Cancer is the second leading cause of death and is responsible for approximately 9.6 million deaths worldwide in 2018. Among all oncological diseases, lung cancer claims the highest mortality (male: 23.5%; female: 22%) and the second most new cases (male: 13%; female: 12%) in the US. Approximately 40% of newly diagnosed lung cancer patients are in the advanced stage IV, for which platinum-based chemotherapy is the first-line treatment, either by itself or in combination with surgery or radiotherapy. Cisplatin, the first-generation platinum-based anticancer chemotherapeutic agent, has the highest potency against lung cancer but carries many severe adverse effects. Cisplatin also induces drug resistance during long-term chemotherapy. Many more platinum complexes have been investigated as better alternatives, which led to the approval of carboplatin and oxaliplatin by Food and Drug Administration (FDA). In addition, miriplatin suspended in iodolipds (lipiodolization) was approved in Japan for the treatment of hepatocellular carcinoma (HCC) in 2009. Miriplatin has the same non-leaving group as oxaliplatin but different leaving groups of two myristate chains, which make it highly lipophilic. Several characteristics of solid tumors in lung cancer constitute a physiochemical barrier to the homogenous distribution and deep penetration of chemotherapy agents. Nanocarriers provide a promising platform to overcome the physiochemical barrier and to reduce the systemic toxicity of anticancer chemotherapy. In this study, miriplatin is formulated with various lipid-based nanocarriers including micelles and solid lipid nanoparticles (SLNs) thanks to its highly lipophilic structure. The goal of this thesis is to develop and evaluate miriplatin-loaded nano formulations against lung cancer. Miriplatin-loaded formulations were prepared by different methods, including thin film hydration and several scale-up methods including chloroform dripping, chloroform injection, chloroform evaporation, co-solvent evaporation, chloroform slow evaporation and co-solvent slow evaporation. Between the two types of nano formulations under this study, micelles were much smaller (~10 nm in diameter) and more homogeneous (PDI < 0.3), while SLNs were bigger (~ 100 nm in diameter) and more heterogeneous (PDI ~0.8). A quantification method of miriplatin was established using inductively coupled plasma-optical emission spectrometry (ICP-OES). The quantification of platinum recovery from different miriplatin-loaded nano formulations was facilitated by digestion with 70% nitric acid and heating. The co-solvent slow evaporation method to prepare miriplatin-loaded nano formulations improved the platinum recovery prominently from 10% to 70%. Thus, co-solvent slow evaporation has been established as a pharmaceutically viable scale-up method to prepare nano formulations of miriplatin. Miriplatin-loaded nano formulations of different compositions were negatively stained with uranyl acetate and then imaged by transmission electron microscopy (TEM), which showed the formulations’ size and morphology that were consistent with the size and PDI data from dynamic light scattering studies by the Malvern Zetasizer. In the TEM studies, micelles showed a morphology of spherical dots at around 10 nm in diameter while SLNs showed both spherical and rod structures with a size distribution from 50 to 150 nm. A three-dimensional multicellular spheroid (3D MCS) model of A549-iRFP cells was used for in vitro evaluation of the nano formulations’ activity against lung cancer. A549-iRFP cells were engineered from the common lung cancer cell line A549 to stably express the near-infrared fluorescent protein (iRFP). The viability of A549-iRFP 3D MCS after exposure to cisplatin or nano formulations was similar to A549 3D MCS. The anticancer activity of miriplatin-loaded nano formulations against 3D MCS was positively associated with the platinum recovery as quantified by ICP-OES. The miriplatin-loaded nano formulations that had been prepared by the co-solvent slow evaporation method showed substantial anticancer activities against A549 3D MCS and A549-iRFP 3D MCS, which were comparable to cisplatin. Taken together, miriplatin-loaded nano formulations were successfully prepared by co-solvent slow evaporation. The formulations were developed to carry favorable physiochemical properties to enhance the activities of platinum drugs against lung cancer.

Contexte : Le tabagisme actif et passif, la pollution atmosphérique, le radon, les expositions professionnelles à certains agents chimiques tels que l’amiante, la silice cristalline, les hydrocarbures aromatiques polycycliques sont des facteurs de risque établis du cancer du poumon. De plus, certains facteurs alimentaires comme la faible consommation de fruits et de légumes ont été associés à une augmentation de risque de cancer du poumon. Des études épidémiologiques antérieures consacrées à l’étude de l’association entre le cancer du poumon et d’autres expositions comme la consommation de café et l’indice de masse corporelle (IMC) ont été peu concluantes.Objectif : L’objectif de ce travail est d’étudier l’association entre la consommation de café, l’IMC et le risque de cancer du poumon.Matériels et Méthodes : L’étude du rôle du café dans la survenue du cancer du poumon s’est basée sur les données d’une étude cas-témoins en population générale de grande envergure, l’étude ICARE. Les analyses concernaient 2 684 cas de cancer du poumon et 3 481 témoins. Une description détaillée de la consommation de café a été recueillie à l’aide de questionnaires standardisés réalisés au cours d’entretiens en face à face. L’étude de l’association entre l’IMC et le risque de cancer du poumon s’est basée sur une étude cas-témoins nichée dans quatre cohortes aux Etats-Unis, en Europe, en Chine et à Singapour, incluant 4 172 cas de cancer du poumon et 8 471 témoins. L’IMC a été calculé à partir de du poids et de la taille mesurés ou auto-déclarés à l’inclusion. Les Odds ratios (ORs) et les intervalles de confiance à 95% (IC) ont été estimés à l’aide de la régression logistique non conditionnelle, en ajustant sur les facteurs de confusion potentiels.Résultats : Nous n’avons pas observé d’association entre la consommation de café et le risque de cancer du poumon. Les ORs ajustés étaient de l’ordre de 1,07 (0,77-1,48) pour une consommation ≥ 5 tasses/jour, de 1,02 (0,72-1,43) pour une durée de consommation ≥ 49 ans et de 1,02 (0,73-1,42) pour une consommation cumulée vie entière ≥ 184 tasses-années par rapport aux non consommateurs. L’étude cas-témoins nichée dans les 4 cohortes a montré une association inverse significative entre l’IMC et le risque de cancer du poumon. Les ORs ajustés pour les sujets en surpoids (IMC, 25-30 kg/m2) et les sujets obèses (IMC ≥30 kg/m2) étaient respectivement de 0,77 (0,68-0,86) et de 0.69 (0,59-0,82) en comparaison avec les par rapport aux/comparés aux sujets de poids normal (IMC, 18,5-24,9 kg/m2). Cette association était accentuée chez les anciens et actuels fumeurs.Conclusions : La consommation de café ne semble pas être associée au risque de cancer du poumon. L’obésité est associée à une réduction de risque de cancer du poumon, particulièrement chez les anciens et les actuels fumeurs. / Context: Smoking, second-hand smoke, air pollution, radon, and occupational exposure to chemical agents such as asbestos, silica and polycyclic aromatic hydrocarbons are well-known risk factors for lung cancer. In addition, dietary factors involving low intake of vegetables and fruits has been associated with an increased risk of lung cancer. Previous epidemiological studies on the association between lung cancer with other exposures such as coffee intake and body mass index (BMI) have been inconclusive.Objective: The aim of the present work is to investigate the association between coffee consumption and BMI and risk of lung cancer.Materials and Methods: The work on coffee was based on a large French population based case-control study, the ICARE study. Analyses involved 2,684 lung cancer cases and 3,481 controls. Detailed information on coffee was collected using standardized questionnaires through face-to-face interviews. For BMI, a case-control study was nested within four cohorts in USA, Europe, China and Singapore, which included 4,172 lung cancer cases and 8,471 controls. BMI was calculated based on the measured/self-reported height and weight at the baseline. Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated using unconditional logistic regression, adjusting for potential confounders.Results: We found no significant association between coffee consumption and lung cancer risk. The adjusted OR was 1.07 (95%-CI: 0.77-1.48) for ≥ 5 cups /day, 1.02 (95%-CI: 0.72-1.43) for duration of consumption ≥49 years and 1.02 (95%-CI: 0.73-1.42) for life time cumulative consumption ≥184 cup-years compared with never consumers. In the analysis of nested case-control study, we found statistically significant inverse association between BMI and lung cancer risk. Compared with normal weight subjects (BMI, 18.5-24.9 kg/m2), the adjusted OR for overweight (BMI, 25-30 kg/m2) and obese subjects (BMI, ≥30 kg/m2) were 0.77 (95% CI: 0.68-0.86) and 0.69 (95% CI: 0.59-0.82) respectively. This association was strengthened in both current and former smokers.Conclusions: Coffee consumption does not appear to be associated to the risk of lung cancer. Obesity is associated with decreased lung cancer risk, particularly in former and current smokers.

Symptom research with advanced lung cancer patients has primarily focused on symptom severity, frequency, and distress; yet, little is known about advanced lung cancer patients’ priorities and success criteria for symptom improvement. To address these gaps in the literature, this study examined these outcomes using a modified Patient Centered Outcomes Questionnaire (PCOQ), which has largely been used with adults with chronic pain. Advanced lung cancer patients (<i>N</i> = 102) were recruited from the Indiana University Simon Cancer Center to participate in a one-time self-report survey, including demographic and medical questionnaires, symptom treatment history, standardized measures of symptom severity and quality of life, and the modified PCOQ focused on eight common symptoms in advanced lung cancer. Cancer information was collected from medical records. My primary aim was to evaluate the construct validity of the PCOQ. As hypothesized, symptom severity ratings on the PCOQ were positively correlated with standardized assessments of the same symptoms as well as functional status. Greater severity of most symptoms on the PCOQ was also correlated with worse quality of life, and greater severity of four symptoms was correlated with having more medical comorbidities. Positive, moderate correlations were found between the severity and importance of seeing improvement in cough, fatigue, sleep problems, and pain on the PCOQ. Patients considered low levels of symptom severity to be acceptable following symptom treatment; no differences were found across the eight symptoms. Latent profile analysis identified four patient subgroups based on the importance of seeing improvement in each of the symptoms: (1) those who rated all symptoms as low in importance (<i>n</i> = 12); (2) those who rated bronchial symptoms and sleep problems as low in importance and all other symptoms as moderately important (<i>n</i> = 29); (3) those who rated nausea and emotional distress as low in importance and all other symptoms as moderately important (<i>n</i> = 23); and (4) those who rated all symptoms as highly important (<i>n</i> = 33). These subgroups were unrelated to demographic and clinical factors, except for functional status. Findings suggest that symptom severity and importance are related yet distinct aspects of the advanced lung cancer symptom experience. Furthermore, patients have heterogeneous priorities for symptom management, which has implications for tailoring treatment.

Einteilung:Das Lungenkarzinom ist eine der häufigsten Krebstodesursachen der Welt. Die chirurgische Therapie mit onkologischer Resektion des Tumors bietet bessere Chancen für einen dauerhaften Therapieerfolg. Die Bedeutung der systematischen Lymphadenektomie im Sinne eines akkuraten Stagings und einer besseren Lokalkontrolle des Tumors ist unumstritten. In der Literatur wurden verschiedene LK-Befallsmuster bei den operierten NSCLC anhand verschiedener histomorphologischer Parameter beschrieben, um letztendlich eine passende Technik der Lymphadenektomie zu entwickeln. Patienten und Methoden: In unserer retrospektiven Studie wurde ein Kollektiv von 111 Patienten mit operierten nicht kleinzelligen Lungenkarzinome zwischen 2008 und 2013 untersucht. Das LK-Metastasierungsmuster wurde anhand verschiedener histomorphologischer Parameter untersucht. Ergebnisse: Eine zentrale Tumorlage, L1-Kategorie, sowie die zunehmende Tumorgröße zeigten eine signifikante Neigung zur LK-Metastasierung. Anhand der Tumorlokalisation im Lungenlappen ließ sich jedoch kein bestimmtes LK- Befallmuster sichern. Schlussfolgerung: Diese Daten unterstützen die Angaben der Literatur, in der eine systematische Lymphadenektomie unabhängig von den anderen Parametern weiter gefordert wird, um ein akkurates Staging zur erreichen und so eine optimale Therapie durchzuführen.fi

Bakgrund: Lungcancer är den cancerform nationellt och internationellt som orsakar flest dödsfall. Den låga överlevnadsgraden innebär att patienter med lungcancer vanligtvis har behov av palliativ vård. För att vårda patienter ur ett holistiskt perspektiv kan personcentrerad omvårdnad tillämpas när vårdpersonal utgår från patientberättelsen och bildar ett partnerskap med patienten. Syfte: Syftet var att belysa patienters erfarenheter av palliativ vård vid lungcancer.  Material och metod: En litteraturöversikt med kvalitativ design och induktiv ansats. Litteratursökning i databaserna Medline och Cinahl resulterade i 13 kvalitativa artiklar publicerade mellan åren 2011 – 2020 som analyserades genom Friberg (2017).  Resultat: I resultatet framkom två huvudteman och sex underteman. Palliativa vårdens prövningar och potential med underteman Lidande och hopp vid cytostatikabehandling, Positiva effekter av egenvård och strategier för att återfå kontroll. Ambivalens gentemot vårdpersonal och organisation med undertemana Missnöje med planering och organisering, Bristfälligt bemötande och otillräcklig kommunikation och Tillgodosedda behov av planering och organisering  Slutsats: Resultatet påvisar patienters behov av adekvat hantering av sina symtom och biverkningar från behandling. Vårdpersonal måste ha ett gott bemötande, en anpassad kommunikation, ett effektivt teamarbete och involvera anhöriga för att tillgodose patienters behov av planering och organisering. Det krävs en kontinuitet inom dessa aspekter oavsett om patienterna befinner sig i tidig palliativ fas eller i vård vid livets slutskede. / Background: Lung cancer is the type of cancer that causes the highest number of cancer related deaths both on a national and international level. Considering the low survival rate many patients diagnosed with lung cancer will need palliative care. To care for patients from a holistic perspective, person-centered care can be applied when the health care professionals takes part of the patient’s narrative and forms a partnership with the patient. Aim: The aim was to illustrate patients experiences of palliative care when diagnosed with lung cancer. Material and method: A literature review with qualitative design and inductive method. A literature search in the databases Medline and Cinahl resulted in 13 qualitative articles published between 2011 -– 2020which then were analyzed according to Friberg (2017).Results:  In the result two main themes and six subthemes emerged. The palliative care’s trials and potential with sub-themes suffering and hope during chemotherapy, positive effects of self-care and strategies to regain control. Ambivalence towards healthcare personnel with sub-themes dissatisfaction with planning and organizing, inadequate reception and insufficient communication and met needs of planning and organizing. Conclusion: The result demonstrates patients needs for adequate management of their symptoms and side effects from treatment. Healthcare personnel need to have a good reception, a well adapted communication, an effective teamwork and involve relatives to meet the patients need for planning and organizing. It takes a continuity within these aspects regardless if the patients are in the early stage of palliative care or is receiving end of life care.

DNA-damaging chemotherapeutics are a consistently employed for the treatment of cancer, and are regularly part of first-line combination therapeutic regimens. However, these regimens often display limited activity in cancers including of the lung and breast. Novel therapeutic strategies are urgently required. Understanding the molecular mechanisms regulating DNA-damaging chemotherapeutics activity will lead to such novel strategies. Activating transcription factor 3 (ATF3) is a stress inducible gene that plays a significant role in regulating cellular stress including DNA damage. This thesis investigates the role of ATF3 in mediating the cytotoxic effects of two commonly employed DNA-damaging chemotherapeutics, cisplatin and doxorubicin. This study also identifies other independent ATF3 inducing agents in potential novel combination therapeutic strategies. In this study, cell line models of cisplatin-resistance were generated independently from two non-small cell lung cancer (NSCLC) cell lines, Calu6 and H23. Full transcriptome RNA-sequencing analysis identified ATF3 as the most highly dysregulated apoptosis regulatory gene in the cisplatin-resistant compared to their respective parental cell lines following treatment with cisplatin. Further characterization identified cisplatin induced activation of JNK as the key regulator of ATF3 induction in these cell lines. Restoring JNK activity resulted in induced ATF3 expression and re-sensitization of the resistant cell lines to cisplatin treatment. FDA-approved 1200 compound library screens were employed to identify agents that can enhance cisplatin cytotoxicity as well as whose cytotoxicity was dependent on ATF3 expression. Vorinostat, an HDAC inhibitor, was identified in both screens and importantly displayed synergistic cytotoxicity in combination with cisplatin. In addition, ATF3 was also induced with treatments of the DNA damaging agent doxorubicin in these NSCLC cell lines including in the cisplatin resistant models. This work suggested a different mechanism of ATF3 induction by doxorubicin and the potential role of ATF3 in mediating doxorubicin cytotoxicity was further investigated in breast cancer cells. Doxorubicin robustly increased ATF3 expression in human breast cancer cell lines and tumor tissue ex-vivo. Loss of ATF3 in MEFs resulted in reduced sensitivity to doxorubicin treatment compared to wild-type MEFs. Employing the same library screen as above, compounds with ATF3 dependent mechanisms that could enhance doxorubicin cytotoxicity were identified. Vorinostat, as well as, the nucleoside analogues trifluridine and 6-mercaptopurine induced ATF3 expression and enhanced doxorubicin cytotoxicity. This study demonstrated that ATF3 plays an important role in mediating the cytotoxic effect of the DNA-damaging chemotherapeutics cisplatin and doxorubicin. It also provides rationale for ATF3 as a potential therapeutic target, and for the incorporation of ATF3 inducing agents in novel combination therapeutic strategies.

Non-small cell lung cancer (NSCLC) makes up the majority of lung cancers, which remains the leading cause of cancer mortality worldwide. NSCLC with mutant epidermal growth factor receptor (EGFR) is currently treated with tyrosine kinase inhibitors (TKIs). TKIs have proven effective in improving survival until resistance is conferred, mostly by way of the exon 20, threonine 790 to methionine (T790M) point mutation in EGFR. The mechanism by which this point mutation arises is poorly understood. Herein we report a possible pathway by which the C to T transition that leads to T790M comes about. We show that activation-induced cytidine deaminase (AID) mRNA expression is induced upon treatment with EGFR TKIs in mutant-EGFR human lung cancer cell lines but not in control cell lines. We also show that stable expression of AID is sufficient to produce resistance to one such TKI, erlotinib, and is sufficient to produce T790M itself. We also report that B-cell lymphoma 6 (BCL6) may precede AID in this pathway. Our results show that BCL6 is upregulated in these cell lines treated with EGFR TKIs but not in normal bronchial cells. We then treated human lung cancer cell lines with EGFR TKIs in combination with BCL6 inhibitors. Our results show that AID is dependent upon BCL6 expression. Finally, we report on results from a transient BCL6 overexpression which lead us to believe that AID mRNA receives input from at least one alternate pathway in addition to BCL6. We also performed these experiments on a family of apolipoprotein B mRNA editing enzyme, catalytic polypeptide-like (APOBEC) cytidine deaminases, that show they may be involved in this pathway downstream of AID. Taken together, our results suggest a potential pathway involving BCL6, AID, and APOBEC cytidine deaminases that lead to the C to T transition that produces T790M, thereby conferring resistance to EGFR TKIs in mutant-EGFR NSCLC. They also provide potential new targets for treatment should further study confirm our results. / 2021-10-07T00:00:00Z

No description available.

Tumor lysis syndrome is an oncologic emergency that usually occurs after chemotherapy in patients with hematologic malignancies. Tumor lysis syndrome is rare in cases of solid tumors, especially when it occurs spontaneously. Herein, we present a case of spontaneous tumor lysis syndrome in a 55-year-old woman who presented with dyspnea and was found to have extensive metastatic small cell lung cancer. She developed acute oliguric renal failure and multiple electrolyte abnormalities requiring hemodialysis. The findings of this case suggest that clinicians should maintain a high index of suspicion for patients with malignancies who demonstrate the classic symptom of laboratory abnormalities even in the absence of chemotherapy.

Introduction: Small Cell Lung Cancer (SCLC) is an aggressive malignancy with poor prognosis that accounts for 10% of all clinical lung cancer. SCLC commonly metastasizes to the mediastinum, liver, bone, adrenals, and the brain but secondary endotracheal metastasis is an especially rare occurrence. We discuss the case of a 74-year-old male with principal complaint of cough, wheezing and hemoptysis found to have secondary endotracheal lesions on bronchoscopy. Case report: A 74-year-old male, former smoker with a past medical history of pulmonary embolism, bullous emphysema, and limited stage small cell lung cancer with wedge resection and chemotherapy 3 years ago presented with cough, wheezing, weight loss and intermittent hemoptysis ongoing for few weeks. CT scan of the chest showed multiple polypoid masses arising in the anterior wall of the trachea. He underwent bronchoscopy with biopsy. Pathology was consistent with small-cell lung cancer. Conclusion: Secondary tracheal metastasis from early stage small cell cancer is a rare occurrence. The likelihood of tracheal metastasis of lung cancer is amplified when an endotracheal nodule or eccentric thickening of the tracheal wall is seen on CT of patients with high suspicion. It is important for clinicians to suspect endotracheal lesions when a patient presents with recurrent respiratory complaints despite stable surveillance CT scan of chest in patients with history of lung cancer.