Radiotherapy with or without immunotherapy in metastatic melanoma: efficacy and tolerability.

INTRODUCTION: Radiotherapy (RT) is primarily considered as a palliative treatment in patients with metastatic melanoma. However, observations suggest that when RT is combined with immune checkpoint inhibitors (ICI), it can induce an immune response leading to an anti-tumoral effect also distant from the irradiated area - a phenomenon called 'abscopal effect'. The frequency and circumstances of abscopal effect among metastatic melanoma patients remains uncertain and further research is necessary. MATERIAL AND METHOD: This retrospective study included all metastatic melanoma patients who received non-stereotactic RT in Stockholm, Sweden in 2015-2020. Patients were grouped depending on if RT was given at start of ICI (RT + ICI(start)), at ICI progression (RT + ICI(salvage)) or without ICI (RT(only)). Response rates in irradiated (RR(irradiated)) and overall response rates in non-irradiated (ORR(non-irradiated)) metastases were evaluated together with survival and toxicity in each cohort. RESULTS: In the RT + ICI(start) (n = 47), RT + ICI(salvage) (n = 41) and RT(only) (n = 55) cohorts, RR(irradiated) was 70.7%, 67.5% and 43.1% (p = 0.018) while the ORR(non-irradiated) was 36.1%, 14.8% and 0.0% (p = 0.003), and the median overall survival was 18.2, 15.0 and 7.2 months, respectively (p = 0.014). Local response to RT was in all cohorts associated with longer survival (p < 0.001). The frequency of grade ≥3 immune-related adverse events was 17.0% and 19.5% in the RT + ICI(start) and RT + ICI(salvage) cohorts. No increased frequency of RT-related adverse events was seen in the RT + ICI cohorts, compared to the RT(only) cohort. CONCLUSION: This retrospective study showed that melanoma patients receiving RT in combination with ICI had a superior antitumoral response in both irradiated and non-irradiated lesions as compared to patients receiving only RT. Additionally, a subgroup of patients receiving RT when progressing on ICI experienced tumor regression also in non-irradiated areas.

Expanded HILUS Trial: A Pooled Analysis of Risk Factors for Toxicity From Stereotactic Body Radiation Therapy of Central and Ultracentral Lung Tumors.

PURPOSE: Stereotactic body radiation therapy for tumors near the central airways implies high-grade toxic effects, as concluded from the HILUS trial. However, the small sample size and relatively few events limited the statistical power of the study. We therefore pooled data from the prospective HILUS trial with retrospective data from patients in the Nordic countries treated outside the prospective study to evaluate toxicity and risk factors for high-grade toxic effects. METHODS AND MATERIALS: All patients were treated with 56 Gy in 8 fractions. Tumors within 2 cm of the trachea, the mainstem bronchi, the intermediate bronchus, or the lobar bronchi were included. The primary endpoint was toxicity, and the secondary endpoints were local control and overall survival. Clinical and dosimetric risk factors were analyzed for treatment-related fatal toxicity in univariable and multivariable Cox regression analyses. RESULTS: Of 230 patients evaluated, grade 5 toxicity developed in 30 patients (13%), of whom 20 patients had fatal bronchopulmonary bleeding. The multivariable analysis revealed tumor compression of the tracheobronchial tree and maximum dose to the mainstem or intermediate bronchus as significant risk factors for grade 5 bleeding and grade 5 toxicity. The 3-year local control and overall survival rates were 84% (95% CI, 80%-90%) and 40% (95% CI, 34%-47%), respectively. CONCLUSIONS: Tumor compression of the tracheobronchial tree and high maximum dose to the mainstem or intermediate bronchus increase the risk of fatal toxicity after stereotactic body radiation therapy in 8 fractions for central lung tumors. Similar dose constraints should be applied to the intermediate bronchus as to the mainstem bronchi.

Predicting the benefit of stereotactic body radiotherapy of colorectal cancer metastases.

Aim: To evaluate Stereotactic body radiotherapy (SBRT) in metastatic colorectal cancer (mCRC) and identify the benefit of the treatment by using a predictive algorithm. Methods: 85 patients treated with SBRT for mCRC were retrospectively analyzed. The CLInical Categorical Algorithm (CLICAL©) was used to predict probability of relapse after SBRT. Variables pre-SBRT were tested for significance for time to relapse (TTR). The patients' CLICAL© score was the mean of sub-scores of each significant variable's effect on the endpoint. Patients with similar scores were grouped into four signatures dependent on level of benefit after SBRT. Results: Median age was 69 years (42-88), 63 % had a performance status 0 and 47 % were treated for a single metastasis. At the time of the analysis, 90 % had relapsed (95 % out-of-field). Median TTR was 7.3 months (4.6-8.5), and the 2-year relapse-free rate was 15 % (95 %CI = 7-22). The CLICAL© signature III-IV predicted a low risk of relapse if receiving high dose SBRT to all metastases or to lung metastases only. Signature I-II had a short TTR, why SBRT for these patients was judged non-beneficial. Conclusion: The benefit from SBRT varies among mCRC patients. CLICAL© may serve as a screening tool for SBRT referrals but needs to be validated.

Mental health and psychosocial consequences linked to radiation emergencies-increasingly recognised concerns.

A major radiological or nuclear emergency may, apart from causing a substantial loss of life and physical damage, also put a substantial strain on affected societies with social, economic and political consequences. Although such emergencies are relatively uncommon, it is now being increasingly recognised that their subsequent psychosocial impact can be widespread and long lasting. Mental health effects, such as depression, anxiety and post-traumatic stress disorder, are highly represented in a population affected by a radiation disaster. In order to reach the majority of the people affected by radiation accidents, we need to be aware of how to distribute relevant and accurate information related to both short- and long-term medical effects. Effective risk communication is associated with improved compliance with any given recommendations. It is important to protect the public from physical radiation damage, but it is also essential to take into account the social and mental health effects that radiation disasters may induce. This article provides a brief review of recent reporting on the psychological consequences after a major radiation emergency.

The acute radiation syndrome-need for updated medical guidelines.

The major immediate and severe medical consequences in man following exposure to high doses of ionising radiation can be summarised within the concept of the acute radiation syndrome (ARS). In a dose-dependent fashion, a multitude of organ systems can be affected by such irradiation, presenting considerable medical challenges to treating physicians. Accidents or malevolent events leading to ARS can provoke devastating effects, but they occur at a low frequency and in a highly varying manner and magnitude. Thus, it is difficult to make precise medical predictions and planning, or to draw conclusive evidence from occurred events. Therefore, knowledge from on-going continuous developments within related medical areas needs to be acknowledged and incorporated into the ARS setting, enabling the creation of evidence-based guidelines. In 2011 the World Health Organization published a first global consensus on the medical management of ARS among patients subjected to nontherapeutic radiation. During the recent decade the understanding of and capability to counteract organ damage related to radiation and other agents have improved considerably. Furthermore, legal and logistic hurdles in the process of formally approving appropriate medical countermeasures have been reduced. We believe the time is now ripe for developing an update of internationally consented medical guidelines on ARS.

Medical consequences of radiation exposure of the bronchi-what can we learn from high-dose precision radiation therapy?

The bronchial tolerance to high doses of radiation is not fully understood. However, in the event of a radiological accident with unintended exposure of the central airways to high doses of radiation it would be important to be able to anticipate the clinical consequences given the magnitude of the absorbed dose to different parts of the bronchial tree. Stereotactic body radiation therapy (SBRT) is a radiation treatment technique involving a few large fractions of photon external-beam radiation delivered to a well-defined target in the body. Despite generally favourable results, with high local tumour control and low-toxicity profile, its utility for tumours located close to central thoracic structures has been questioned, considering reports of severe toxic symptoms such as haemoptysis (bleedings from the airways), bronchial necrosis, bronchial stenosis, fistulas and pneumonitis. In conjunction with patient- and tumour-related risk factors, recent studies have analysed the absorbed radiation dose to different thoracic structures of normal tissue to better understand their tolerance to these high doses per fraction. Although the specific mechanisms behind the toxicity are still partly unknown, dose to the proximal bronchial tree has been shown to correlate with high-grade radiation side effects. Still, there is no clear consensus on the tolerance dose of the different bronchial structures. Recent data indicate that a too high dose to a main bronchus may result in more severe clinical side effects as compared to a smaller sized bronchus. This review analyses the current knowledge on the clinical consequences of bronchial exposure to high dose hypofractionated radiation delivered with the SBRT technique, and the tolerance doses of the bronchi. It presents the current literature regarding types of high-grade clinical side effects, data on dose response and comments on other risk factors for high-grade toxic effects.

Estimation of delivered dose to lung tumours considering setup uncertainties and breathing motion in a cohort of patients treated with stereotactic body radiation therapy.

INTRODUCTION: Dose-response relationships for local control of lung tumours treated with stereotactic body radiotherapy (SBRT) have proved ambiguous, however, these have been based on the prescribed or planned dose. Delivered dose to the target may be a better predictor for local control. In this study, the probability of the delivered minimum dose to the clinical target volume (CTV) in relation to the prescribed dose was estimated for a cohort of patients, considering geometrical uncertainties. MATERIALS AND METHODS: Delivered doses were retrospectively simulated for 50 patients treated with SBRT for lung tumours, comparing two image-guidance techniques: pre-treatment verification computed tomography (IG1) and online cone-beam computed tomography (IG2). The prescribed dose was typically to the 67% isodose line of the treatment plan. Simulations used in-house software that shifted the static planned dose according to a breathing motion and sampled setup/matching errors. Each treatment was repeatedly simulated, generating a multiplicity of dose-volume histograms (DVH). From these, tumour-specific and population-averaged statistics were derived. RESULTS: For IG1, the probability that the minimum CTV dose (D98%) exceeded 100% of the prescribed dose was 90%. With IG2, this probability increased to 99%. CONCLUSIONS: Doses below the prescribed dose were delivered to a considerably larger part of the population prior to the introduction of online soft-tissue image-guidance. However, there is no clear evidence that this impacts local control, when compared to previous published data.

The HILUS-Trial-a Prospective Nordic Multicenter Phase 2 Study of Ultracentral Lung Tumors Treated With Stereotactic Body Radiotherapy.

INTRODUCTION: Stereotactic body radiation therapy of thoracic tumors close to the central airways implies risk of severe toxicity. We report a prospective multicenter phase 2 trial for tumors located less than or equal to 1 cm from the proximal bronchial tree with primary end point of local control and secondary end point of toxicity. METHODS: Stereotactic body radiation therapy with 7 Gy × 8 was prescribed to the 67% isodose encompassing the planning target volume. The patients were stratified to group A (tumors ≤ 1 cm from the main bronchi and trachea) or group B (all other tumors). Risk factors for treatment-related death were tested in univariate analysis, and a logistic regression model was developed for fatal bronchopulmonary bleeding versus dose to the main bronchi and trachea. RESULTS: A total of 65 patients (group A/group B, n = 39/26) were evaluated. The median distance between the tumor and the proximal bronchial tree was 0 mm (0-10 mm). The 2-year local control was 83%. Grade 3 to 5 toxicity was noted in 22 patients, including 10 cases of treatment-related death (bronchopulmonary hemorrhage, n = 8; pneumonitis, n = 1; fistula, n = 1). Dose to the combined structure main bronchi and trachea and tumor distance to the main bronchi were important risk factors. Dose modeling revealed minimum dose to the "hottest" 0.2 cc to the structure main bronchi and trachea as the strongest predictor for lethal bronchopulmonary hemorrhage. CONCLUSIONS: On the basis of the presented data, 7 Gy × 8, prescribed to the planning target volume-encompassing isodose, should not be used for tumors located within 1 cm from the main bronchi and trachea. Group B-type tumors may be considered for the treatment on the basis of an individual risk-benefit assessment and a maximum dose to the main bronchi and trachea in the order of 70 to 80 Gy (equivalent dose in 2 Gy fractions).

Extending hypofractionated stereotactic body radiotherapy to tumours larger than 70cc - effects and side effects.

BACKGROUND AND PURPOSE: Stereotactic body radiotherapy (SBRT) for tumours ≥5 cm is poorly studied and its utility and feasibility is uncertain. We here report the Karolinska experience of SBRT in this setting. MATERIAL AND METHODS: All patients had a gross tumour volume (GTV) ≥70 cc, a prescribed physical dose of at least 40 Gy and received treatment between 1995-2012. RESULTS: We included 164 patients with 175 tumours located in the thorax (n = 86), the liver (n = 27) and the abdomen (n = 62) and treated with a median prescribed dose (BEDα/ß 10Gy) of 80 Gy (71.4-113). One- and 2- year local control rates were 82% and 61%. In multivariate analyses, minimum dose to the GTV and histological subtype were associated with local control. Renal cell carcinoma (RCC) histology showed the most favourable local control - 94% at 2 years for all histologies. Thirty-seven patients experienced grade 3-5 toxicity most likely related to SBRT. Seven of the ten patients with grade 5 toxicity, had a centrally located tumour in the thorax. CONCLUSION: SBRT of tumours >5 cm in diameter may be an option for peripherally located lung and abdominal tumours. Histological origin and tumour location should be considered before treatment.

Practice Recommendations for Lung Cancer Radiotherapy During the COVID-19 Pandemic: An ESTRO-ASTRO Consensus Statement.

BACKGROUND: The COVID-19 pandemic has caused radiotherapy resource pressures and led to increased risks for lung cancer patients and healthcare staff. An international group of experts in lung cancer radiotherapy established this practice recommendation pertaining to whether and how to adapt radiotherapy for lung cancer in the COVID-19 pandemic. METHODS: For this ESTRO & ASTRO endorsed project, 32 experts in lung cancer radiotherapy contributed to a modified Delphi consensus process. We assessed potential adaptations of radiotherapy in two pandemic scenarios. The first, an early pandemic scenario of risk mitigation, is characterized by an altered risk-benefit ratio of radiotherapy for lung cancer patients due to their increased susceptibility for severe COVID-19 infection, and minimization of patient travelling and exposure of radiotherapy staff. The second, a later pandemic scenario, is characterized by reduced radiotherapy resources requiring patient triage. Six common lung cancer cases were assessed for both scenarios: peripherally located stage I NSCLC, locally advanced NSCLC, postoperative radiotherapy after resection of pN2 NSCLC, thoracic radiotherapy and prophylactic cranial irradiation for limited stage SCLC and palliative thoracic radiotherapy for stage IV NSCLC. RESULTS: In a risk-mitigation pandemic scenario, efforts should be made not to compromise the prognosis of lung cancer patients by departing from guideline-recommended radiotherapy practice. In that same scenario, postponement or interruption of radiotherapy treatment of COVID-19 positive patients is generally recommended to avoid exposure of cancer patients and staff to an increased risk of COVID-19 infection. In a severe pandemic scenario characterized by reduced resources, if patients must be triaged, important factors for triage include potential for cure, relative benefit of radiation, life expectancy, and performance status. Case-specific consensus recommendations regarding multimodality treatment strategies and fractionation of radiotherapy are provided. CONCLUSION: This joint ESTRO-ASTRO practice recommendation established pragmatic and balanced consensus recommendations in common clinical scenarios of radiotherapy for lung cancer in order to address the challenges of the COVID-19 pandemic.

Practice recommendations for lung cancer radiotherapy during the COVID-19 pandemic: An ESTRO-ASTRO consensus statement.

BACKGROUND: The COVID-19 pandemic has caused radiotherapy resource pressures and led to increased risks for lung cancer patients and healthcare staff. An international group of experts in lung cancer radiotherapy established this practice recommendation pertaining to whether and how to adapt radiotherapy for lung cancer in the COVID-19 pandemic. METHODS: For this ESTRO & ASTRO endorsed project, 32 experts in lung cancer radiotherapy contributed to a modified Delphi consensus process. We assessed potential adaptations of radiotherapy in two pandemic scenarios. The first, an early pandemic scenario of risk mitigation, is characterized by an altered risk-benefit ratio of radiotherapy for lung cancer patients due to their increased susceptibility for severe COVID-19 infection, and minimization of patient travelling and exposure of radiotherapy staff. The second, a later pandemic scenario, is characterized by reduced radiotherapy resources requiring patient triage. Six common lung cancer cases were assessed for both scenarios: peripherally located stage I NSCLC, locally advanced NSCLC, postoperative radiotherapy after resection of pN2 NSCLC, thoracic radiotherapy and prophylactic cranial irradiation for limited stage SCLC and palliative thoracic radiotherapy for stage IV NSCLC. RESULTS: In a risk-mitigation pandemic scenario, efforts should be made not to compromise the prognosis of lung cancer patients by departing from guideline-recommended radiotherapy practice. In that same scenario, postponement or interruption of radiotherapy treatment of COVID-19 positive patients is generally recommended to avoid exposure of cancer patients and staff to an increased risk of COVID-19 infection. In a severe pandemic scenario characterized by reduced resources, if patients must be triaged, important factors for triage include potential for cure, relative benefit of radiation, life expectancy, and performance status. Case-specific consensus recommendations regarding multimodality treatment strategies and fractionation of radiotherapy are provided. CONCLUSION: This joint ESTRO-ASTRO practice recommendation established pragmatic and balanced consensus recommendations in common clinical scenarios of radiotherapy for lung cancer in order to address the challenges of the COVID-19 pandemic.

Radiation-induced brachial plexus toxicity after SBRT of apically located lung lesions.

Purpose: To evaluate the rate and dose response of brachial plexus toxicity post stereotactic body radiation therapy (SBRT) of apically situated lung lesions. Material/methods: We retrospectively identified all patients with apically located tumors, defined by the epicenter of the tumor being located superiorly to the aortic arch, and treated with SBRT between 2008 and 2013. Patients with a shorter follow-up than 6 months were excluded. Primary aim was to evaluate radiation-induced brachial plexopathy (RIBP). Dose to the plexus was assessed by a retrospective delineation of the brachial plexus on the CT used for treatment planning. Then, Dmax, D0.1cc, D1cc and D3.0cc of the brachial plexus were collected from the dose-volume histograms (DVH) and recalculated to the biologically effective dose (BED) using α/ß = 3 Gy. A normal tissue complication probability (NTCP) model, based on four different dose-volume parameters (BED3,max, BED3,0.1cc, BED3,1.0cc, BED3,3.0cc) was fitted to the data. Results: Fifty-two patients with 56 apically located tumors were identified. Median prescription dose per fraction was 15 Gy (range 6-17) and median number of fractions was 3 (3-10). With a median follow-up of 30 months (6.1-72) seven patients experienced maximum grade 2 (scored 3 times) or 3 (scored 4 times) RIBP after a median of 8.7 months (range 4.0-31). Three patients had combined symptoms with pain, sensory and motor affection and four patients had isolated pain. Median BED3,max for the patients experiencing RIBP was 381 Gy (range 30-524) versus BED3,max of 34 Gy (range 0.10-483) for the patients without RIBP. The NTCP models showed a very high predictive ability (area under the receiver operating characteristic curve (AUC) 0.80-0.88). Conclusion: SBRT of apically located lung lesions may cause severe neurological symptoms; for a three-fraction treatment, we suggest that the maximum dose to the plexus should be kept ≤30 Gy (130 Gy BED3).

Long-term results of a prospective phase II trial of medically inoperable stage I NSCLC treated with SBRT - the Nordic experience.

BACKGROUND: Presentation of long term results of a phase II multicenter Nordic trial of medically inoperable stage I non-small cell lung cancer (NSCLC) treated with stereotactic body radiotherapy (SBRT). MATERIAL AND METHODS: We report the extended outcome, focusing on long-term effects, of a prospective cohort of 57 evaluable patients with peripherally located T1N0M0 (72%) and T2N0M0 (28%) NSCLC, treated with SBRT 15 Gy × 3, prescribed to the 67% isodose line encompassing the PTV. The patients were inoperable due to chronic obstructive pulmonary disease (65%), cardiovascular disease (25%) or other illnesses (3%) or refused surgery (7%). Median Karnofsky score pre-treatment was 80% (70-100%). Late effects were defined as occurring > 36 months. RESULTS: Thirty-eight patients (67%) were relapse free during their entire follow-up. Local control rate at four and five years were 79% (CI 95% 64-95%) and local relapses occurred at 10-76 months post-treatment. Seven local failures were noted, four occurring ≤ 36 months (all T2a-tumors; two isolated and two in combination with out-of-field relapses) and three occurring > 36 months (T1b-tumors n = 3). Thirteen patients had out-of-field failure only as first presentation of recurrence. Overall survival rate and lung cancer-specific survival rate at five years were 30% and 74%, respectively. Toxicity throughout the entire observation period was acceptable without any grade 5 toxicities. Seventeen grade 3-4 toxicities were noted, three presenting > 36 months (rib fracture, dyspnea and ventricle tachycardia). Median follow-up was 41.5 months (3.4-113.0) for the entire cohort and 59.3 months (36.4-113.0) for the 34 patients (60%) with a follow-up of > 36 months. CONCLUSION: Throughout the observation period local control was excellent and toxicity limited with no increase in late presenting local relapses or late treatment-related morbidity. This further supports SBRT as an efficient local treatment modality even in a medically impaired patient cohort.

Toxicity after reirradiation of pulmonary tumours with stereotactic body radiotherapy.

PURPOSE: To assess toxicity and feasibility of reirradiation with stereotactic body radiotherapy (SBRT) after prior lung SBRT for primary lung cancer or lung metastases. PATIENTS AND MATERIALS: Twenty-nine patients reirradiated with SBRT on 32 lung lesions (11 central, 21 peripheral) were retrospectively reviewed. Median follow-up time was 12 months (range 1-97). The primary endpoint was toxicity, secondary endpoints were local control and overall survival time. Toxicity was scored according to the NCI-CTCAE version 3. RESULTS: Grade 3-4 toxicity was scored 14 times in eight patients. Three patients died because of massive bleeding (grade 5). Larger clinical target volumes (CTV) and central tumour localization were associated with more severe toxicity. There was no correlation between mean lung dose (MLD) and lung toxicity. Local control at 5 months after reirradiation was 52%, as assessed by CT-scan (n=12) or X-thorax (n=3). A larger CTV was associated with poorer local control. Kaplan-Meier estimated 1- and 2-year survival rates were 59% and 43%, respectively. CONCLUSIONS: Reirradiation with SBRT is feasible although increased risk of toxicity was reported in centrally located tumours. Further research is warranted for more accurate selection of patients suitable for reirradiation with SBRT.

Tube associated otorrhea in children with recurrent acute otitis media; results of a prospective randomized study on bacteriology and topical treatment with or without systemic antibiotics.

OBJECTIVE: To establish if otorrhea associated to tympanostomy tubes in infants suffering from recurrent acute otitis media is similar to acute otitis media, and if topical treatment alone is sufficient or if addition of systemic antibiotics is required. METHODS: Children under 3 years of age with tympanostomy tubes due to recurrent acute otitis media were recruited to the study. The study design was open label randomized and prospective. Fifty patients were allocated to either of two treatment groups and were monitored for 6 months. Group I received only topical treatment (commercially available ear drops and saline solution) in case of otorrhea. Group II was treated with topical treatment together with systemic antibiotics. All episodes of acute otorrhea were registered. Main outcome measure was duration of otorrhea in days. Bacterial samples from the ear discharge were taken. RESULTS: Forty-one episodes were treated according to protocol. The bacteriological testing mainly showed bacteria typical of acute otitis media. A majority of episodes were cured within 7 days in both groups, and statistical analysis showed no significant difference between the treatment groups in duration of otorrhea. In Group I systemic antibiotics were added in one-third (7/21) of the episodes due to signs of affected general condition such as high fever and severe earache. CONCLUSIONS: The otorrhea episodes in the study were similar to acute otitis media based on the bacteriological results. Topical treatment alone might be used as first treatment of choice. Although systemic antibiotics were added in several cases in the topical treatment group, the findings of the study do not support use of systemic antibiotics for tube associated otorrhea in RAOM children in general.

Influence of peroxisome proliferator-activated receptor alpha agonists on the intracellular turnover and secretion of apolipoprotein (Apo) B-100 and ApoB-48.

The peroxisome proliferator-activated receptor (PPAR) alpha agonist WY 14,643 increased the secretion of apolipoprotein (apo) B-100, but not that of apoB-48, and decreased triglyceride biosynthesis and secretion from primary rat hepatocytes. These effects resulted in decreased secretion of apoB-100-very low density lipoprotein (VLDL) and an increased secretion of apoB-100 on low density lipoproteins/intermediate density lipoproteins. ApoB-48-VLDL was also replaced by more dense particles. The proteasomal inhibitor lactacystin did not influence the recovery of apoB-100 or apoB-48 in primary rat hepatocytes, indicating that co-translational (proteasomal) degradation is of less importance in these cells. Treatment with WY 14,643 made the recovery of apoB-100 sensitive to lactacystin, most likely reflecting the decreased biosynthesis of triglycerides. The PPAR alpha agonist induced a significant increase in the accumulation of pulse-labeled apoB-100 even after a short pulse (2-5 min). There was also an increase in apoB-100 nascent polypeptides, indicating that the co-translational degradation of apoB-100 was inhibited. However, a minor influence on an early posttranslation degradation cannot be excluded. This decreased co-translational degradation of apoB-100 explained the increased secretion of the protein. The levels of apoB-48 remained unchanged during these pulse-chase experiments, and albumin production was not affected, indicating a specific effect of PPAR alpha agonists on the co-translational degradation of apoB-100. These findings explain the difference in the rate of secretion of the two apoB proteins seen after PPAR alpha activation. PPAR alpha agonists increased the expression and biosynthesis of liver fatty acid-binding protein (LFABP). Increased expression of LFABP by transfection of McA-RH7777 cells increased the secretion of apoB-100, decreased triglyceride biosynthesis and secretion, and increased PPAR alpha mRNA levels. These findings suggest that PPAR alpha and LFABP could interact to amplify the effect of endogenous PPAR alpha agonists on the assembly of VLDL.