoma: integrating 18fluorodeoxyglucose positron emission tomography to the International Workshop Criteria.

BACKGROUND: Revised response criteria for aggressive lymphomas have been proposed (Cheson, J Clin Oncol, 2007) stressing the role of (18)fluorodeoxyglucose-positron emission tomography (PET) in posttreatment evaluation. The value of PET after four cycles compared with the International Workshop Criteria (IWC) remains to be established. PATIENTS AND METHODS: In all, 103 patients with untreated diffuse large B-cell lymphoma were prospectively enrolled to evaluate the prognostic impact of PET after two and four cycles. RESULTS: Median age was 53 years (19-79), 68% male. The International Prognostic Index was low=22%, low-intermediate=19%, intermediate-high=33% and high risk=26%. Treatment consisted of cyclophosphamide, doxorubicin, vincristine, prednisone (CHOP) (30%) or dose-intensified CHOP (70%), with rituximab (49%) or without (51%). Ninety-nine patients were evaluated by PET and IWC at four cycles: 77 (78%) had a negative PET, while 22 (22%) remained positive. The 5-year event-free survival (EFS) was 36% for patients with a positive PET versus 80% with a negative examination, whatever the response [complete response (CR) versus partial response (PR)] according to IWC (P<0.0001). Positive PET patients had a 5-year EFS of 58% if in CR/CR unconfirmed by IWC and 0% if not (P<0.0001). The same observations could be made in patients treated with and without rituximab. CONCLUSION: The integration of PET in treatment evaluation offers a powerful tool to predict outcome.

Early detection of recurrence by 18FDG-PET in the follow-up of patients with colorectal cancer.

We assessed the potential benefits of including systematic 18fluorodeoxyglucose positron emission tomography (FDG-PET) for detecting tumour recurrence in a prospective randomised trial. Patients (N=130) who had undergone curative therapy were randomised to undergo either conventional (Con) or FDG-PET procedures during follow-up. The two groups were matched at baseline. Recurrence was confirmed histologically. 'Intention-to-treat' analysis revealed a recurrence in 46 patients (25 in the FDG-PET group, and 21 in the Con group; P=0.50), whereas per protocol analysis revealed a recurrence in 44 out of 125 patients (23 and 21, respectively; P=0.60). In another three cases, PET revealed unexpected tumours (one gastric GIST, two primary pulmonary cancers). Three false-positive cases of FDG-PET led to no beneficial procedures (two laparoscopies and one liver MRI that were normal). We failed to identify peritoneal carcinomatosis in two of the patients undergoing FDG-PET. The overall time in detecting a recurrence from the baseline was not significantly different in the two groups. However, recurrences were detected after a shorter time (12.1 vs 15.4 months; P=0.01) in the PET group, in which recurrences were also more frequently (10 vs two patients) cured by surgery (R0). Regular FDG-PET monitoring in the follow up of colorectal cancer patients may permit the earlier detection of recurrence, and influence therapy strategies.

[Interpretation of sentinel node identification in vulvar cancer]. / Interprétation de l'identification du ganglion sentinelle dans les cancers vulvaires.

OBJECTIVE: Sentinel node (SN) identification in vulvar carcinoma would avoid groin dissection and its complications in early stages, but we first have to validate the method, as an unrecognised node metastasis is detrimental to survival. PATIENTS AND METHODS: Since June 2002, 38 patients with T1 or T2 lesions underwent SN identification by radioactive tracer injection and scintigraphy with, on the following day, per operative use of a handheld probe +/- patent blue dye. In case of a midline lesion, a bilateral inguinal dissection was performed whatever the result of SN identification. SN free from disease were ultrastaged with immunohistochemistry. RESULTS: 1 or more SN were identified in 36 out of 38 patients. 64 groins were analysed, 15 with node metastases. In 9 out of these 15 cases the SN was metastatic, in 5 it had not been identified, and in 1 it was a false negative. In these last 6 cases, there were massively metastatic nodes in the groin. In 19 out of the 26 midline lesions the surgeon identified only unilateral SN. The side without SN contained metastatic nodes in 5 cases. DISCUSSION AND CONCLUSION: Failure in SN identification is sometimes related to a massively invaded node. This should be taken into account especially in the management of midline tumors where a seemingly unilateral drainage at scintigraphy warrants nevertheless a surgical assessment of the mute groin.

[18-Fluoro-deoxy-glucose (15FDG) positon emission tomography (PET) for the evaluation of malignant pleural disease]. / La tomographie par émission de positons (TEP) au 18-fluoro-déoxy-glucose (18FDG) dans l'évaluation de la pathologie pleurale maligne.

Use of 18FDG-PET for malignant tumors of the pleura raises certain technical difficulties because of the small size of the tumors and their diffuse distribution, but hybrid PET/CT machines offer a better localization of FDG uptake. FDG-PET can discriminate between malignant and benign pleural tumors FDG uptake in the pleura is the best diagnostic criteria of malignancy. The presence of FDG uptake in pleural effusion is less discriminate between benign and malignant disease. For mesotheliomas, FDG-PET can difference malignant tumors from benign tumors of the pleura on the basis of the SUV value ( 2). It does not enable detection of mediastinal node involvement and regional extension but is effective in detecting extra-thoracic regional spread not identified with other imaging methods. FDG-PET can thus affect the therapeutic strategy. The intensity of uptake has prognostic value. SUV<4 associated with an epithelial tumor is a sign of good prognosis at three years. SUV > 4 associated with a non-epithelial tumor is a sign of poor prognosis. For mesotheliomas, FDG uptake can be used to assess the effect of chemotherapy and determine whether patients are good responders or not.

Pulmonary scintigraphy for diagnosis of aspiration during intravenous propofol anaesthesia for colonoscopy.

A specific technique for detection of pulmonary aspiration during the perioperative period is lacking. In this study, we developed a scintigraphic method for its diagnosis. Technetium 99m sulphur colloid was given orally 2 h before an i.v. infusion of propofol in patients undergoing elective colonoscopy. During the procedure, patients were spontaneously breathing 100% oxygen via a face mask. After recovery from anaesthesia, patients had a chest scinti-scan. As a control group, 10 healthy men were studied. The lung scan was considered positive if any tracer activity greater than background level was detected in the lung field. Among 96 patients studied, three patients had a positive chest scinti-scan. One of the three patients developed pneumonia while the other two remained asymptomatic. In none of the control asymptomatic group was tracer detected in the chest. We suggest that this technique is specific and can be used as a tool to assess the risk of pulmonary aspiration during different anaesthetic procedures.

[18F]-FDG positron imaging in clinical management of lymphoma patients.

[18F]-FDG is a glucose analogue labelled with a short-lived positron emitter. During the past decade, it has been proposed to detect in vivo lymphoma lesions with PET, a new non-invasive imaging modality. We aimed at reviewing the current experience with FDG in several clinical settings of lymphoma. Due to the lack of specificity of FDG for lymphoma, histology remains compulsory to establish the diagnosis. Nevertheless, in the case of AIDS, FDG imaging has been proposed to differentiate lymphoma and opportunistic infections in brain lesions. To explore lymphoma extension, FDG-PET highlights more lesions than CT or the clinical examination and results in upstaging 13% of cases. It could also be used for selecting a site for biopsy when the location considered first clinically is difficult to access. Staging lymphoma with FDG-PET also provides baseline images for subsequent evaluation of therapy, which is one of the most promising indications: a negative scan predicts response to therapy and subsequent remission with a predictive value of 89%, and a positive scan either reflects resistance or predicts relapse with a predictive value of 83%. The current achievement of FDG imaging is the early detection of recurrence or of viable tissue in residual masses that remain several months after treatment. Both its sensitivity (84%) and its specificity (95%) overwhelm the values of conventional imaging, mainly CT and gallium-67 scintigraphy. When PET, as a new clinical imaging modality, is not yet widely demanded by clinicians and/or the number of FDG examinations is less than 500 per year, a 'hybrid' gamma-camera or CDET can be an alternative to dedicated PET. For 3 years, we have been using FDG-CDET in the 2D mode without attenuation correction, and obtained the following accuracy in a total of 40 examinations that could be evaluated: 85% for assessment of chemotherapy and 92% to detect recurrences and evaluate residual masses. Our preliminary results also stress the interest in FDG examination in childhood lymphoma, with the same indications as in adults.

Optimization of aerosol deposition by pressure support in children with cystic fibrosis: an experimental and clinical study.

Nebulized aerosols are commonly used to deliver drugs into the lungs of patients with cystic fibrosis (CF). The aim of this study was to assess the effectiveness of pressure-support (PS) ventilation in increasing aerosol deposition within the lungs of children with CF. An in vitro study demonstrated the feasibility of coupling a breath-actuated nebulizer to a PS device. An in vivo study was done with 18 children (ages 6 to 21 yr) with clinically stable CF, each of whom underwent both a standard and a PS-driven ventilation scan (control session and PS session, respectively). In addition, a perfusion scan was used to determine lung outlines and to construct a geometric model for quantifying aerosol deposition by radioactivity counting in MBq. Homogeneity of nebulization was evaluated from the four first-order moments of aerosol distribution in the peripheral and central lung regions. The time-activity nebulization curve was linear in all patients, with higher slopes during the PS than during the control session (0.43 +/- 0.07 [mean +/- SD] MBq/min and 0.32 +/- 0.23 MBq/min, respectively; p < 0.018). Quantitatively, aerosol deposition was about 30% greater after the PS session (4.4 +/- 2.7 MBq) than after the control session (3.4 +/- 2.1 MBq; p < 0.05). Similarly, deposition efficacy (as a percentage of nebulizer output) was significantly better during the PS session than during the control session (15.3 +/- 8.3% versus 11.5 +/- 5.7%, p < 0.05). No differences in the regional deposition pattern or in homogeneity of uptake were observed. In conclusion, our data show that driving the delivery of a nebulized aerosol by noninvasive PS ventilation enhances total lung aerosol deposition without increasing particle impaction in the proximal airways.

Experimental radiation pneumonitis studied with indium-111-pentetreotide.

OBJECTIVES: To understand the evolution of lung uptake of 111-In-Pentetreotide in a rat model of pulmonary radiation pneumonitis. METHODS: A 15 Gy 60-Co thoracic irradiation (1.4 Gy/min) was delivered to Wistar rats. Irradiated and control animals were studied during 8 weeks after irradiation. 24 hours after an injection of 111-In-pentetreotide (12-18 MBq), the uptake in the lung tissue (ULT), in the alveolar cells (UpC) and in different organs, was determined. Histological examinations were performed. RESULTS: ULT and UpC after irradiation increased significantly peaking at 4 weeks (ULT: 32.8 +/- 13.0 in 10(-5) of the injected dose versus 10.8 +/- 2.0 for control; and, UpC was 19.3 +/- 7.2 versus 7.3 +/- 4.1) and decreased afterwards. Pre-injection of cold octreotide decreased the lung uptake. This evolution parallels the histological changes: alveolitis with granulomas in the interstitium at 4 weeks followed by development of sites of interstitial fibrosis. These observations suggest that the uptake is due to activated cells, mainly macrophages within the granulomas and in the alveoli, expressing somatostatin receptors. CONCLUSION: 1) The uptake of 111-In-pentetreotide in injured lungs after irradiation, already described in man, was confirmed in a rat model; 2) our results suggest that it is possible to follow the evolution of radiation lung injury by using In-111-pentetreotide.

The value of combined radionuclide and magnetic resonance imaging in the diagnosis and conservative management of minimal or localized osteomyelitis of the foot in diabetic patients.

Early diagnosis of osteomyelitis is helpful for a successful conservative treatment. The value of bone scanning combined with granulocytes labeled with hexamethylpropylene amine oxime (HMPAO) granulocyte-Tc99m (GN) radionuclide imaging (combined [RI]) with magnetic resonance imaging (MRI) for the diagnosis of osteomyelitis was assessed in 24 diabetic patients with foot ulcers. Evidence of osteomyelitis was based on the presence of at least one of the following criteria: (1) clinical bone involvement, (2) radiological bone involvement, (3) both positive combined RI and MRI, and (4) evidence of clinical bone involvement during the follow-up period. Thirteen patients had osteomyelitis. Seven patients had clinical bone involvement (sensitivity, 54%), five had radiological bone involvement (sensitivity, 38%), and 10 had positive combined RI for osteomyelitis (sensitivity, 77%). MRI demonstrated a higher sensitivity (100%). The specificity for combined RI and MRI was 82%. These results lead to a new diagnostic strategy for the early detection of minimal or localized osteomyelitis to avoid amputations. MRI is most appropriate following a negative x-ray in determining whether to treat osteomyelitis, since a negative MRI result rules out osteomyelitis. Antibiotic therapy should be used in the case of a positive MRI result, but Charcot joint disease can lead to false-positive MRI results. In this case, combined RI should be performed.

Acute bacterial pneumonia in rats increases alveolar epithelial fluid clearance by a tumor necrosis factor-alpha-dependent mechanism.

To study the rate and regulation of alveolar fluid clearance in acute pneumonia, we created a model of Pseudomonas aeruginosa pneumonia in rats. To measure alveolar liquid and protein clearance, we instilled into the airspaces a 5% bovine albumin solution with 1.5 microCi of 125I-human albumin, 24 h after intratracheal instillation of bacteria. The concentration of unlabeled and labeled protein in the distal airspaces over 1 h was used as an index of net alveolar fluid clearance. Since there was histologic evidence of alveolar epithelial injury, several methods were used to measure alveolar fluid clearance, including the use of experiments in rats with blood flow and the use of experiments in rats without blood flow, so that movement across the epithelial barrier would be minimized in the latter group. The results with each method were identical. We found that P. aeruginosa pneumonia increased alveolar liquid clearance over 1 h by 48% in studies with blood flow, and by 43% in rats without blood flow, compared with respective controls (P < 0.05). In both studies, this increase was inhibited with amiloride. However, propranolol had no inhibitory effect, thus ruling out a catecholamine-dependent mechanism to explain the increase in alveolar fluid clearance. An antitumor necrosis factor-alpha neutralizing antibody, instilled into the lung 5 min before bacteria, prevented the increase in alveolar liquid clearance in rats with pneumonia (P < 0.05). Also, TNFalpha (5 microg) instilled in normal rats increased alveolar liquid clearance by 43% over 1 h compared with control rats (P < 0.05). In normal rats instilled with TNFalpha, propranolol had no inhibitory effect. In conclusion, gram-negative pneumonia markedly upregulates net alveolar epithelial fluid clearance, in part by a TNFalpha-dependent mechanism. This finding provides a novel mechanism for the upregulation of alveolar epithelial sodium and fluid transport from the distal airspaces of the lung.

Pulmonary clearance and lung function: influence of acute tobacco intoxication and of vitamin E.

Cigarette smoking increases the alveolar epithelial permeability to small solutes, as assessed by the pulmonary clearance of aerosolized 99mTc-labeled diethylenetriaminepentaacetate. The involvement of lipid peroxidation in this increased clearance was tested in eight asymptomatic young smokers by investigating the effects of a 3-wk supplementation with oral vitamin E (1,000 IU/day) on pulmonary clearance according to a protocol designed as a single-blind crossover study. Indexes of acute tobacco intoxication (exhaled CO, carboxyhemoglobin, and urinary cotinine) and lung function parameters [including Krogh factor (KCO)] were also studied. Under control conditions, pulmonary clearance was abnormally increased (2.93 +/- 0.78%/min), whereas KCO was in the normal range. Pulmonary clearance correlated strongly with expired CO (P < 0.04), HbCO (P < 0.005), urinary cotinine (P < 0.003), and KCO (P < 0.004). Supplementation with vitamin E, a highly efficient antioxidant, neither decreased the pulmonary clearance nor altered the above correlations. However, the strong correlations observed between pulmonary clearance and indexes of acute tobacco intoxication, which reflect the amount of inhaled smoke and the resultant oxidant stress, do not allow exclusion of the involvement of lipid peroxidation in the pulmonary clearance increase observed in smokers.