A new tidal breathing measurement device detects bronchial obstruction during methacholine challenge test.

PURPOSE: Bronchial hyperresponsiveness (BHR), a hallmark of bronchial asthma, is typically diagnosed through a methacholine inhalation test followed by spirometry, known as the methacholine challenge test (MCT). While spirometry relies on proper patients' cooperation and precise execution of forced breathing maneuvers, we conducted a comparative analysis with the portable nanomaterial-based sensing device, SenseGuard™, to non-intrusively assess tidal breathing parameters. MATERIALS AND METHODS: In this prospective study, 37 adult participants with suspected asthma underwent sequential spirometry and SenseGuard™ measurements after inhaling increasing methacholine doses. RESULTS: Among the 37 participants, 18 were MCT responders, 17 were non-responders and 2 were excluded due to uninterpretable data. The MCT responders exhibited a significant lung function difference when comparing the change from baseline to maximum response. This was evident through a notable decrease in forced expiratory volume in 1 â€‹s (FEV1) levels in spirometry, as well as in prominent changes in tidal breathing parameters as assessed by SenseGuard™, including the expiratory pause time (Trest) to total breath time (Ttot) ratio, and the expiratory time (Tex) to Ttot ratio. Notably, the ratios Trest/Ttot (∗p â€‹= â€‹0.02), Tex/Ttot (∗p â€‹= â€‹0.002), and inspiratory time (Tin) to Tex (∗p â€‹= â€‹0.04) identified MCT responders distinctly, corresponding to spirometry (∗p â€‹< â€‹0.0001). CONCLUSIONS: This study demonstrates that tidal breathing assessment using SenseGuard™ device reliably detects clinically relevant changes of respiratory parameter during the MCT. It effectively distinguishes between responders and non-responders, with strong agreement to conventional spirometry-measured FEV1. This technology holds promise for monitoring clinical respiratory changes in bronchial asthma patients pending further studies.

Changes in tidal breathing biomarkers as indicators of treatment response in AECOPD patients in an acute care setting.

PURPOSE: Acute exacerbation of chronic obstructive pulmonary disease (AECOPD) is a complication of COPD that typically necessitates intensified treatment and hospitalization. It is linked to higher morbidity, mortality and healthcare spending. Assessment of therapy response for AECOPD is difficult due to the variability of symptoms and limitations in current measures. Hence, there is a need for new biomarkers to aid in the management of AECOPD in acute care settings. MATERIALS AND METHODS: Fifteen hospitalized AECOPD patients (GOLD 3-4) were enrolled in this study. Treatment response was assessed daily through clinical evaluations and by monitoring tidal breathing biomarkers (respiratory rate [RR], expiratory time [Tex], inspiratory time [Tin], expiratory pause [Trst], total breath time [Ttot]), using a novel, wearable nanosensor-based device (SenseGuard™). RESULTS: Patients who showed significant clinical improvement had substantial changes in ΔTex/Ttot (+14%), ΔTrst/Ttot (-18%), and ΔTin/Tex (+0.09), whereas patients who showed mild or no clinical improvement had smaller changes (+5%, +3%, and -0.03, respectively). Linear regression between change in physician's assessment score and the median change in tidal breathing parameters was significant for Tin/Tex (R2 â€‹= â€‹0.449, ∗p â€‹= â€‹0.017), Tex/Ttot (R2 â€‹= â€‹0.556, ∗p â€‹= â€‹0.005) and Trst/Ttot (R2 â€‹= â€‹0.446, ∗p â€‹= â€‹0.018), while no significant regression was observed for RR, Tin/(Trst â€‹+ â€‹Tex) and Tin/Ttot. CONCLUSIONS: Our study demonstrates the potential of the SenseGuard™ to monitor treatment response in AECOPD patients by measuring changes in tidal breathing biomarkers, which were shown to be associated with significant changes in the patients' respiratory condition as evaluated by physicians. However, further large-scale clinical studies are needed to confirm these findings.

Clinical Scores, Biomarkers and IT Tools in Lung Cancer Screening-Can an Integrated Approach Overcome Current Challenges?

As most lung cancer (LC) cases are still detected at advanced and incurable stages, there are increasing efforts to foster detection at earlier stages by low dose computed tomography (LDCT) based LC screening. In this scoping review, we describe current advances in candidate selection for screening (selection phase), technical aspects (screening), and probability evaluation of malignancy of CT-detected pulmonary nodules (PN management). Literature was non-systematically assessed and reviewed for suitability by the authors. For the selection phase, we describe current eligibility criteria for screening, along with their limitations and potential refinements through advanced clinical scores and biomarker assessments. For LC screening, we discuss how the accuracy of computerized tomography (CT) scan reading might be augmented by IT tools, helping radiologists to cope with increasing workloads. For PN management, we evaluate the precision of follow-up scans by semi-automatic volume measurements of CT-detected PN. Moreover, we present an integrative approach to evaluate the probability of PN malignancy to enable safe decisions on further management. As a clear limitation, additional validation studies are required for most innovative diagnostic approaches presented in this article, but the integration of clinical risk models, current imaging techniques, and advancing biomarker research has the potential to improve the LC screening performance generally.

Improved guideline adherence in oncology through clinical decision-support systems: still hindered by current health IT infrastructures?

PURPOSE OF REVIEW: Despite several efforts to enhance guideline adherence in cancer management, the rate of adherence remains often dissatisfactory in clinical routine. Clinical decision-support systems (CDSS) have been developed to support the management of cancer patients by providing evidence-based recommendations. In this review, we focus on both current evidence supporting the beneficial effects of CDSS on guideline adherence as well as technical and structural requirements for CDSS implementation in clinical routine. RECENT FINDINGS: Some studies have demonstrated a significant improvement of guideline adherence by CDSSs in oncologic diseases such as breast cancer, colon cancer, cervical cancer, prostate cancer, and hepatocellular carcinoma as well as in the management of cancer pain. However, most of these studies were rather small and designs rather simple. One reason for this limited evidence might be that CDSSs are only occasionally implemented in clinical routine. The main limitations for a broader implementation might lie in the currently existing clinical data infrastructures that do not sufficiently allow CDSS interoperability as well as in some CDSS tools themselves, if handling is hampered by poor usability. SUMMARY: In principle, CDSSs improve guideline adherence in clinical cancer management. However, there are some technical und structural obstacles to overcome to fully implement CDSSs in clinical routine.

Beyond tissue biopsy: a diagnostic framework to address tumor heterogeneity in lung cancer.

PURPOSE OF REVIEW: The objective of this review is to discuss the strength and limitations of tissue and liquid biopsy and functional imaging to capture spatial and temporal tumor heterogeneity either alone or as part of a diagnostic framework in non-small cell lung cancer (NSCLC). RECENT FINDINGS: NSCLC displays genetic and phenotypic heterogeneity - a detailed knowledge of which is crucial to personalize treatment. Tissue biopsy often lacks spatial and temporal resolution. Thus, NSCLC needs to be characterized by complementary diagnostic methods to resolve heterogeneity. Liquid biopsy offers detection of tumor biomarkers and for example, the classification and monitoring of EGFR mutations in NSCLC. It allows repeated sampling, and therefore, appears promising to address temporal aspects of tumor heterogeneity. Functional imaging methods and emerging image analytic tools, such as radiomics capture temporal and spatial heterogeneity. Further standardization of radiomics is required to allow introduction into clinical routine. SUMMARY: To augment the potential of precision therapy, improved diagnostic characterization of tumors is pivotal. We suggest a comprehensive diagnostic framework combining tissue and liquid biopsy and functional imaging to address the known aspects of spatial and temporal tumor heterogeneity on the example of NSCLC. We envision how this framework might be implemented in clinical practice.

Radiation Exposure During Uterine Fibroid Embolization (UFE): A Confounder-Controlled Comparison Between a State-of-the-Art Angiography Unit and a Conventional Angiography unit.

PURPOSE: To compare radiation exposure of a state-of-the-art and a conventional angiography unit in patients undergoing uterine fibroid embolization (UFE). MATERIALS AND METHODS: Between January 2009 and December 2016, 286 patients underwent UFE in our Interdisciplinary Fibroid Center. The inclusion criteria for this retrospective analysis were first-time transarterial embolization for symptomatic fibroids, bilateral embolization, procedures applying a state-of-the-art (Group 1) or a conventional angiography unit (Group 2), and bilateral technical success with an adequate embolization endpoint after the injection of microspheres. Study endpoints included radiation exposure, major complications, morphological success (MRI), and clinical success (questionnaire on quality-of-life). Propensity score matching controlled for confounders. RESULTS: The inclusion criteria were met by 58 (Group 1) and 177 (Group 2) patients. After propensity score matching, there was no significant difference between Group 1 (n = 46) and Group 2 (n = 92) regarding age, body-mass index, volume of the dominant fibroid and the uterus, fluoroscopy time, and amount of embolic agent (p ≥ 0.10 each). The dose-area product was significantly lower in Group 1 than in Group 2 (1159.0 cGycm2 vs. 3123.5 cGycm2; p < 0.001), while major complication rates (both groups 0 %) and dominant fibroid devascularization (both groups 100 %) were equal (p > 0.99). There were no significant differences between both groups regarding shrinkage of the dominant fibroid and the uterus and no relevant differences regarding patient-reported quality-of-life. CONCLUSION: A state-of-the-art angiography unit has the potential to reduce radiation exposure in patients undergoing UFE without increasing the risk of major complications and with comparably high morphological and clinical success. KEY POINTS: · A state-of-the-art angiography unit potentially reduces radiation exposure in patients undergoing UFE.. · Reduced radiation exposure does not seem to negatively influence the rate of major complications.. · Reduced exposure does not seem to negatively affect morphological and clinical success.. CITATION FORMAT: · Sommer C, Voigt W, Oliger MK et al. Radiation Exposure During Uterine Fibroid Embolization (UFE): A Confounder-Controlled Comparison Between a State-of-the-Art Angiography Unit and a Conventional Angiography unit. Fortschr Röntgenstr 2018; 190: 250 - 258.

Advanced PET imaging in oncology: status and developments with current and future relevance to lung cancer care.

PURPOSE OF REVIEW: This review highlights the status and developments of PET imaging in oncology, with particular emphasis on lung cancer. We discuss the significance of PET for diagnosis, staging, decision-making, monitoring of treatment response, and drug development. The PET key advantage, the noninvasive assessment of functional and molecular tumor characteristics including tumor heterogeneity, as well as PET trends relevant to cancer care are exemplified. RECENT FINDINGS: Advances of PET and radiotracer technology are encouraging for multiple fields of oncological research and clinical application, including in-depth assessment of PET images by texture analysis (radiomics). Whole body PET imaging and novel PET tracers allow assessing characteristics of most types of cancer. However, only few PET tracers in addition to F-fluorodeoxyglucose have sufficiently been validated, approved, and are reimbursed for a limited number of indications. Therefore, validation and standardization of PET parameters including tracer dosage, image acquisition, post processing, and reading are required to expand PET imaging as clinically applicable approach. SUMMARY: Considering the potential of PET imaging for precision medicine and drug development in lung and other types of cancer, increasing efforts are warranted to standardize PET technology and to provide evidence for PET imaging as a guiding biomarker in nearly all areas of cancer treatment.

Management of Progressive Pulmonary Nodules Found during and outside of CT Lung Cancer Screening Studies.

Although the effectiveness of screening for lung cancer remains controversial, it is a fact that most lung cancers are diagnosed at an advanced stage outside of lung cancer screening programs. In 2013, the U.S. Preventive Services Task Force revised its lung cancer screening recommendation, now supporting lung cancer screening by low-dose computed tomography in patients at high risk. This is also endorsed by many major medical societies and advocacy group stakeholders, albeit with different eligibility criteria. In Europe, population-based lung cancer screening has so far not been recommended or implemented, as some important issues remain unresolved. Among them is the open question of how enlarging pulmonary nodules detected in lung cancer screening should be managed. This article comprises two parts: a review of the current lung cancer screening approaches and the potential therapeutic options for enlarging pulmonary nodules, followed by a meeting report including consensus statements of an interdisciplinary expert panel that discussed the potential of the different therapeutic options.

Efficacy of targeted drugs in germ cell cancer cell lines with differential cisplatin sensitivity.

METHODS: The in vitro activity of kinase inhibitors targeting mTOR (RAD001), EGFR, HER2/neu, VEGFR (AEE788) and IGF-1R (AEW541) alone or in combination with cisplatin was tested in the cisplatin sensitive TGCT cell lines H12.1 and GCT72 as well as in the resistant cell lines H12.1RA, H12.1D, 1411HP and 1777NRpmet using the sulforhodamin-B-(SRB)-cytotoxicity-assay. To evaluate the activity of the kinase inhibitors, western blot analysis of the targeted receptors and their phosphorylated state was performed before and after exposure to each substance. RESULTS: The different kinase inhibitors demonstrated significant cell growth inhibition in both cisplatin sensitive and resistant cell lines. The examined cell lines showed different protein expression levels of the targeted receptors. However there was no correlation between the targeted receptor expression and phosphorylation level and the antiproliferative effect of the respective agent. Furthermore, the combination of cisplatin and the kinase inhibitors exerted both additive and antagonistic effects in the studied cell lines. CONCLUSION: Our data suggest potential activity of the investigated kinase inhibitors in both cisplatin sensitive and resistant TGCT cell lines as a single agent. However, when combined with cisplatin they did not demonstrate any promising ability to overcome cisplatin resistance in TGCTs.

From diagnosis to therapy in lung cancer: management of CT detected pulmonary nodules, a summary of the 2015 Chinese-German Lung Cancer Expert Panel.

The first Chinese-German Lung Cancer Expert Panel was held in November 2015 one day after the 7th Chinese-German Lung Cancer Forum, Shanghai. The intention of the meeting was to discuss strategies for the diagnosis and treatment of lung cancer within the context of lung cancer screening. Improved risk classification criteria and novel imaging approaches for screening populations are highly required as more than half of lung cancer cases are false positive during the initial screening round if the National Lung Screening Trial (NLST) demographic criteria [≥30 pack years (PY) of cigarettes, age ≥55 years] are applied. Moreover, if the NLST criteria are applied to the Chinese population a high number of lung cancer patients are not diagnosed due to non-smoking related risk factors in China. The primary goal in the evaluation of pulmonary nodules (PN) is to determine whether they are malignant or benign. Volumetric based screening concepts such as investigated in the Dutch-Belgian randomized lung cancer screening trial (NELSON) seem to achieve higher specificity. Chest CT is the best imaging technique to identify the origin and location of the nodule since 20% of suspected PN found on chest X-ray turn out to be non-pulmonary lesions. Moreover, novel state-of-the-art CT systems can reduce the radiation dose for lung cancer screening acquisitions down to a level of 0.1 mSv with improved image quality to novel reconstruction techniques and thus reduce concerns related to chest CT as the primary screening technology. The aim of the first part of this manuscript was to summarize the current status of novel diagnostic techniques used for lung cancer screening and minimally invasive treatment techniques for progressive PNs that were discussed during the first Chinese-German Lung Cancer. This part should serve as an educational part for the readership of the techniques that were discussed during the Expert Panel. The second part summarizes the consensus recommendations that were interdisciplinary discussed by the Expert Panel.

Perspectives of novel imaging techniques for staging, therapy response assessment, and monitoring of surveillance in lung cancer: summary of the Dresden 2013 Post WCLC-IASLC State-of-the-Art Imaging Workshop.

Modern imaging techniques that can provide functional information on tumor vascularization, metabolic activity, or cellularity have seen significant improvements over the past decade. However, most of these techniques are currently not broadly utilized neither in clinical trials nor in clinical routine, although there is a large agreement on the fact that conventional approaches for therapy response assessment such as Response Evaluation Criteria in Solid Tumors or World Health Organization criteria-that exclusively focus on the change in tumor size-are of less value for response assessment in modern thoracic oncology. The aim of this article comprises two parts: a short review of the most promising state-of-the-art imaging techniques that have the potential to play a larger role in thoracic oncology within the near future followed by a meeting report including recommendations of an interdisciplinary expert panel that discussed the potential of the different techniques during the Dresden 2013 Post World Congress of Lung Cancer (WCLC)--International Association for the Study of Lung Cancer (IASLC) meeting. It is intended to provide a comprehensive summary about ongoing trends and future perspectives on functional imaging in thoracic oncology.

'Act on oncology' as a new comprehensive approach to assess prostate cancer centres--method description and results of a pilot study.

BACKGROUND: Multidisciplinary care of prostate cancer is increasingly offered in specialised cancer centres. It requires the optimisation of medical and operational processes and the integration of the different medical and non-medical stakeholders. OBJECTIVE: To develop a standardised operational process assessment tool basing on the capability maturity model integration (CMMI) able to implement multidisciplinary care and improve process quality and efficiency. DESIGN, SETTING, AND PARTICIPANTS: Information for model development was derived from medical experts, clinical guidelines, best practice elements of renowned cancer centres, and scientific literature. Data were organised in a hierarchically structured model, consisting of 5 categories, 30 key process areas, 172 requirements, and more than 1500 criteria. Compliance with requirements was assessed through structured on-site surveys covering all relevant clinical and management processes. Comparison with best practice standards allowed to recommend improvements. 'Act On Oncology'(AoO) was applied in a pilot study on a prostate cancer unit in Europe. RESULTS AND LIMITATIONS: Several best practice elements such as multidisciplinary clinics or advanced organisational measures for patient scheduling were observed. Substantial opportunities were found in other areas such as centre management and infrastructure. As first improvements the evaluated centre administration described and formalised the organisation of the prostate cancer unit with defined personnel assignments and clinical activities and a formal agreement is being worked on to have structured access to First-Aid Posts. CONCLUSIONS: In the pilot study, the AoO approach was feasible to identify opportunities for process improvements. Measures were derived that might increase the operational process quality and efficiency.

Prospective Assessment of an innovative test for prostate cancer screening using the VITA process model framework.

Healthcare innovations are crucial for enhancing patient treatment and a high-quality healthcare system. However, bringing new technologies, methods and procedures into the healthcare market is challenging. Enormous amounts of financial, personnel and organizational resources are required with no upfront certainty for the medical and economic benefit. A new and innovative approach uses interdisciplinary medical, technical and economic expertise to forecast effects of healthcare innovations already at the early research and concept phase of an idea and before major investments are made. A process model framework was developed to operationalize this structured assessment of healthcare innovations. The Visionary Iterative Tailored Approach (VITA) is based on conceptual modeling, simulation and health economics evaluation. Its application for the prospective assessment of an innovative prostate cancer screening is presented.

Economic constraints - the growing challenge for Western breast cancer centers.

Breast cancer care in Western countries has reached a considerable level of quality and standardization, which has contributed to the decline in breast cancer mortality. Certified Breast Cancer Centers (BCC) represent an important element of this development. Related to changes in reimbursement and growing costs, BCC face economic constraints which ultimately could endanger the achievements of the past. Thus, BCC have to optimize their care strategies from an economic perspective, particularly by increasing efficiency but also by adapting their service portfolio. This could result in competitive advantages and additional revenue by increasing case numbers and extra charges to patients. Furthermore, an intensification of collaboration with the outpatient sector resulting in an integrated and managed 'trans-sectoral' care approach which could allow to shift unprofitable procedures to the outpatient sector - in the sense of a win-win situation for both sectors and without loss of care quality - seems reasonable. Structured and specialized consulting approaches can further be a lever to fulfill economic requirements in order to avoid cuts in medical care quality for the sake of a balanced budget. In this review, economic constraints of BCC with a focus on the German healthcare system and potential approaches to ameliorate these financial burdens are being discussed.

Fermented wheat germ extract--nutritional supplement or anticancer drug?

BACKGROUND: Fermented wheat germ extract (FWGE) is a multisubstance composition and, besides others, contains 2-methoxy benzoquinone and 2, 6-dimethoxy benzoquinone which are likely to exert some of its biological effects. FWGE interferes with anaerobic glycolysis, pentose cycle and ribonucleotide reductase. It has significant antiproliferative effects and kills tumor cells by the induction of apoptosis via the caspase-poly [ADP-ribose] polymerase-pathway. FWGE interacts synergistically with a variety of different anticancer drugs and exerted antimetastatic properties in mouse models. In addition, FWGE modulates immune response by downregulation of MHC-I complex and the induction of TNF-α and various interleukins. Data in the F-344 rat model provide evidence for a colon cancer preventing effect of FWGE.Clinical data from a randomized phase II trial in melanoma patients indicate a significant benefit for patients treated with dacarbazine in combination with FWGE in terms of progression free survival (PFS) and overall survival (OS). Similarly, data from studies in colorectal cancer suggested a benefit of FWGE treatment. Besides extension of OS and PFS, FWGE improved the quality of life in several studies. CONCLUSION: In conclusion, available data so far, justify the use of FWGE as a non-prescription medical nutriment for cancer patients. Further randomized, controlled and large scale clinical studies are mandatory, to further clarify the value of FWGE as a drug component of future chemotherapy regimens.

Promising cytotoxic activity profile of fermented wheat germ extract (Avemar®) in human cancer cell lines.

Fermented wheat germ extract (FWGE) is currently used as nutrition supplement for cancer patients. Limited recent data suggest antiproliferative, antimetastatic and immunological effects which were at least in part exerted by two quinones, 2-methoxy benzoquinone and 2,6-dimethoxybenzquinone as ingredients of FWGE. These activity data prompted us to further evaluate the in vitro antiproliferative activity of FWGE alone or in combination with the commonly used cytotoxic drugs 5-FU, oxaliplatin or irinotecan in a broad spectrum of human tumor cell lines. We used the sulforhodamine B assay to determine dose response relationships and IC50-values were calculated using the Hill equation. Drug interaction of simultaneous and sequential drug exposure was estimated using the model of Drewinko and potential clinical activity was assessed by the model of relative antitumor activity (RAA). Apoptosis was detected by DNA gel electrophoresis.FWGE induced apoptosis and exerted significant antitumor activity in a broad spectrum of 32 human cancer cell lines. The highest activity was found in neuroblastoma cell lines with an average IC50 of 0.042 mg/ml. Furthermore, IC50-range was very narrow ranging from 0.3 mg/ml to 0.54 mg/ml in 8 colon cancer cell lines. At combination experiments in colon cancer cell lines when FWGE was simultaneously applied with either 5-FU, oxaliplatin or irinotecan we observed additive to synergistic drug interaction, particularly for 5-FU. At sequential drug exposure with 5-FU and FWGE the observed synergism was abolished.Taken together, FWGE exerts significant antitumor activity in our tumor model. Simultaneous drug exposure with FWGE and 5-FU, oxaliplatin or irinotecan yielded in additive to synergistic drug interaction. However, sequential drug exposure of 5-FU and FWGE in colon cancer cell lines appeared to be schedule-dependent (5-FU may precede FWGE).Further evaluation of FWGE as a candidate for clinical combination drug regimens appeared to be warranted.

Magnetic resonance imaging of intramuscular metastases.

OBJECTIVE: The aim of the present study was to analyse magnetic resonance findings of intramuscular metastases (IM) in a relatively large series. MATERIALS AND METHODS: From January 2000 to January 2010, 28 patients (207 metastases) were retrospectively identified in the radiological database of the Martin-Luther-University. Several different scanning protocols were used depending on the localisation of IM. In 12 patients diffusion-weighted (DW) images were obtained with a multi-shot SE-EPI sequence. Apparent diffusion coefficient (ADC) maps were also calculated. Furthermore, fusion images were manually generated between the DW and half-Fourier acquisition single-shot turbo spin echo (HASTE) images. RESULTS: On T2-weighted images, 97% of the recognised IM were hyperintense in comparison to unaffected musculature, and 3% were mixed iso- to hyperintense. On T1-weighted images most IM (91%) were homogeneously isointense in comparison to muscle tissue, whereas 4% were hypointense, and 5% lightly hyperintense. ADC maps were calculated for 91 metastases ranging from 0.99 to 4.00 mm(2)s(-1) (mean value 1.99 ± 0.66). ADC values of low (<1.5) signal intensity (SI) were identified in 26%, moderate SI (from 1.5 to 3.0) in 68%, and high SI (>3.0) in 6%. Of the IM that were investigated with contrast medium, 88.5% showed marked enhancement. It was homogeneous in 88% and heterogenous in 6%. Rim enhancement with central low attenuation was seen in 6%. There was no difference in enhancement characteristics with respect to ADC values or fusion patterns. Peritumoral enhancement was identified in 2.4%. CONCLUSION: Magnetic resonance features of muscle metastases are relatively typical and consist of round or oval intramuscular masses with well-defined margins, marked enhancement, low or moderate ADC values, and moderate to high signal intensity on fusion images.

Sequential X-irradiation induced acquired resistance to oxaliplatin but increased sensitivity to cisplatin in two human teratoma cell lines in vitro.

UNLABELLED: Cisplatin (CDDP) and oxaliplatin (OXA-P) are potential therapeutic drugs in the treatment of testicular cancer. However, the emergence of drug resistance has been documented not only in patients after chemotherapy but also subsequently to fractionated X-irradiation. Specific radiation-induced biochemical alterations may play a role in the observed resistance. Since irradiation influences the cellular responses to chemotherapy, this study investigated changes in the expression of key proteins in the regulation of DNA repair and apoptosis subsequent to sequential irradiation. MATERIALS AND METHODS: Logarithmically growing human teratocarcinoma cell lines 2101 EP and H 12.1 were irradiated (10 fractions of 4 Gy in vitro) to establish the sub-lines 2101 EP/DXR-10 and H 12.1/DXR-10. Radiosensitivity was assayed using a clonogenic survival assay. Drug response was assayed using a sulforhodamine B assay. Expression of p53, PARP, hMSH2 and Fas was detected by Western blotting. RESULTS: Both DXR-10 sub-lines showed a significant increase in sensitivity towards CDDP as compared to their parental cell line, however, there was a concomitant increase in resistance against OXA-P. No significant changes in radiosensitivity between parental and DXR-10 cell lines were observed. In addition, there was an up-regulation of PARP, p53, hMSH2 and Fas in the DXR-10 sub-lines, implicating induced damage tolerance and repair mechanisms following irradiation. CONCLUSION: These results suggest that radiation preceding chemotherapy might induce resistance to subsequent chemotherapy with oxaliplatin but not to cisplatin. This is a novel observation and, if confirmed, particularly in other tumor types, may have clinical implications.

Chemotherapy-induced diarrhea: pathophysiology, frequency and guideline-based management.

Diarrhea is one of the main drawbacks for cancer patients. Possible etiologies could be radiotherapy, chemotherapeutic agents, decreased physical performance, graft versus host disease and infections. Chemotherapy-induced diarrhea (CID) is a common problem, especially in patients with advanced cancer. The incidence of CID has been reported to be as high as 50-80% of treated patients (≥30% CTC grade 3-5), especially with 5-fluorouracil bolus or some combination therapies of irinotecan and fluoropyrimidines (IFL, XELIRI). Regardless of the molecular targeted approach of tyrosine kinase inhibitors and antibodies, diarrhea is a common side effect in up to 60% of patients with up to 10% having severe diarrhea. Furthermore, the underlying pathophysiology is still under investigation. Despite the number of clinical trials evaluating therapeutic or prophylactic measures in CID, there are just three drugs recommended in current guidelines: loperamide, deodorized tincture of opium and octreotide. Newer strategies and more effective agents are being developed to reduce the morbidity and mortality associated with CID. Recent research focusing on the prophylactic use of antibiotics, budesonide, probiotics or activated charcoal still have to define the role of these drugs in the routine clinical setting. Whereas therapeutic management and clinical work-up of patients presenting with diarrhea after chemotherapy are rather well defined, prediction and prevention of CID is an evolving field. Current research focuses on establishing predictive factors for CID like uridine diphosphate glucuronosyltransferase-1A1 polymorphisms for irinotecan or dihydropyrimidine-dehydrogenase insufficiency for fluoropyrimidines.

Safety and efficacy of weekly 5-fluorouracil/folinic acid/oxaliplatin/irinotecan in the first-line treatment of gastrointestinal cancer.

BACKGROUND: Standard chemotherapy for patients with metastatic colorectal cancer (mCRC) or gastric cancer (GC) consists of two-drug, usually fluoropyrimidine-based, combinations, with or without the addition of biological agents. Studies of triple-drug regimens combining 5-fluorouracil (5-FU)/folinic acid (FA) with both oxaliplatin and irinotecan have shown promising efficacy in studies of patients with mCRC or GC. However, improved efficacy has often been achieved at the expense of high rates of grade 3 or 4 toxicities such as neutropenia and diarrhoea, occasionally even resulting in toxic deaths. OBJECTIVE/METHODS: We performed a phase II study of previously untreated patients with mCRC or GC to assess the safety and efficacy of our 5-fluorouracil/folinic acid/oxaliplatin/irinotecan (FUFOXIRI) regimen with weekly administration of irinotecan 70 mg/m(2), oxaliplatin 50 mg/m(2), FA 500 mg/m(2) and 5-FU 2000 mg/m(2) on days 1, 8, 15 and 22, repeated from day 36. RESULTS: A total of 22 patients were enrolled, 11 each with mCRC and GC receiving a median of four cycles per patient. The FUFOXIRI regimen was generally well tolerated with no toxic deaths, neutropenic fever or grade 4 toxicities. Most common grade 3 side effects were diarrhoea and neutropenia each affecting 24% of patients. Dose reductions due to toxicity were performed in 48% of all and 60% of patients having received at least two cycles of FUFOXIRI. The overall response rate was 46% (all partial responses), 55% and 36% for patients with mCRC and GC, respectively. Median progression-free survival for all patients, mCRC and GC patients was 9.5, 10.0 and 8.0 months, respectively. The median overall survival for all patients was 16.5, 18.0 and 15.0 months for patients with mCRC and GC, respectively. CONCLUSION: These data show excellent tolerance and efficacy of the FUFOXIRI regimen in both mCRC and GC. Therefore, FUFOXIRI is a promising backbone for future studies incorporating biologic 'targeted' agents for the treatment of gastrointestinal cancers.