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Current Treatment Options in Oncology Jun 2020Relapse is still a common scenario in acute myeloid leukemia (AML) treatment and occurs in 40-50% of younger and the great majority of elderly patients. The prognosis in... (Review)
Review
Relapse is still a common scenario in acute myeloid leukemia (AML) treatment and occurs in 40-50% of younger and the great majority of elderly patients. The prognosis in relapsed AML patients is generally poor but depends largely on the timing of relapse (early versus late) and the possibility of allogeneic hematopoietic stem cell transplantation (HSCT). At the time of relapse, we again perform a mutational screening and cytogenetic analysis in all AML patients as clonal evolution of disease is frequent. Clinical trials should be first priority in all relapsed patients. In fit patients without prior transplant, we aim to perform HSCT after salvage therapy. In AML patients relapsing after HSCT and good performance status, intensive therapy can be considered with subsequent cellular therapy such as donor lymphocyte infusion (DLI) or a second HSCT. However, less than 20% of these patients are alive after 5 years. For those patients that are unfit, the therapeutic aim is to prolong life with acceptable quality of life. Here, hypomethylating agents (HMA), low-dose AraC (LDAC), and solely cytoreductive therapy with hydroxurea are options depending on first-line therapy. For those patients that have not been treated with venetoclax in first line, the combination therapy of venetoclax with demethylating agents achieves encouraging response rates. Venetoclax is currently also studied in combination with intensive salvage therapy. Importantly, for patients with isocitrate dehydrogenase (IDH) 1/2-mutated AML, ivosidenib, an IDH1 inhibitor, and enasidenib, an IDH2 inhibitor, present well-tolerated options in the setting of refractory or relapsed (r/r) disease even in elderly and heavily pre-treated patients with response rates of 30-40%. Both substances have been approved by the U.S. Food and Drug Administration (FDA) for r/r AML patients with IDH1/2 mutations (but not yet by the European Medicines Agency (EMA)). For patients with FMS-like tyrosine kinase 3 (FLT3) mutations, treatment with the selective FLT3 inhibitor gilteritinib is well tolerated and leads to improved outcome compared with standard salvage therapy. The approval has been granted by the FDA and the EMA. Generally, we would recommend targeted therapy for IDH1/2- and FLT3-mutated AML if available. In order to improve outcome in relapsed AML, it will be important to intelligently combine novel substances with each other as well as chemotherapy in prospective clinical trials. The development of therapies with bispecific antibodies or chimeric antigen receptor T cells (CAR-T) are still in early development.
Topics: Biomarkers, Tumor; Clinical Decision-Making; Combined Modality Therapy; Disease Management; Disease Susceptibility; Humans; Leukemia, Myeloid, Acute; Recurrence; Retreatment; Standard of Care; Treatment Outcome
PubMed: 32601974
DOI: 10.1007/s11864-020-00765-5 -
Journal of Hematology & Oncology Sep 2021Immunotherapies such as immune checkpoint blockade (ICB) and adoptive cell therapy (ACT) have revolutionized cancer treatment, especially in patients whose disease was... (Review)
Review
Immunotherapies such as immune checkpoint blockade (ICB) and adoptive cell therapy (ACT) have revolutionized cancer treatment, especially in patients whose disease was otherwise considered incurable. However, primary and secondary resistance to single agent immunotherapy often results in treatment failure, and only a minority of patients experience long-term benefits. This review article will discuss the relationship between cancer immune response and mechanisms of resistance to immunotherapy. It will also provide a comprehensive review on the latest clinical status of combination therapies (e.g., immunotherapy with chemotherapy, radiation therapy and targeted therapy), and discuss combination therapies approved by the US Food and Drug Administration. It will provide an overview of therapies targeting cytokines and other soluble immunoregulatory factors, ACT, virotherapy, innate immune modifiers and cancer vaccines, as well as combination therapies that exploit alternative immune targets and other therapeutic modalities. Finally, this review will include the stimulating insights from the 2020 China Immuno-Oncology Workshop co-organized by the Chinese American Hematologist and Oncologist Network (CAHON), the China National Medical Product Administration (NMPA) and Tsinghua University School of Medicine.
Topics: Animals; Cancer Vaccines; Combined Modality Therapy; Humans; Immune Checkpoint Inhibitors; Immunotherapy; Neoplasms; Oncolytic Virotherapy
PubMed: 34579759
DOI: 10.1186/s13045-021-01164-5 -
Revista Espanola de Salud Publica 2014Plantar fasciitis is the most common disease of non-traumatic pain in the ankle-foot. It is more common in women aged 40-70 years and diffuse progressive start the foot... (Review)
Review
BACKGROUND
Plantar fasciitis is the most common disease of non-traumatic pain in the ankle-foot. It is more common in women aged 40-70 years and diffuse progressive start the foot or ankle that gradually worsens preventing progress. The aim of this work is to determine whether different physical therapies used in the conservative treatment of plantar fasciitis of at least one month duration in adults are effective individually and / or in combination.
METHODS
A systematic review databases in The Cochrane Library, Medline, Lilacs, IBECS, IME, PEDro and ENFISPO no date restriction, in Spanish and English languages. Randomized controlled trials were included of adult patients diagnosed with plantar fasciitis, intervention studies, prospective and systematic reviews. Assessment of study eligibility was developed by two reviewers independently and unblinded standardized. To classify, we used the PEDro scale critical, form of methodological quality plus a critical review of each summary and if this was not conclusive assessment of the full text.
RESULTS
32 full-text articles were reviewed. Most used techniques are the stretches and shock waves, although the best results are obtained by combining several techniques. Shock waves are effective when other techniques have failed.
CONCLUSION
Physical therapies used in the various studies have proven effective to varying degrees either to reduce pain or relieve the symptoms of plantar fasciitis.
Topics: Combined Modality Therapy; Fasciitis, Plantar; Humans; Muscle Stretching Exercises; Physical Therapy Modalities; Prospective Studies; Treatment Outcome; Ultrasonic Therapy
PubMed: 24728397
DOI: 10.4321/S1135-57272014000100010 -
Frontiers in Immunology 2022Despite advances in treatment for multiple myeloma, the majority of patients ultimately develop relapsed disease marked by immune evasion and resistance to standard... (Review)
Review
Despite advances in treatment for multiple myeloma, the majority of patients ultimately develop relapsed disease marked by immune evasion and resistance to standard therapy. Immunotherapy has emerged as a powerful tool for tumor-directed cytotoxicity with the unique potential to induce immune memory to reduce the risk of relapse. Understanding the specific mechanisms of immune dysregulation and dysfunction in advanced myeloma is critical to the development of further therapies that produce a durable response. Adoptive cellular therapy, most strikingly CAR T cell therapy, has demonstrated dramatic responses in the setting of refractory disease. Understanding the factors that contribute to immune evasion and the mechanisms of response and resistance to therapy will be critical to developing the next generation of adoptive cellular therapies, informing novel combination therapy, and determining the optimal time to incorporate immune therapy in the treatment of myeloma.
Topics: Humans; Multiple Myeloma; Neoplasm Recurrence, Local; Immunotherapy; Immunotherapy, Adoptive; Combined Modality Therapy
PubMed: 36389674
DOI: 10.3389/fimmu.2022.1027385 -
Molecular Cancer Nov 2021Colorectal cancer (CRC) is a heterogeneous disease at the cellular and molecular levels. Kirsten rat sarcoma (KRAS) is a commonly mutated oncogene in CRC, with mutations... (Review)
Review
Colorectal cancer (CRC) is a heterogeneous disease at the cellular and molecular levels. Kirsten rat sarcoma (KRAS) is a commonly mutated oncogene in CRC, with mutations in approximately 40% of all CRC cases; its mutations result in constitutive activation of the KRAS protein, which acts as a molecular switch to persistently stimulate downstream signaling pathways, including cell proliferation and survival, thereby leading to tumorigenesis. Patients whose CRC harbors KRAS mutations have a dismal prognosis. Currently, KRAS mutation testing is a routine clinical practice before treating metastatic cases, and the approaches developed to detect KRAS mutations have exhibited favorable sensitivity and accuracy. Due to the presence of KRAS mutations, this group of CRC patients requires more precise therapies. However, KRAS was historically thought to be an undruggable target until the development of KRAS allele-specific inhibitors. These promising inhibitors may provide novel strategies to treat KRAS-mutant CRC. Here, we provide an overview of the role of KRAS in the prognosis, diagnosis and treatment of CRC.
Topics: Biomarkers, Tumor; Colorectal Neoplasms; Combined Modality Therapy; Disease Management; Disease Susceptibility; Drug Development; Gene Expression Regulation, Neoplastic; Humans; Liquid Biopsy; Molecular Diagnostic Techniques; Molecular Targeted Therapy; Mutation; Oncogenes; Prognosis; Proto-Oncogene Proteins p21(ras); Sensitivity and Specificity; Signal Transduction; Structure-Activity Relationship; Treatment Outcome
PubMed: 34742312
DOI: 10.1186/s12943-021-01441-4 -
Frontiers in Immunology 2022Immune checkpoint therapy PD-1 antibodies has shown exciting clinical value and robust therapeutic potential in clinical practice. It can significantly improve... (Review)
Review
Immune checkpoint therapy PD-1 antibodies has shown exciting clinical value and robust therapeutic potential in clinical practice. It can significantly improve progression-free survival and overall survival. Following surgery, radiotherapy, chemotherapy, and targeted therapy, cancer treatment has now entered the age of immunotherapy. Although cancer immunotherapy has shown remarkable efficacy, it also suffers from limitations such as irAEs, cytokine storm, low response rate, etc. In this review, we discuss the basic classification, research progress, and limitations of cancer immunotherapy. Besides, by combining cancer immunotherapy resistance mechanism with analysis of combination therapy, we give our insights into the development of new anticancer immunotherapy strategies.
Topics: Immunotherapy; Combined Modality Therapy; Immunologic Factors; Neoplasms
PubMed: 36304470
DOI: 10.3389/fimmu.2022.961805 -
Cancer May 2019Despite the significant advances in screening methods for early diagnosis, breast cancer remains a global threat and continues to be the leading cancer diagnosed in... (Review)
Review
Despite the significant advances in screening methods for early diagnosis, breast cancer remains a global threat and continues to be the leading cancer diagnosed in women, requiring effective therapy. Currently, combination therapy has become the hallmark of breast cancer treatment due to the high incidence of tumor recurrence and disease progression after monotherapeutic treatments, including surgery, radiotherapy, endocrine therapy, and chemotherapy. Over the past decades, there has been considerable interest in studying the anticancer effect of bioactive phytochemicals from medicinal plants combined with these conventional therapies. The rationale for this type of therapy is to use combinations of drugs that work by different mechanisms, thereby decreasing the likelihood that cancer cells will develop resistance, and also reduce the therapeutic dose and toxicity of single treatments. Three agents have received great attention with regard to their anticancer properties: 1) piperine, a dietary phytochemical isolated from black pepper (Piper nigrum L.) and long pepper (Piper longum L.); 2) sulforaphane, an isothiocyanate mainly derived from cruciferous vegetables; and 3) thymoquinone, the active compound from black seed (Nigella sativa L.). This review focused on the combined effect of these 3 compounds on conventional cancer therapy with the objective of observing enhanced efficacy compared with single treatments. This review also highlights the importance of the nanoformulation of such bioactive phytochemicals that could enhance their bioavailability by providing an efficient targeted delivery system with a reduced systemic dose while resulting in a more efficient dosing at the target site.
Topics: Alkaloids; Antineoplastic Agents; Benzodioxoles; Benzoquinones; Breast Neoplasms; Cell Line, Tumor; Chemotherapy, Adjuvant; Combined Modality Therapy; Female; Humans; In Vitro Techniques; Isothiocyanates; Patient Selection; Phytochemicals; Phytotherapy; Piperidines; Polyunsaturated Alkamides; Radiotherapy, Adjuvant; Sensitivity and Specificity; Sulfoxides
PubMed: 30811596
DOI: 10.1002/cncr.32022 -
Cancer Discovery Mar 2022Combination therapies are superior to monotherapy for many cancers. This advantage was historically ascribed to the ability of combinations to address tumor... (Review)
Review
UNLABELLED
Combination therapies are superior to monotherapy for many cancers. This advantage was historically ascribed to the ability of combinations to address tumor heterogeneity, but synergistic interaction is now a common explanation as well as a design criterion for new combinations. We review evidence that independent drug action, described in 1961, explains the efficacy of many practice-changing combination therapies: it provides populations of patients with heterogeneous drug sensitivities multiple chances of benefit from at least one drug. Understanding response heterogeneity could reveal predictive or pharmacodynamic biomarkers for more precise use of existing drugs and realize the benefits of additivity or synergy.
SIGNIFICANCE
The model of independent drug action represents an effective means to predict the magnitude of benefit likely to be observed in new clinical trials for combination therapies. The "bet-hedging" strategy implicit in independent action suggests that individual patients often benefit from only a subset-sometimes one-of the drugs in a combination. Personalized, targeted combination therapy, consisting of agents likely to be active in a particular patient, will increase, perhaps substantially, the magnitude of therapeutic benefit. Precision approaches of this type will require a better understanding of variability in drug response and new biomarkers, which will entail preclinical research on diverse panels of cancer models rather than studying drug synergy in unusually sensitive models.
Topics: Biomarkers; Combined Modality Therapy; Drug Therapy, Combination; Humans; Medical Oncology; Neoplasms; Precision Medicine
PubMed: 34983746
DOI: 10.1158/2159-8290.CD-21-0212 -
Current Treatment Options in Oncology Oct 2021Pancreatic cancer is mainly diagnosed at an advanced, often metastatic stage and still has a poor prognosis. Over the last decades, chemotherapy of metastatic pancreatic... (Review)
Review
Pancreatic cancer is mainly diagnosed at an advanced, often metastatic stage and still has a poor prognosis. Over the last decades, chemotherapy of metastatic pancreatic cancer (mPDAC) has proven to be superior to a mere supportive treatment with respect to both survival and quality of life. Recently, even sequential treatment of mPDAC could be established. Options for first-line treatment are combination chemotherapy regimens such as FOLFIRINOX and gemcitabine plus nab-paclitaxel when the performance status of the patient is good. For patients with poorer performance status, gemcitabine single-agent treatment is a valid option. Recently, the PARP inhibitor olaparib has been demonstrated to improve progression-free survival when used as a maintenance treatment in the subgroup of patients with mPDAC and a BRCA1/-2 germ line mutation having received at least 16 weeks of platinum-based chemotherapy. This group of patients also benefits from platinum-based chemotherapy combinations. Therefore, the BRCA1/-2 stats should be examined early in patients with mPDAC even when the occurrence of these mutations is only about 5% in the general Caucasian population. After the failure of first-line treatment, patients should be offered a second-line treatment if their ECOG permits further treatment. Here, the combination of 5-FU/FA plus nanoliposomal irinotecan has shown to be superior to 5-FU/FA alone with respect to overall survival. Immune checkpoint inhibitors like PD1/PD-L1 mAbs are particularly efficacious in tumors with high microsatellite instability (MSI-h). Limited data in mPDACs shows that only a part of the already small subgroup of MSI-H mPDACs (frequency about 1%) appears to benefit substantially from a checkpoint inhibitor treatment. The identification of further subgroups, e.g., tumors with DNA damage repair deficiency, gene fusions, as well as novel approaches such as tumor-organoid-informed treatment decisions, may further improve therapeutic efficacy.
Topics: Age Factors; Biomarkers, Tumor; Clinical Decision-Making; Clinical Trials as Topic; Combined Modality Therapy; Disease Management; Disease Susceptibility; Humans; Molecular Diagnostic Techniques; Neoplasm Grading; Neoplasm Metastasis; Neoplasm Staging; Pancreatic Neoplasms; Prognosis; Retreatment; Treatment Outcome
PubMed: 34665339
DOI: 10.1007/s11864-021-00895-4 -
Journal For Immunotherapy of Cancer Sep 2021Tumor-associated macrophages (TAMs) play a key immunosuppressive role that limits the ability of the immune system to fight cancer and hinder the antitumoral efficacy of...
BACKGROUND
Tumor-associated macrophages (TAMs) play a key immunosuppressive role that limits the ability of the immune system to fight cancer and hinder the antitumoral efficacy of most treatments currently applied in the clinic. Previous studies have evaluated the antitumoral immune response triggered by (TLR) agonists, such as poly(I:C), imiquimod (R837) or resiquimod (R848) as monotherapies; however, their combination for the treatment of cancer has not been explored. This study investigates the antitumoral efficacy and the macrophage reprogramming triggered by poly(I:C) combined with R848 or with R837, versus single treatments.
METHODS
TLR agonist treatments were evaluated in vitro for toxicity and immunostimulatory activity by Alamar Blue, ELISA and flow cytometry using primary human and murine M-CSF-differentiated macrophages. Cytotoxic activity of TLR-treated macrophages toward cancer cells was evaluated with an in vitro functional assay by flow cytometry. For in vivo experiments, the CMT167 lung cancer model and the MN/MCA1 fibrosarcoma model metastasizing to lungs were used; tumor-infiltrating leukocytes were evaluated by flow cytometry, RT-qPCR, multispectral immunophenotyping, quantitative proteomic experiments, and protein-protein interaction analysis.
RESULTS
Results demonstrated the higher efficacy of poly(I:C) combined with R848 versus single treatments or combined with R837 to polarize macrophages toward M1-like antitumor effectors in vitro. In vivo, the intratumoral synergistic combination of poly(I:C)+R848 significantly prevented tumor growth and metastasis in lung cancer and fibrosarcoma immunocompetent murine models. Regressing tumors showed increased infiltration of macrophages with a higher M1:M2 ratio, recruitment of CD4 and CD8 T cells, accompanied by a reduction of immunosuppressive CD206 TAMs and FOXP3/CD4 T cells. The depletion of both CD4 and CD8 T cells resulted in complete loss of treatment efficacy. Treated mice acquired systemic antitumoral response and resistance to tumor rechallenge mediated by boosted macrophage cytotoxic activity and T-cell proliferation. Proteomic experiments validate the superior activation of innate immunity by poly(I:C)+R848 combination versus single treatments or poly(I:C)+R837, and protein-protein-interaction network analysis reveal the key activation of the STAT1 pathway.
DISCUSSION
These findings demonstrate the antitumor immune responses mediated by macrophage activation on local administration of poly(I:C)+R848 combination and support the intratumoral application of this therapy to patients with solid tumors in the clinic.
Topics: Animals; Antiviral Agents; Cell Line, Tumor; Combined Modality Therapy; Drug Synergism; Humans; Imidazoles; Immunotherapy; Mice; Neoplasms; Poly I-C; Tumor-Associated Macrophages
PubMed: 34531246
DOI: 10.1136/jitc-2021-002408