Major Clinical Advances Research Articles

Economic Considerations in the Use of Novel Targeted Therapies for Lung Cancer: Review of Current Literature.

Lung cancer remains the leading cause of cancer-related death and economic burden worldwide. Despite the heavy toll of lung cancer, multiple new advances have improved patient outcomes, largely through precision medicine and targeted therapy. The associated rising economic burden however may impact the uptake of novel therapeutic agents in lung cancer, thereby limiting patient access. This article identifies and reviews economic evaluations of targeted agents in lung cancer in the era of precision medicine. Articles evaluating biomarker-directed test-and-treat strategies are also reviewed to evaluate the cost impact of novel therapeutic agents at a population level. The Quality of Health Economic Studies instrument is applied to assess the quality of included studies. Forty-six studies are reviewed and encompass studies of epidermal growth factor receptor inhibitors and monoclonal antibodies, anaplastic lymphoma kinase inhibitors, vascular endothelial growth factor and vascular endothelial growth factor receptor inhibitors and immunotherapy (programmed death-1 inhibitors). Key factors influencing results of economic analyses include comparators chosen, perspective used, magnitude of clinical benefit, utility weighting of outcomes and drug acquisition costs. Biomarker-driven decision making should be integrated into cost evaluations given the important role of molecular testing for individualising treatment for non-small-cell lung cancer. We conclude that despite major clinical advances in lung cancer therapeutics, cost remains an important consideration in the adoption of novel therapies.

Major clinical research advances in gynecologic cancer in 2016: 10-year special edition.

In 2016, 13 topics were selected as major research advances in gynecologic oncology. For ovarian cancer, study results supporting previous ones regarding surgical preventive strategies were reported. There were several targeted agents that showed comparable responses in phase III trials, including niraparib, cediranib, and nintedanib. On the contrary to our expectations, dose-dense weekly chemotherapy regimen failed to prove superior survival outcomes compared with conventional triweekly regimen. Single-agent non-platinum treatment to prolong platinum-free-interval in patients with recurrent, partially platinum-sensitive ovarian cancer did not improve and even worsened overall survival (OS). For cervical cancer, we reviewed robust evidences of larger-scaled population-based study and cost-effectiveness of nonavalent vaccine for expanding human papillomavirus (HPV) vaccine coverage. Standard of care treatment of locally advanced cervical cancer (LACC) was briefly reviewed. For uterine corpus cancer, new findings about appropriate surgical wait time from diagnosis to surgery were reported. Advantages of minimally invasive surgery over conventional laparotomy were reconfirmed. There were 5 new gene regions that increase the risk of developing endometrial cancer. Regarding radiation therapy, Post-Operative Radiation Therapy in Endometrial Cancer (PORTEC)-3 quality of life (QOL) data were released and higher local control rate of image-guided adaptive brachytherapy was reported in LACC. In addition, 4 general oncology topics followed: chemotherapy at the end-of-life, immunotherapy with reengineering T-cells, actualization of precision medicine, and artificial intelligence (AI) to make personalized cancer therapy real. For breast cancer, adaptively randomized trials, extending aromatase inhibitor therapy, and ribociclib and palbociclib were introduced.

General Biomarker Recommendations for Lymphoma.

Lymphoid malignancies are a heterogeneous group of tumors that have distinctive clinical and biological behaviors. The increasing prevalence of disease reflects both treatment advances and the fact that some of these tumors are indolent. The ability to determine treatment needs at diagnosis remains problematic for some of the tumors, such as in follicular lymphomas. Major clinical advances will likely depend on precision oncology that will enable identification of specific disease entities, prognostic determination at diagnosis, and identification of precise therapeutic targets and essential pathways. However, refinement in diagnostic evaluation is an evolving science. The ability to determine prognosis at diagnosis is variable, and for many of the lymphoid malignancies prognosis can only be made after initial treatment. Clinical trials that aim to evaluate specific features of these diseases are required in order to advance clinical practice that meaningfully addresses this important public health challenge. Herein, we describe the process and general recommendation from the National Cancer Institute (NCI) clinical trials planning meeting in November 2014 to address clinical trial design and biomarker proposals in the context of NCI-supported lymphoma clinical trials in the National Clinical Trials Network.

Development of Complex Models to Study Co- and Polymicrobial Infections and Diseases

There is an inherent catch-22 in performing research that aims to better understand a clinical disease: to make true strides, one needs to simplify the system sufficiently to test individual variables. However, reducing a complex process to an experimentally approachable, simplified system may be so reductionist that the results are irrelevant to the disease in question. For many of us, animal models have proven to be remarkably powerful. Indeed, many biological principles were uncovered and major clinical advances made using animal models, and the advent of transgenic, knockout, and conditional animals has further cemented their value to the pathogenesis field. While animal models of infection have been invaluable, the simplified nature of most models has prevented a complete understanding of the more complex ways by which pathogens can cause human disease. For example, much of what we know about infectious agent pathogenesis has been gained from the use of adult, immunocompetent, immunologically naive, inbred mice infected with a single pathogen. In stark contrast, humans with vastly different immunological histories and genetic backgrounds are colonized by a diverse array of microbial communities and likely bombarded with temporally overlapping antigenic stimuli. Despite this discrepancy between mouse models and the human experience, we know very little about how concurrent immune responses interact and contribute to disease in either humans or mice. This gap in knowledge is important to remedy because many human diseases are caused by polymicrobial exposures—including pneumonia, peritonitis, and others (e.g., hepatitis and Lyme’s disease [1,2])—that can have exacerbated symptoms when combined with a second pathogen. Moreover, any immunogen, even those that are noninfectious, may be relevant in this context, including allergens and vaccinations or preexisting chronic conditions such as cancer or autoimmunity. Many who have begun to explore this area in more depth have contended that temporally overlapping infections or immune responses may play a foundational role in some poorly understood inflammatory illnesses in humans.

Multi-technique hybrid imaging in PET/CT and PET/MR: what does the future hold?

Integrated positron-emission tomography and computed tomography (PET/CT) is one of the most important imaging techniques to have emerged in oncological practice in the last decade. Hybrid imaging, in general, remains a rapidly growing field, not only in developing countries, but also in western industrialised healthcare systems. A great deal of technological development and research is focused on improving hybrid imaging technology further and introducing new techniques, e.g., integrated PET and magnetic resonance imaging (PET/MRI). Additionally, there are several new PET tracers on the horizon, which have the potential to broaden clinical applications in hybrid imaging for diagnosis as well as therapy. This article aims to highlight some of the major technical and clinical advances that are currently taking place in PET/CT and PET/MRI that will potentially maintain the position of hybrid techniques at the forefront of medical imaging technologies.

Major clinical research advances in gynecologic cancer in 2015.

In 2015, fourteen topics were selected as major research advances in gynecologic oncology. For ovarian cancer, high-level evidence for annual screening with multimodal strategy which could reduce ovarian cancer deaths was reported. The best preventive strategies with current status of evidence level were also summarized. Final report of chemotherapy or upfront surgery (CHORUS) trial of neoadjuvant chemotherapy in advanced stage ovarian cancer and individualized therapy based on gene characteristics followed. There was no sign of abating in great interest in immunotherapy as well as targeted therapies in various gynecologic cancers. The fifth Ovarian Cancer Consensus Conference which was held in November 7–9 in Tokyo was briefly introduced. For cervical cancer, update of human papillomavirus vaccines regarding two-dose regimen, 9-valent vaccine, and therapeutic vaccine was reviewed. For corpus cancer, the safety concern of power morcellation in presumed fibroids was explored again with regard to age and prevalence of corpus malignancy. Hormone therapy and endometrial cancer risk, trabectedin as an option for leiomyosarcoma, endometrial cancer and Lynch syndrome, and the radiation therapy guidelines were also discussed. In addition, adjuvant therapy in vulvar cancer and the updated of targeted therapy in gynecologic cancer were addressed. For breast cancer, palbociclib in hormone-receptor-positive advanced disease, oncotype DX Recurrence Score in low-risk patients, regional nodal irradiation to internal mammary, supraclavicular, and axillary lymph nodes, and cavity shave margins were summarized as the last topics covered in this review.

Program Director Survey: Attitudes Regarding Child Neurology Training and Testing

BackgroundAs a result of major clinical and scientific advances and changes in clinical practice, the role of adult neurology training for Child Neurology and Neurodevelopmental Disability (NDD) certification has become controversial. The most recently approved requirements for board eligibility for child neurology and neurodevelopmental disability residents still include 12 months in adult neurology rotations. The objective of this study was to assess United States child neurology and neurodevelopmental disability residency program directors' opinions regarding optimal residency training. MethodsThe authors developed an 18-item questionnaire and contacted all 80 child neurology and neurodevelopmental disability program directors via e-mail, using SurveyMonkey. ResultsA total of 44 program directors responded (55%), representing programs that train 78 categorical and 94 total resident positions, approximately 70% of those filled in the match. Respondents identified multiple areas where child neurology residents need more training, including genetics and neuromuscular disease. A substantial majority (73%) believed child neurology and neurodevelopmental disability residents need less than 12 adult neurology training months; however, most (75%) also believed adult hospital service and man-power needs (55%) and finances (34%) would pose barriers to reducing adult neurology. Most (70%) believed reductions in adult neurology training should be program flexible. A majority believed the written initial certification examination should be modified with more child neurology and fewer basic neuroscience questions. Nearly all (91%) felt the views of child neurology and neurodevelopmental disability program directors are under-represented within the Accreditation Council for Graduate Medical Education Residency Review Committee. ConclusionsThe requirement for 12 adult neurology months for Child Neurology and Neurodevelopmental Disability certification is not consistent with the views of the majority of program directors, who favor more training in subspecialized fields of child neurology.

Major clinical research advances in gynecologic cancer in 2014.

In 2014, 9 topics were selected as major advances in clinical research for gynecologic oncology: 2 each in cervical and corpus cancer, 4 in ovarian cancer, and 1 in breast cancer. For cervical cancer, several therapeutic agents showed viable antitumor clinical response in recurrent and metastatic disease: bevacizumab, cediranib, and immunotherapies including human papillomavirus (HPV)-tumor infiltrating lymphocytes and Z-100. The HPV test received FDA approval as the primary screening tool of cervical cancer in women aged 25 and older, based on the results of the ATHENA trial, which suggested that the HPV test was a more sensitive and efficient strategy for cervical cancer screening than methods based solely on cytology. For corpus cancers, results of a phase III Gynecologic Oncology Group (GOG) 249 study of early-stage endometrial cancer with high-intermediate risk factors are followed by the controversial topic of uterine power morcellation in minimally invasive gynecologic surgery. Promising results of phase II studies regarding the effectiveness of olaparib in various ovarian cancer settings are summarized. After a brief review of results from a phase III study on pazopanib maintenance therapy in advanced ovarian cancer, 2 outstanding 2014 ASCO presentations cover the topic of using molecular subtypes in predicting response to bevacizumab. A review of the use of opportunistic bilateral salpingectomy as an ovarian cancer preventive strategy in the general population is presented. Two remarkable studies that discussed the effectiveness of adjuvant ovarian suppression in premenopausal early breast cancer have been selected as the last topics covered in this review.

Immunosuppression associated with novel chemotherapy agents and monoclonal antibodies.

The introduction of novel agents to the therapeutic armamentarium for oncologic, rheumatologic, and neurologic disorders has resulted in major clinical advances. These agents impact immune function, resulting in a discrete spectrum of infectious complications. Purine analogues and alemtuzumab alter cell-mediated immunity, resulting in opportunistic viral/fungal infections. Herpes zoster incidence increases with bortezomib. Hepatitis B reactivation may occur with rituximab. Cases of progressive multifocal leukoencephalopathy have occurred following monoclonal antibody therapy. Tumor necrosis factor-α inhibitor therapy is complicated by tuberculosis reactivation and fungal infections. We summarize the impact of these therapies on pathogenesis and spectrum of infection complicating their usage.

Genomic medicine and targeted therapy for solid tumors.

A marked paradigm shift in cancer therapy has occurred over the past 20 years. Systemic treatment has evolved from nonspecific cytotoxic chemotherapy to targeting cancer-associated pathways, profoundly changing treatment approaches in the metastatic and adjuvant settings. This review will highlight some of the major clinical advances in targeted cancer therapy in select epithelial malignancies made possible by the understanding of the molecular mechanisms driving tumor growth through genomic methods.

Major clinical research advances in gynecologic cancer in 2013.

In 2013, 10 topics were selected for major clinical research advances in gynecologic oncology; these included three topics regarding cervical cancer, three regarding ovarian cancer, two regarding endometrial cancer, and one each regarding breast cancer and radiation oncology. For cervical cancer, bevacizumab was first demonstrated to exhibit outstanding clinical efficacy in a recurrent, metastatic setting. Regarding cervical cancer screening, visual inspections with acetic acid in low-resource settings, p16/Ki-67 double staining, and the follow-up results of four randomized controlled trials of human papillomavirus-based screening methods were reviewed. Laparoscopic para-aortic lymphadenectomy before chemoradiation for locally advanced cervical cancer was the final topic for cervical cancer. Regarding front-line ovarian cancer therapies, dose-dense paclitaxel and carboplatin, intraperitoneal chemotherapy, and other targeted agents administered according to combination or maintenance schedules were discussed. Regarding recurrent ovarian cancer treatment, cediranib, olaparib, and farletuzumab were discussed for platinum-sensitive disease. The final overall survival data associated with a combination of bevacizumab and chemotherapy for platinum-resistant disease were briefly summarized. For endometrial cancer, the potential clinical efficacy of metformin, an antidiabetic drug, in obese patients was followed by integrated genomic analyses from the Cancer Genome Atlas Research Network. For breast cancer, three remarkable advances were reviewed: the long-term effects of continued adjuvant tamoxifen for 10 years, the effects of 2-year versus 1-year adjuvant trastuzumab for human epidermal growth factor receptor 2-positive disease, and the approval of pertuzumab in a neoadjuvant setting with a pathologic complete response as the surrogate endpoint. Finally, the recent large studies of intensity-modulated radiotherapy for gynecologic cancer were briefly summarized.

Evolving concepts of tumor heterogeneity.

Past and recent findings on tumor heterogeneity have led clinicians and researchers to broadly define cancer development as an evolving process. This evolutionary model of tumorigenesis has largely been shaped by seminal reports of fitness-promoting mutations conferring a malignant cellular phenotype. Despite the major clinical and intellectual advances that have resulted from studying heritable heterogeneity, it has long been overlooked that compositional tumor heterogeneity and tumor microenvironment (TME)-induced selection pressures drive tumor evolution, significantly contributing to tumor development and outcomes of clinical cancer treatment. In this review, we seek to summarize major milestones in tumor evolution, identify key aspects of tumor heterogeneity in a TME-dependent evolutionary context, and provide insights on the clinical challenges facing researchers and clinicians alike.

Advances in the treatment of acute graft‐versus‐host disease

Allogeneic hematopoietic stem cell transplantation (HSCT) has been widely used for the treatment of hematologic malignant and non-malignant hematologic diseases and other diseases. However, acute graft-versus-host disease (GVHD) is a life-threatening complication of allogeneic transplantation. Acute GVHD may occur in 30% of transplant recipients, which is a syndrome of erythematous skin eruption, cholestatic liver disease and intestinal dysfunction, resulting from the activation of donor T lymphocytes by host antigen-presenting cells, resulting in an immune-mediated inflammatory response. Recent scientific advances in the understanding of the pathogenesis involved in the development of acute GVHD and clinical investigation have provided more effective therapeutic strategies for acute GVHD. This review focuses on major scientific and clinical advances in the treatment of acute GVHD.

Special Issue on Precision Risk Stratification-Based Screening in Colorectal Cancer

Cancer remains a formidable public health burden, as over half a million Americans succumb to this disease each year. The fight to vanquish cancer is stronger than ever. The pace of acquisition of new, cutting-edge scientific knowledge about the complex biology of cancer, and the development of technologies, targeted therapeutics and innovative approaches to prevent, detect and treat the disease have accelerated considerably over the past decade. Hence, in just over a century we have witnessed an extraordinary evolution of medical practice from seeking to understand disease in a physician-directed healthcare paradigm, to evidence-based medicine, and on to the modern era of emerging personalized, predictive, precision medicine (which applies predictive and prognostic biomarkers and patient-specific attributes using a “personalized lifespan approach”). During the past year we have witnessed not only a multi-faceted national effort to improve quality and value of cancer care aligned with the Institute for Healthcare Improvement's “triple aim” Initiative [improving the individual patient care experience, the health of populations, and thereby the efficiency and cost of care], but also realized several major clinical advances in cancer treatment [http://www.ihi.org/offerings/Initiatives/TripleAim/Pages/default.aspx]. In 2012 alone, the FDA approved seven new targeted systemic agents and expanded the anti-cancer indications for five existing agents. Noteworthy progress has been made in overcoming treatment resistance (combining targeted drugs, use of multi-targeted agents, targeting new pathways), understanding molecular drivers of cancer and tumor heterogeneity across the genomic landscape to include gene-environment interactions, advancing precision medicine, improving and enabling risk stratification-based screening and early detection. To this latter point, a minimally invasive technique (flexible sigmoidoscopy) has been shown in a large randomized clinical trial to significantly reduce both incidence (by 21%; relative risk, 0.79; 95% confidence interval [CI], 0.72 to 0.85; P<0.001) and overall colorectal cancer mortality (by 26%; relative risk, 0.74; 95% CI, 0.63 to 0.87; P<0.001) [N Engl J Med. 2012 Jun 21;366(25):2345-57]. This represents a major advance in cancer screening and early disease detection. It is decidedly poised to transform population-based screening, and to support concerted efforts to unravel socioeconomic disparities in cancer screening. What's more, this safe and effective screening approach will be used to educate screening populations about the importance of early detection, and could inspire wide-ranging compliance with recommended colorectal screening guidelines. The current special edition of the Journal of Cancer is centered on colorectal cancer and it highlights advances made in the prevention, screening, early detection, and treatment of this disease. It communicates an ambitious vision aimed at conquering colorectal cancer, and provides recommendations for leveraging innovative technological advances, particularly those that provide insights into patient-specific tumor biology, genetic make-up and epigenetic regulation. It emphasizes the way forward through progress made in screening for colorectal cancer in an ethnically and socio-economically diverse population with equal access to care. The special edition further emphasizes safe, effective, quality-based, innovative colorectal cancer care early detection and individualized precision medicine through Precision Risk Stratification-Based Screening. The principal aim of this risk identification and screening approach is to identify patients at risk for or diagnoses patients early in the natural history of colorectal cancer. It further defines evidence-based methods by which to avoid the toxicity of systemic therapy in appropriately risk-stratified patients identified as low risk for disease recurrence that are likely cured by surgery alone; appropriately classify patients with clinically latent or stable residual disease for whom systemic therapy can be withheld, and accurately recognize those high-risk node-negative patients with colorectal cancer or those with treatment-responsive disease likely to progress and treat them at the optimal time in the course of their disease. This special edition charts an ambitious and attainable way forward, and allows us ample basis by which to imagine a world without cancer.

Hydrogen as a New Class of Radioprotective Agent

It is well known that most of the ionizing radiation-induced damage is caused by hydroxyl radicals (·OH) follows radiolysis of H2O. Molecular hydrogen (H2) has antioxidant activities by selectively reducing ·OH and peroxynitrite(ONOO-). We firstly hypothesized and demonstrated the radioprotective effect of H2 in vitro and in vivo, which was also repeated on different experimental animal models by different departments. A randomized, placebo-controlled study showed that consumption of hydrogen-rich water reduces the biological reaction to radiation-induced oxidative stress without compromising anti-tumor effects. These encouraging results suggested that H2 represents a potentially novel preventative strategy for radiation-induced oxidative injuries. H2 is explosive. Therefore, administration of hydrogen-rich solution (physiological saline/pure water/other solutions saturated with H2) may be more practical in daily life and more suitable for daily consumption. This review focuses on major scientific and clinical advances of hydrogen-rich solution/H2 as a new class of radioprotective agent.

Major clinical research advances in gynecologic cancer in 2012.

Ten topics were chosen among major clinical research achievements in gynecologic oncology in 2012. For ovarian cancer, comprehensive review of the history of bevacizumab studies was followed by poly adenosine diphosphate [ADP]-ribose polymerase (PARP) inhibitors and other molecular targeted agents such as epidermal growth factor receptor tyrosine kinase inhibitor and AMG 386. For the development of genomic study in gynecologic cancers, BRCA and DICER1 mutations were covered in epithelial and nonepithelial ovarian cancer, respectively. For endometrial cancer, targeted agents including mammalian target of rapamycin (mTOR) inhibitors and bevacizumab were discussed. Radiation therapy "sandwiched" between combination chemotherapy schedules for the treatment of uterine papillary serous carcinoma was also reviewed. Preoperative prediction of lymph node metastasis, definition of low-risk group, and recurrence and survival outcomes of laparoscopic approaches were addressed. For cervical cancer, we reviewed long-term benefit of human papillomavirus test and efficacy of paclitaxel/carboplatin versus paclitaxel/cisplatin in stage IVB, persistent or recurrent disease. In addition, the effect of three dimensional image-based high-dose rate brachytherapy was also reviewed. For vulvar cancer, the diagnostic value of sentinel lymph node biopsy was discussed. For breast cancer, positive results of three outstanding phase III randomized clinical trials, CLEOPATRA, EMILIA, and BOLERO-2 were introduced. Lastly, updates of major practice guidelines were summarized.

Medicine In The Thrall Of The Culture Of DrugsPharmageddon By Healy David Berkeley (CA) : University of California Press , 2012 302 pp.; $39.95

Medicine In The Thrall Of The Culture Of DrugsPharmageddon By Healy David Berkeley (CA) : University of California Press , 2012 302 pp.; $39.95

PCN16 Comparison of the Efficacy and Cost of Novel Targeted Cancer Therapies

For several years, cytotoxic agents have been the backbone of cancer treatment. There has increasingly, however, been an emergence of new drugs that are more specific to the target molecule. Some of these novel agents have resulted in a prolongation of survival and even clinical cures in some cancers. In order to assess the costs and overall benefits of these new drug therapies, a descriptive evaluation across seven major tumor types was undertaken. A literature search was conducted from 2000 to 2011 to identify randomized trials of novel therapies in breast, lung, colorectal, kidney, lymphoma, multiple myeloma and chronic myelogenous leukemia. Clinical outcomes in terms of progression free (PFS) and overall survival (OS) benefit were extracted. Economic data in terms of cost per month of therapy was obtained from a U.S. cancer clinic. Almost 22 novel therapies were approved across the seven cancers. Four of the 22 (18%) were used with a curative intent while the remainder were used in the palliative setting (n=18). Ten of these 18 latter agents (56%) also demonstrated an OS benefit. The median month cost for novel therapies used with a curative intent and those with a survival benefit in the palliative setting were $5450 and $6450 respectively. In contrast, the median monthly cost for drugs that did not offer either of these benefits was $7900. Of the agents identified, imatinib, lenalidomide, rituximab and trastuzumab provided the greatest magnitude of benefit for both PFS and OS and would be considered major clinical advances. Approximately 64% of novel cancer drugs approved over the past 11 years are used with a curative intent or provide a survival benefit in the palliative care setting. However, the monthly cost for agents not providing these benefits was higher, indicating a disconnect between efficacy and cost.

Major clinical research advances in gynecologic cancer in 2011.

The annual review of 2011 comprised 11 themes of major research achievements in gynecologic oncology including breast cancer. A potential paradigm shift in the management of ovarian cancer was reviewed through comprehensive genomic analyses and a tumor-specific new intraoperative fluorescence imaging technique using folate receptor-α targeted agent, which is expected to improve intraoperative staging and more radical cytoreduction. In addition, updates of bevacizumab and poly (ADP-ribose) polymerase inhibitors, risk-reducing salpingo-oophorectomy, and risk evaluation of pelvic mass were discussed. Regarding cervical cancer, this review covered new findings on human papillomavirus vaccines and human papillomavirus tests as well as the current status of clinical trials on locally advanced cervical cancer. The promising role of sentinel lymph node biopsy in the management of early stage endometrial cancer was followed by two notable clinical researches on: exemestane, an aromatase inhibitor, for the prevention of breast cancer and eribulin, a non-taxane microtubule dynamics inhibitor for the treatment of metastatic breast cancer. Lastly, in premenopausal women with breast cancer, the effect of gonadotropin-releasing hormone analogue on the occurrence of chemotherapy-induced early menopause was discussed.

Finding new medicines to fight CF: multiple steps of a success story

Background Cystic fibrosis (CF) is a major life-limiting genetic disease leading to severe respiratory symptoms caused by mutations in CF trans membrane conductance regulator (CFTR), a chloride channel expressed at the apical membrane of epithelial cells. Absence of functional CFTR from the surface of respiratory cells reduces mucociliary clearance, promoting airways obstruction, chronic infection and ultimately lung failure [1]. Despite major clinical advances treating the symptoms, which pushed survival beyond the second decade (~25 years in Europe), CF is still a life-limiting condition [2]. However, to further increase CF patients life expectancy, CF needs to be treated beyond its symptoms, i.e., through treatments addressing the basic defect associated with CFTR gene mutations [3]. So far ~1,900 CFTR mutations were reported [4], but one single mutation, F508del remains the most common one, as it occurs in ~90% of CF patients in at least one allele [5] and is associated with a severe clinical phenotype. Despite that most of efforts are focused on correcting the F508del-CFTR which causes intracellular retention of the mutant channel at the endoplasmic reticulum (ER), several additional strategies are emerging to rescue other (rarer mutants) which, in some populations, also have high prevalence. To this end, CFTR mutations are usually grouped into functional classes, towards a “mutation-specific” therapeutic approach by which mutations within the same functional class can be corrected by the same therapeutic strategy towards a “personalized medicine” approach [6]. Materials and methods/ results To apply such strategy CFTR mutations are thus classified into six main functional categories [7,8], namely: i) class I mutations (often mutations generating premature stop codons, e.g., R1162X) prevent protein production; ii) class II mutations (includes F508del) cause intracellular retention and premature degradation, thus preventing mutant CFTR from reaching the cell surface; iii) class III mutants (e.g., G551D) cause impairment in the channel gating (i.e., decreased open probability); iv) class IV mutants have substantially reduced flow of Cl ions through the CFTR channel (e.g., R334W); v) class V mutants include mostly alternative splicing mutants (e.g., 3272-26A>G) which allow synthesis of some normal CFTR mRNA (and protein), albeit at very low levels; and vi) class VI mutants (e.g., c.120del23 [9] or membrane-rescued F508del) impair the plasma membrane stability of CFTR.