Diagnosis and management of pneumonitis following chemoradiotherapy and immunotherapy in stage III non-small cell lung cancer.

BACKGROUND: In inoperable stage III NSCLC, the standard of care is chemoradiotherapy and adjuvant durvalumab (IO) for 12 months. Pneumonitis is the commonest toxicity leading to discontinuation of IO. A failure to distinguish between expected radiation-induced changes, IO pneumonitis and infection can lead to unnecessary durvalumab discontinuation. We investigated the use of a structured multidisciplinary review of CT-scans, radiation dose distributions and clinical symptoms for the diagnosis of IO pneumonitis. METHODS: A retrospective study was conducted at an academic medical center for patients treated for stage III NSCLC with chemoradiotherapy and adjuvant durvalumab between 2018 and 2021. An experienced thoracic radiologist reviewed baseline and follow-up chest CT-scans, systematically scored radiological features suspected for pneumonitis using a published classification system (Veiga C, Radioth Oncol 2018), and had access to screenshots of radiation dose distributions. Next, two experienced thoracic oncologists reviewed each patients' case record, CT-scans and radiation fields. A final consensus diagnosis incorporating views of expert clinicians and the radiologist was made. RESULTS: Among the 45 included patients, 14/45 (31.1%) had a pneumonitis scored in patient records and durvalumab was discontinued in 11/45 cases (24.4%). Review by the radiologist led to a diagnosis of immune-related pneumonitis only in 6/45 patients (13.3%). Review by pulmonary oncologists led to a diagnosis of immune-related pneumonitis in only 4/45 patients (8.9%). In addition a suspicion of an immune-related pneumonitis was rejected in 3 separate patients (6.7%), after the thoracic oncologists had reviewed the patients' radiation fields. CONCLUSIONS: In patients treated using the PACIFIC regimen, multidisciplinary assessment of CT-scans, radiation doses and patient symptoms, resulted in fewer diagnoses of immune-related pneumonitis (8.9%). Our study underscores the challenges in accurately diagnosing either IO-related or radiation pneumonitis in patients undergoing adjuvant immunotherapy after chemoradiotherapy and highlights the need for multidisciplinary review in order to avoid inappropriate cessation of adjuvant IO.

Morbidity and extent of surgical resection of carcinoid tumors after endobronchial treatment.

OBJECTIVES: This study assessed whether endobronchial therapy (EBT) for bronchial carcinoid, if not curative, reduces the extent of the surgical resection and whether EBT is associated with increased surgical morbidity. MATERIAL AND METHODS: Analysis was performed in a cohort of patients with bronchial carcinoid who have undergone surgical resection. A group that underwent EBT before the surgery (S + EBT) was compared with a group where no EBT was performed (S-EBT). Postoperative complications were also compared between both groups. RESULTS: A total of 254 patients treated for a bronchial carcinoid tumor between 2003 and 2019 were screened for inclusion. A total of 65 surgically treated patients were included, of whom 41 (63%) underwent EBT prior to surgery. In 5 out of 41 patients (12%) from the S + EBT group, less parenchyma was resected versus 2 out of 24 (8%) from the S-EBT group (OR 1.528, 95% CI 0.273-8.562, p = 1.000). Two patients from the S + EBT group (5%) underwent lobectomy instead of sleeve lobectomy versus 0 from the S-EBT group (OR 1.051, 95% CI 0.981-1.127, p = 0.527). Comparing complications between the S + EBT and S-EBT group did not result in increased postoperative surgical morbidity (15% S + EBT, 24% S-EBT). CONCLUSION: EBT, if not curative, does not reduce the extent of the subsequent surgical resection. Therefore, if curative EBT is not anticipated, patients should directly be referred for surgery. If curative EBT seems feasible, it should be attempted not only because surgical resection can be prevented, but also because failure of EBT is not associated with excess surgical morbidity.

Impact of health care organization on surgical lung cancer care.

OBJECTIVES: Organization and governance of national healthcare might play an important role in decision-making and outcomes in patients with lung cancer. Both Denmark and the Netherlands have a high level of healthcare but a different financial coverage, governance and level of centralization. By using both national databases we analyzed the consequences of these differences on patterns of care and outcomes with a focus on morbidity, mortality and clinical staging. MATERIALS AND METHODS: General numbers on both healthcare systems were requested. All patients who had surgery for lung cancer from 2013 to 2016 were included. Mortality, morbidity and clinical staging were analyzed for patients with NSCLC without metastases, only one operation and no neo-adjuvant therapy. RESULTS: In 2016 annual budget as share of gross national product was 10.4% for both countries. In Denmark 4 hospitals performed lung surgery in 2016, compared to 43 hospitals in the Netherlands. We included 4030 Danish and 8286 Dutch patients. In the subgroup 30-day mortality was 1.5% in Denmark compared to 1.9% in the Netherlands. The percentage of patients with a complicated course was 24.4% and 34.8% respectively (p < 0.05). Accuracy between cTNM and pTNM was 53.0% in Denmark and 52.9% in the Netherlands. CONCLUSION: Surgery for lung cancer is at a high level in both countries, reflected by low mortality-rates. Centralization has been implemented successfully in Denmark, which might explain the lower rate of patients with a complicated post-operative course, although different definitions preclude firm conclusions. In both countries correct clinical staging of lung cancer remains a challenge.

Endobronchial and surgical treatment of pulmonary carcinoid tumors: A systematic literature review.

The treatment of pulmonary carcinoid has changed over the last decades. Although surgical resection is still the gold standard, minimally invasive endobronchial procedures have emerged as a parenchyma sparing alternative for tumors located in the central airways. This review was performed to identify the optimal treatment strategy for pulmonary carcinoid, with a particular focus on the feasibility and outcome of parenchyma sparing techniques versus surgical resection. A systematic review of the literature was carried out using MEDLINE, Embase and the Cochrane databases, based on the Preferred Reporting Items for Systematic Reviews and Meta-Analysis statement. Two separate searches of publications in endobronchial and surgical treatment in patients with pulmonary carcinoid, were performed. Outcomes were overall survival, disease free survival, recurrence rate, complications, quality of life, and healthcare costs. Combining the two main searches for endobronchial therapy and surgical therapy yielded 3111 records. Finally, 43 studies concerning surgical treatment and 9 studies related to endobronchial treatment for pulmonary carcinoid were included. Assessment of included studies showed that lymph node involvement, histological grade, tumor location and tumor diameter were identified as poor prognostic factors and seem to be important for patients with pulmonary carcinoid. For patients with a more favorable prognosis, tumor location and tumor diameter are important factors that can help decide on the optimal treatment strategy. Centrally located small intraluminal pulmonary carcinoids, without signs of metastasis can be treated with minimally invasive alternatives such as endobronchial treatment or parenchyma sparing surgical resection. Patients with parenchyma sparing resections should be followed with long term follow up to exclude recurrence of disease. In a multidisciplinary setting, it should be determined whether individual patients are eligible for parenchyma sparing procedures or anatomical resection. Overall evidence is of low quality and future studies should focus on prospective trials in the treatment of pulmonary carcinoid.

Coulomb Mediated Hybridization of Excitons in Coupled Quantum Dots.

We report Coulomb mediated hybridization of excitonic states in optically active InGaAs quantum dot molecules. By probing the optical response of an individual quantum dot molecule as a function of the static electric field applied along the molecular axis, we observe unexpected avoided level crossings that do not arise from the dominant single-particle tunnel coupling. We identify a new few-particle coupling mechanism stemming from Coulomb interactions between different neutral exciton states. Such Coulomb resonances hybridize the exciton wave function over four different electron and hole single-particle orbitals. Comparisons of experimental observations with microscopic eight-band k·p calculations taking into account a realistic quantum dot geometry show good agreement and reveal that the Coulomb resonances arise from broken symmetry in the artificial semiconductor molecule.

Exhaled molecular profiles in the assessment of cystic fibrosis and primary ciliary dyskinesia.

BACKGROUND: Early diagnosis and monitoring of disease activity are essential in cystic fibrosis (CF) and primary ciliary dyskinesia (PCD). We aimed to establish exhaled molecular profiles as the first step in assessing the potential of breath analysis. METHODS: Exhaled breath was analyzed by electronic nose in 25 children with CF, 25 with PCD and 23 controls. Principle component reduction and canonical discriminant analysis were used to construct internally cross-validated ROC curves. RESULTS: CF and PCD patients had significantly different breath profiles when compared to healthy controls (CF: sensitivity 84%, specificity 65%; PCD: sensitivity 88%, specificity 52%) and from each other (sensitivity 84%, specificity 60%). Patients with and without exacerbations had significantly different breath profiles (CF: sensitivity 89%, specificity 56%; PCD: sensitivity 100%, specificity 90%). CONCLUSION: Exhaled molecular profiles significantly differ between patients with CF, PCD and controls. The eNose may have potential in disease monitoring based on the influence of exacerbations on the VOC-profile.

Peak expiratory flow rate shows a gender-specific association with vitamin D deficiency.

CONTEXT: To our knowledge, no previous studies examined the longitudinal relationship between vitamin D status and pulmonary function in a population-based sample of older persons. OBJECTIVE: Our objective was to examine the cross-sectional as well as the longitudinal relationship between vitamin D status and peak expiratory flow rate (PEFR) in a representative sample of the Dutch older population. DESIGN, SETTING, AND PARTICIPANTS: Participants included men and women in the Longitudinal Aging Study Amsterdam, an ongoing cohort study in older people. MAIN OUTCOME MEASURE: PEFR was measured using the mini-Wright peak flow meter. RESULTS: Men with serum 25-hydroxyvitamin D (25-OHD) levels below 10 ng/ml (25 nmol/liter) had a significantly lower PEFR in the cross-sectional analyses, and men with serum 25-OHD levels below 20 ng/ml (50 nmol/liter) had a significantly lower PEFR in the longitudinal analyses as compared with men with serum 25-OHD levels above 30 ng/ml (75 nmol/liter) (cross-sectional: ß = -47.0, P = 0.01 for serum 25-OHD <10 ng/ml; longitudinal: ß = -45.0, P < 0.01 for serum 25-OHD <10 ng/ml; and ß = -20.2, P = 0.03 for serum 25-OHD = 10-20 ng/ml in the fully adjusted models). Physical performance (ß = -32.5, P = 0.08 for serum 25-OHD <10 ng/ml) and grip strength (ß = -40.0, P = 0.03 for serum 25-OHD <10 ng/ml) partly mediated the cross-sectional associations but not the longitudinal associations. In women, statistically significant associations between 25-OHD and PEFR were observed in the cross-sectional analyses after adjustment for age and season of blood collection but not in the fully adjusted models or in the longitudinal analyses. CONCLUSIONS: A strong relationship between serum 25-OHD and PEFR was observed in older men, both in the cross-sectional as well as longitudinal analyses, but not in older women. The association in men could partly be explained by physical performance and muscle strength.

A rare pulmonary infection caused by Arthrographis kalrae.

Arthrographis kalrae is a rare isolate in clinical specimens. Only ten cases of infection with this species have been described so far. To our knowledge, we report the first case of a pulmonary infection caused by A. kalrae in a patient with a past history of stage IIA Hodgkin's lymphoma and demonstrate that this organism can act as an opportunistic human pathogen.

Omega-3 fatty acids modulate collagen signaling in human platelets.

Dietary intake of the omega-3 fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) results in cardioprotective benefits. However, the cellular and physiological bases for these benefits remain unclear. We hypothesized that EPA and DHA treatments would interfere with collagen-mediated platelet signaling. Thirty healthy volunteers received 28 days of 3.4 g/d EPA+DHA with and without a single dose of aspirin. Clinical hematologic parameters were then measured along with assays of collagen-stimulated platelet activation and protein phosphorylation. Omega-3 therapy led to a small but significant reduction in platelets (6.3%) and red blood cells (1.7%), but did not impair clinical time-to-closure assays. However, collagen-mediated platelet signaling events of integrin activation, α-granule secretion, and phosphatidylserine exposure were all reduced by roughly 50% after omega-3 incorporation, and collagen-induced tyrosine phosphorylation was significantly impaired. The diminished platelet response to collagen may account for some of the cardioprotective benefits provided by DHA and EPA.

Lattice fluctuations at a double phonon frequency with and without squeezing: an exactly solvable model of an optically excited quantum dot.

Time-dependent lattice fluctuations of an optically excited strongly confined quantum dot are investigated with the aim to analyze the characteristics commonly used for identifying the presence of squeezed phonon states. It is demonstrated that the appearance of fluctuations oscillating with twice the phonon frequency, commonly regarded as a clear indication of squeezed states, cannot be considered as such. The source of the discrepancy with earlier investigations is discussed. Conditions for generating a squeezed state by using a two-pulse excitation are analyzed.

Sputum colour reported by patients is not a reliable marker of the presence of bacteria in acute exacerbations of chronic obstructive pulmonary disease.

Sputum colour is regarded as a good marker of bacterial involvement in acute exacerbations of chronic obstructive pulmonary disease (COPD) and guides many physicians in deciding on antibiotic treatment. Although most doctors rely on the sputum colour that is reported by patients, it can also be assessed using a validated colour chart. In this study, reported sputum colour and assessed sputum colour were compared as markers of the presence of bacteria, bacterial load, and systemic inflammation. Data on 257 exacerbations in 216 patients hospitalized with an acute exacerbation were analysed (mean age, 72 years; mean forced expiratory volume in 1 s, 44.8% + or - 17.8% (+ or - standard deviation)). Sputum colour was reported by the patients and assessed at the laboratory with a colour chart. Subsequently, quantitative sputum cultures were performed. C-reactive protein was measured as a marker of systemic inflammation. A sputum sample was obtained in 216 exacerbations (84%), of which 177 (82%) were representative. A pathogen was identified in 155 patients (60%). Assessed sputum colour was a better marker of the presence of bacteria (OR 9.8; 95% CI 4.7-20.4; p <0.001) than reported sputum colour (OR 1.7; 95% CI 1.0-3.0; p 0.041). The sensitivity and specificity were 73% and 39% for reported sputum colour, and 90% and 52% for assessed sputum colour. Assessed sputum colour was clearly related to sputum bacterial load and C-reactive protein levels, whereas reported sputum colour was not. It is concluded that sputum colour reported by patients is an unreliable marker of the presence of bacteria in acute exacerbations of COPD. Assessed sputum colour is clearly superior and is also related to bacterial load and systemic inflammation.

Tuberculosis complicating imatinib treatment for chronic myeloid leukaemia.

Although imatinib is not considered a predisposing factor for tuberculosis (TB), the present case report describes three patients in whom imatinib treatment for chronic myeloid leukaemia was complicated by TB. This raises the question of whether imatinib increases susceptibility to TB. There are several reports suggesting that imatinib might impair the immune system, leading to a variety of infections, including varicella zoster and hepatitis B. Control of TB in healthy individuals is achieved through acquired immunity, in which antigen-specific T-cells and macrophages arrest growth of Mycobacterium tuberculosis bacilli and maintain control over persistent bacilli. In the chronic stage of the infection, CD8+ T-cells assist macrophages in controlling intracellular mycobacteria. The T-cell receptor orchestrates this process. The fact that tyrosine kinases play an important role in T-cell receptor signal transduction and that imatinib has been shown to affect T-cell receptor signal transduction, presents a mechanism by which imatinib might impair control of Mycobacterium tuberculosis; thereby leaving the host susceptible to reactivation of tuberculosis.

Should medical students learn to develop a personal formulary? An international, multicentre, randomised controlled study.

OBJECTIVE: This study was performed to determine whether students who are trained in developing a personal formulary become more competent in rational prescribing than students who have only learned to use existing formularies. METHODS: This was a multicentre, randomised, controlled study conducted in eight universities in India, Indonesia, the Netherlands, the Russian Federation, Slovakia, South Africa, Spain and Yemen. Five hundred and eighty-three medical students were randomised into three groups: the personal formulary group (PF; 94), the existing formulary group (EF; 98) and the control group (C; 191). The PF group was taught how to develop and use a personal formulary, whereas e the EF group was taught how to review and use an existing formulary. The C group received no additional training and participated only in the tests. Student's prescribing skills were measured by scoring their treatment plans for written patient cases. RESULTS: The mean PF group score increased by 23% compared with 19% for the EF group (p < 0.05) and 6% for controls (p < 0.05). The positive effect of PF training was only significant in universities that had a mainly classic curriculum. CONCLUSION: Training in development and use of a personal formulary was particularly effective in universities with a classic curriculum and with traditional pharmacology teaching. In universities with a general problem-based curriculum, pharmacotherapy teaching can be based on either existing or personal formularies.

[Rhabdomyolysis in a bodybuilder using steroids]. / Rabdomyolyse bij een bodybuilder na gebruik van diverse dopingmiddelen.

A 34-year-old bodybuilder presented at the emergency room with fever, vomiting and muscle cramps that had started during a bodybuilding session. Several days before he started training he had used tablets and intramuscular injections containing the anabolic steroids: dehydro-chloro-methyltestosterone, boldenone and trenbolone. In addition, he had taken clenbuterol tablets, liothyronine tablets and subcutaneous injections of phosphatidylcholine. Laboratory investigations revealed massive rhabdomyolysis. The patient was treated with intravenous fluid replacement and sodium bicarbonate to alkalinize the urine. He recovered quickly and his renal function remained unaffected. 'Doping' among amateur athletes in the Netherlands occurs frequently. Apart from long term side-effects, doping can also cause acute health problems. Therefore it is important to ask about doping use during history taking in amateur athletes.

[Pulmonary infection caused by non-tuberculous mycobacteria in two patients with bronchiectasis]. / Infectie met niet-tuberculeuze mycobacteriën bij 2 patiënten met bronchiëctasieën.

Two patients, a woman aged 67 years and a man aged 80 years, had chronic cough among other respiratory symptoms. In the woman, chest radiograph and CT-scan revealed partial atelectasis of the middle lobe and bronchiectasis. In the man, an interstitial pattern was seen on chest radiograph, and CT scan showed diffuse bronchiectasis. In both the man and the woman, non-tuberculous mycobacteria were identified (Mycobacterium avium complex and Mycobacterium abscessus, respectively). Treatment was successful in both patients. Non-tuberculous mycobacteria can cause considerable pulmonary infection in patients with bronchiectasis.

[Bronchocentric granulomatosis and mycoplasmal pneumonia]. / Bronchocentrische granulomatose en Mycoplasma-pneumonie.

A 61-year-old man presented with dyspnoea, chest pain, high fever and rigour. Chest X-ray revealed a combination of alveolar consolidations and abnormal nodular and interstitial markings. His clinical condition deteriorated despite treatment with antibiotics prescribed on a working diagnosis of pneumonia with an atypical pathogen. Finally, an open-lung biopsy specimen showed the characteristic picture of bronchocentric granulomatosis. Serological testing supported a primary infection with Mycoplasma pneumoniae. The patient responded well to treatment with prednisolone and erythromycin and five months after discharge, no radiological abnormalities were found. The combination of bronchocentric granulomatosis and mycoplasmal pneumonia has never been described in the literature and a causal relation can only be suggested. This case-report illustrates the importance of invasive diagnostic procedures if a patient with a clinical pneumonia fails to respond to adequate treatment.

Detection and clearance of prostate cells subsequent to ultrasound-guided needle biopsy as determined by multiplex nested reverse transcription polymerase chain reaction assay.

OBJECTIVES: To determine if circulating prostate cells are detectable subsequent to transrectal ultrasound (TRUS)-guided biopsy, and if so, whether cells remain in circulation for up to 4 weeks. METHODS: Blood samples were drawn from 90 patients with elevated serum prostate-specific antigen (PSA) levels and/or abnormal digital rectal examination. Two samples were drawn from all patients immediately prior to TRUS and 30 minutes postbiopsy. Blood samples were also obtained 1 week postbiopsy from 83 patients, and 1 month postbiopsy from 61 patients. Multiplex nested reverse transcription polymerase chain reaction assay (RT-PCR) for PSA and prostate-specific membrane antigen (PSM) was performed on total ribonucleic acid (RNA) from each sample. Results were reported as positive if at least one of the targets was detected. RESULTS: Of 45 patients with biopsy-proven adenocarcinoma, 22 were RT-PCR positive prebiopsy and all remained positive 30 minutes postbiopsy. Of 23 patients with adenocarcinoma who were RT-PCR negative prebiopsy, 5 (22%) converted to positive 30 minutes postbiopsy (P < 0.001). Four of these 5 patients returned to negative after 1 week or 1 month. Of 45 patients without cancer at biopsy, 32 were RT-PCR negative prebiopsy and 6 (19%) converted to positive 30 minutes postbiopsy (P < 0.001). Although four of six available samples were still positive at 1 week, all four samples available 1 month postbiopsy were negative. CONCLUSIONS: Detection of circulating prostate cells subsequent to biopsy occurred in 11 of 55 (20%) previously RT-PCR negative patients, a proportion twice that reported in the literature. We attribute this higher proportion to the simultaneous detection of PSA and PSM mRNA in our multiplex assay. Conversion rates were similar in patients regardless of biopsy result. Testing of serial postbiopsy blood demonstrates clearing of these cells by 4 weeks in most patients.

Treatment of occupationally acquired low back pain.

Lumbosacral back pain is one of the most common reasons for patients with a work-related injury to present to a primary care physician. In most cases, low back pain has a good prognosis, but the condition is often the source of much frustration for clinicians, patients and employers. The family physician should be able to treat the patient's symptoms and address the psychosocial issues that frequently complicate recovery. Three decision points, based on the history and physical examination, allow the physician to determine the severity of illness and implement an appropriate treatment plan. These three points are as follows: Is it likely that systemic disease or bone pathology is the cause of pain? Has neurologic compromise occurred? Are social or psychologic stressors present that may prolong the clinical course?