Search Results (227)

Resistance to conventional anti-tumor drugs is one of the significant challenges in oncology, responsible for treatment failure and patient death. Introduction of the targeted drugs (e.g., small molecule tyrosine kinase inhibitors (TKIs) and monoclonal antibodies) in cancer therapy significantly improved overall survival (OS) and progression-free survival (PFS) rates for selected groups of cancer patients and delayed the progression of advanced forms of human malignancies. However, the development of secondary resistance to the targeted drugs remains an unbeatable obstacle to a successful outcome in the long run, thereby making prognosis unfavorable for cancer patients with advanced, recurrent, and metastatic forms of disease. The review focuses on several mechanisms that regulate cancer resistance to conventional chemotherapies. This includes the upregulation of main types of ABC transporters (e.g., ABCB1, ABCC1, and ABCG2), which provides the efflux of chemotherapeutic agents from cancer cells. Additionally, the activation of diverse DNA damage repair (DDR) pathways, epithelial-to-mesenchymal transition (EMT), and the population of cancer stem cells (CSCs) are also discussed in detail, thereby illustrating the diverse molecular mechanisms of cancer sensitivity to chemotherapies. Recently, several TKIs, including those that were initially developed to specifically target FGFR and VEGFR pathways, have also been reported to exhibit “off-target” effects by interacting with ABC transporters and inhibiting their function. This, in turn, illustrates their potency in retaining chemotherapeutic agents within cancer cells and possessing a chemosensitizing function. Of note, FGFR and VEGFR inhibitors may behave as inhibitors or substrates of ABC transporters, depending on the expression of specific pumps and affinity for them, concentrations, and types of co-administered agents, thereby disclosing the complexity of this scenario. Additionally, the aforementioned RTKI can interfere with the other molecular mechanisms regulating tumor sensitivity to conventional chemotherapies, including the regulation of diverse DDR pathways, EMT, and the population of CSCs. Thereby, the aforementioned “off-target” functions of FGFR and VEGFR inhibitors can open novel approaches towards anti-cancer therapies and strategies aimed at counteracting cancer multidrug resistance (MDR), which is important especially as second- or third-line treatments in patients who have progressed on modern chemotherapeutic regimens. Notably, the strategy of using TKIs to potentiate the clinical efficacy of chemotherapies can extend beyond inhibitors of FGFR and VEGFR signaling pathways, thereby providing a rationale for repurposing existing TKIs as an attractive therapeutic approach to overcome cancer chemoresistance. Full article

Background: Small cell lung cancer (SCLC) is an aggressive type of cancer known for its rapid progression and poor prognosis. While several chemotherapeutic agents, including topotecan, are approved for use in the second-line treatment setting, their clinical benefits have been modest and often limited by toxicity. As a result, there is a significant need for more effective treatment strategies. Given the high rate of brain metastases in patients with SCLC and temozolomide’s (TMZ) ability to penetrate the central nervous system, combining TMZ with irinotecan (IRI) presents a potentially effective therapeutic approach. This study aimed to evaluate the clinical outcomes of the TMZ and IRI combination compared to other second-line treatment regimens in a real-world patient population. Methods: We conducted a retrospective review of the medical records of 37 patients with relapsed SCLC who underwent second-line therapy at a tertiary oncology center from January 2018 to December 2023. Among these patients, 24 were treated with a combination of TMZ+IRI, while 13 received alternative regimens, which included topotecan, irinotecan, paclitaxel, docetaxel, vinorelbine, or gemcitabine. We collected baseline demographic and clinical data and assessed survival outcomes. Overall survival (OS) and progression-free survival (PFS) were estimated using the Kaplan–Meier method, and prognostic factors were analyzed using Cox regression models. Results: A total of 37 patients were included (mean age 59.7 years, 86.5% male). Baseline characteristics were similar between groups, except for body mass index, which was higher in the TMZ+IRI group (27.9 vs. 24.6, p = 0.033). Median OS was significantly longer in patients treated with TMZ+IRI compared to controls (25 vs. 8 months, p = 0.002). One-year OS rates were 58.2% and 25.4%, respectively. In multivariate analysis, brain metastases (HR 0.37, 95% CI 0.14–0.95, p = 0.039) and receipt of non-TMZ+IRI regimens (HR 2.82, 95% CI 1.03–7.72, p = 0.044) were independent predictors of poor OS. Median PFS did not differ significantly between groups (8 vs. 7 months, p = 0.733), and no independent predictors of PFS were identified. Conclusions: The combination of temozolomide and irinotecan was associated with a significant overall survival benefit compared with other second-line regimens in relapsed SCLC, despite similar progression-free survival. These findings suggest that TMZ+IRI may provide a clinically meaningful option for appropriately selected patients, particularly those with preserved performance status. Prospective randomized studies are warranted to confirm these results and better define the role of this regimen in treatment sequencing. Full article

Background: Appendiceal adenocarcinoma is a rare malignancy, and data guiding its systemic treatment in metastatic settings are limited. This study aimed to determine the clinical outcomes, treatment efficacy, biomarkers, and prognostic factors in patients with metastatic or unresectable appendiceal adenocarcinoma receiving palliative chemotherapy. Methods: We retrospectively reviewed patients with metastatic appendiceal adenocarcinoma who received first-line palliative systemic chemotherapy at the Peter MacCallum Cancer Centre between January 2015 and December 2024. Results: Of the 40 patients included, fluoropyrimidine-based doublet regimens were most commonly used (82.5%) in first-line setting, achieving an objective response rate of 39.4%. Median overall survival (OS) was 21.6 months, and median first-line progression-free survival (PFS) was 8.9 months. 22 patients (55.0%) received second-line treatment. Median OS and PFS were 21.6 and 8.9 months, respectively, among patients treated with oxaliplatin-based doublet regimens, and 66.4 and 10.8 months, respectively, among those treated with irinotecan-based doublet regimens. Molecular biomarker testing was performed in 35 patients (87.5%). KRAS and NRAS mutations were identified in 68.6% and 2.9% of tested patients, respectively. Factors associated with poorer OS included male sex, elevated carcinoembryonic antigen levels, and overweight status. Bevacizumab use was not clearly associated with survival. Conclusions: Palliative systemic chemotherapy, particularly fluoropyrimidine-based doublet regimens, appears to be a reasonable and effective treatment option for patients with advanced appendiceal adenocarcinoma. Although this study was underpowered for formal comparison, the numerically longer OS and PFS of irinotecan-based regimens are hypothesis-generating and support further prospective evaluation. Molecular profiling emphasizes the need for personalized targeted therapeutic strategies. The identified prognostic factors may help guide risk stratification and patient counseling for treatment planning. Full article

Colorectal cancer (CRC) is the second most prevalent cancer globally and remains a significant cause of cancer-related mortality. The limited efficacy and toxicities of conventional therapies underscore the urgent need for novel treatments. Lonidamine (LND), a synthetic indazole-3-carboxylic acid derivative, possesses anticancer properties, yet its clinical use is limited by toxic side effects. Apigenin (AP), a naturally occurring flavonoid present in a variety of fruits and vegetables, has been observed to enhance the efficacy of conventional chemotherapy regimens while mitigating associated side effects. In this study, we explored the potential synergistic anticancer effects and mechanisms of combining LND with AP in colon cancer cell lines MC38 and CT26. The results showed that LND and AP in combination synergistically inhibited the growth of colon cancer cells. In vitro, the combination therapy inhibited cell migration, induced cell cycle arrest in the G2/M phase, and promoted apoptosis by downregulating Bcl-2 and upregulating Bax expression. It disrupted glycolysis by reducing HK2 and GLUT1 expression, resulting in decreased glucose consumption and lactate production. Additionally, our findings suggested that the co-administration led to nucleotide depletion and disrupted NAD⁺ metabolism. The synergistic anticancer effect of LND combined with AP was also validated in MC38 tumor-bearing mice. These findings provide preliminary evidence that the combination of LND and AP may exert beneficial effects against CRC. Full article

Objective: This study aimed to provide the first umbrella review to systematically evaluate the evidence for the efficacy of personalized susceptibility-guided tailored therapy (TT) versus empirical therapy (ET) for Helicobacter pylori eradication. Methods: An umbrella review was conducted following Joanna Briggs Institute standards, registered in PROSPERO (CRD420251104335). A comprehensive literature search across MEDLINE/PubMed, EMBASE, RSCI, and Google Scholar identified systematic reviews and meta-analyses published between 1 January 1985 and 10 June 2025. Studies comparing TT and ET were included. Methodological quality was assessed using a modified AMSTAR-2 tool, GRADE, and the risk of bias was evaluated using the ROBIS tool. Data were synthesized using a random-effects model, with heterogeneity assessed using the I² statistic. Results: A total of 7 systematic reviews and meta-analyses were included, covering 66 primary studies. TT was associated with a significantly higher eradication rate compared to ET (RR = 1.265; 95% CI: 1.137–1.407). In first-line treatment, TT showed consistent superiority (RR = 1.156; 95% CI: 1.117–1.196), which was further supported by high-quality meta-analyses (RR = 1.288; 95% CI: 1.022–1.624). The benefit in second-line therapy did not reach statistical significance (RR = 1.291; 95% CI: 0.834–1.999). The absolute eradication rates were 84.31% (95% CI: 80.94–87.41) for TT and 67.80% (95% CI: 58.48–76.46) for ET. Conclusions: TT is more effective than ET in the first-line H. pylori eradication regimen. However, the benefit is less evident in second-line regimens. Full article

Background/Objectives: To compare oncologic outcomes of second-line chemotherapy regimens in relapsed high-grade serous ovarian cancer (HGSOC) by platinum sensitivity. Methods: We retrospectively reviewed HGSOC patients treated at two centers (June 2003–December 2020), classified by platinum-free interval (6- and 12-month cut-offs). Outcomes were progression-free survival (PFS, primary) and objective response and disease control rates (secondary). Regimens administered to ≥10% of patients or with favorable outcomes were compared using multivariable Cox analyses. Results: Among 468 patients (41.2% sensitive, 32.9% partially sensitive, 25.9% resistant), platinum-sensitive patients were younger (p = 0.024), diagnosed earlier, and more likely to undergo primary debulking surgery (both p < 0.001), achieving best outcomes after second-line chemotherapy (median PFS 14.8 vs. 10.5 and 5.2 months, p < 0.001). In both sensitive groups, the most common regimens were taxane + platinum ± bevacizumab, followed by pegylated liposomal doxorubicin + carboplatin, which was associated with shorter PFS in platinum-sensitive patients (hazard ratio (HR) 1.67, p = 0.016). Second-line maintenance with bevacizumab or poly(ADP-ribose) polymerase inhibitors was associated with improved PFS in both groups (p < 0.001). In platinum-resistant patients, the omission of bevacizumab (HR 2.01, p < 0.001) and a primary treatment history without cytoreduction (HR 4.43, p = 0.044) were associated with inferior outcomes. Conclusions: In platinum-sensitive patients with a favorable prognosis, taxane + platinum regimens were most commonly used and outperformed PLD + carboplatin. Maintenance therapy also conferred a meaningful benefit. In platinum-resistant disease, bevacizumab use and prior cytoreductive surgery may improve outcomes, underscoring the importance of treatment selection and surgical approach. Full article

Endometrial hyperplasia, presenting without atypia (EH) or as atypical hyperplasia (AH), is considered a precursor of endometrial cancer and affects women of reproductive or perimenopausal age, posing a major public health concern. The aim of this study was to review and compare the most recently published influential guidelines providing recommendations on the management of endometrial hyperplasia. Thus, a comparative review of guidelines from the Royal College of Obstetricians and Gynecologists, the Society of Obstetricians and Gynecologists of Canada, and the American College of Obstetricians and Gynecologists was conducted. There is a consensus regarding the optimal management strategies for EH, with observation and medical treatment being the first-line options and surgical treatment with total hysterectomy offering a second line in specific cases. Moreover, there is agreement regarding patients with AH, with surgical treatment being the recommended approach, while medical therapy is preferred for women who seek fertility preservation. Notably, close surveillance with endometrial biopsies every 3 or 6 months is suggested unanimously, as well as long-term follow-up in high-risk patients. Controversy exists regarding the initial diagnostic approach, with RCOG and SOGC suggesting outpatient endometrial biopsy, while ACOG recommends diagnostic hysteroscopy, as well as the therapeutic regimens for the oral treatment of EH. Surgical techniques such as endometrial ablation, intraoperative frozen section analysis, intraoperative visual inspection of the uterus, and morcellation constitute areas of controversy among the reviewed guidelines, and the surveillance protocols for women with EH are addressed differently between RCOG and SOGC. Notably, RCOG is the only medical society offering recommendations regarding women under HRT and those on therapy for breast cancer. The development of consistent international practice protocols for timely management strategies and surveillance protocols is of paramount importance to safely guide clinical practice and subsequently improve women’s health. Full article

Sarcoidosis is a chronic inflammatory disease of unknown etiology that can involve virtually any organ, with pulmonary involvement seen in over 90% of cases. Although many patients experience spontaneous remission, approximately 10–30% develop progressive pulmonary disease, which may lead to fibrocystic changes, respiratory failure, and death. Oral glucocorticoids remain the cornerstone of treatment for symptomatic patients with pulmonary infiltrates and abnormal pulmonary function tests, with typical starting doses ranging from 20 to 40 mg/day followed by a slow taper over 6–18 months based on clinical and radiographic response. However, prolonged glucocorticoid therapy is associated with significant toxicity, and many patients require additional immunosuppressive agents for disease control or steroid-sparing purposes. Antimetabolites such as methotrexate, azathioprine, mycophenolate mofetil, and leflunomide are commonly used second-line therapies. For refractory disease, particularly in those with metabolically active lesions on FDG-PET, anti-tumor necrosis factor (TNF) agents like infliximab may be effective but carry risks of serious adverse effects. In select cases, newer strategies—including RCI, rituximab, JAKi or investigational regimens—are being explored. Management must also account for non-inflammatory complications such as sarcoidosis-associated pulmonary hypertension and bronchiectasis, which can mimic disease progression and require distinct therapeutic approaches. Given the heterogeneity of sarcoidosis and lack of robust clinical trial data, a stepwise and individualized approach to immunosuppression remains essential in optimizing outcomes while minimizing treatment-related harm. Full article

Tuberculosis (TB), caused by Mycobacterium tuberculosis (MTB), remains one of the most devastating infectious diseases worldwide, with rising multidrug resistance limiting the effectiveness of conventional treatments. Novel therapeutic approaches are urgently needed to complement or replace existing regimens. Among emerging candidates, antimicrobial peptides (AMPs) stand out as versatile molecules capable of exerting direct antimycobacterial effects while also modulating the host immune response. This review explores peptide-based strategies against TB, with a focus on four major axes of innovation. First, we examine host-directed pathways, including the vitamin D–cathelicidin axis and other immunomodulatory mechanisms and their regulatory role in the induction of endogenous AMPs such as cathelicidin LL-37, which contributes to host-directed defense. Second, we discuss peptide-based vaccines designed to elicit robust and durable protective immunity, representing a complementary alternative to classical vaccine approaches. Third, we highlight the synergistic potential of AMPs in combination with first-line and second-line anti-TB drugs, aiming to restore or enhance bactericidal activity against resistant strains. Finally, we analyze technological platforms, including nanocarriers and inhalable formulations, that enable targeted pulmonary delivery, improve peptide stability, and enhance bioavailability. By integrating molecular design, immune modulation, and advanced delivery systems, peptide-based strategies provide a multifaceted approach to overcoming the limitations of current TB therapy. Collectively, these advances position AMPs not only as promising standalone agents but also as key components in combination and host-directed therapies, with strong potential to reshape the future clinical management of tuberculosis. Full article

Background: Data on antibiotic treatment for diabetic foot osteomyelitis are limited. This study aims to describe the real-world effectiveness and safety of dalbavancin in treating deep diabetic foot infections. Methods: A retrospective, observational, multicenter study was conducted in nine Spanish hospitals and one Irish hospital. Patients with diabetic foot osteomyelitis treated with dalbavancin were included. Data on demographics, clinical characteristics, microbiology, antibiotic regimens, adverse events, and clinical outcomes were analyzed. Results: Among 136 patients, 76% were male, with a mean age of 69 ± 12 years. Renal insufficiency was observed in 32%, and 6% required renal replacement therapy. Based on the McCabe scale, 70% of patients had a rapidly or ultimately fatal disease. Polypharmacy was noted in 83%, and 60% of infections were moderate. Dalbavancin was primarily used as second-line therapy (92%). The cure rate was 80.9% (95% CI: 73.5–86.6%), achieved after a median of two doses. Patients receiving dalbavancin as first-line therapy had a cure rate of 86%, comparable to 80% in second-line therapy, with no significant differences. Surgical interventions were required in 72% of cases, with minor amputations performed in 40% of patients. Polymicrobial infections were common (55%), and methicillin-resistant Staphylococcus aureus was identified in 26% of cases. Adverse events occurred in 5% of patients. Chronic kidney disease was the sole independent risk factor for therapeutic failure (IRR 0.80, 95% CI: 0.64–1.00, p = 0.045). Conclusions: Dalbavancin is effective and safe for treating diabetic foot osteomyelitis, including in complex patients with resistant microorganisms. Full article

Background: Ovarian cancer is an immunologically cold tumor that is treated with surgery and a chemotherapy regimen of platinum agents with taxanes. Paradoxically, elevated levels of several immune markers are effective at predicting prognosis for patients with ovarian cancer, though it is not clear how chemotherapy might influence this. Chemotherapy elicits immunogenic cell death, yet tumor-controlling doses of chemotherapy are also immunotoxic. Objectives: To evaluate interactions of chemotherapy with the immune system, we studied the impact of chemotherapy in an aggressive mouse model of ovarian cancer developed within our lab. Methods: Using a single-cell transcriptomics sequencing approach, supported by flow cytometry, we evaluated the influence of a first-line therapy, cisplatin and docetaxel, and a second-line therapy, pegylated liposomal doxorubicin (PLD), on control of tumor growth and on tumor-associated immune populations of cells. Results: Both chemotherapy approaches were effective at controlling tumor growth and selectively depleted tumor cells from distinct transcriptional clusters. Both chemotherapies also resulted in relative increases in immune populations compared to untreated tumor-bearing mice, but immune populations from PLD-treated mice were more abundant and expressed a greater fraction of maturity-associated transcripts and increased proportions of tumor resident macrophage populations. PLD treatment selectively upregulated MHC class II on tumor cells, and this could be replicated in vitro across ovarian cancer cell lines and in patient tumor cells ex vivo. Conclusions: Altogether, the results support the notion that PLD has a greater capacity for immunopotentiation, which may be important to consider if immunotherapy approaches are adapted for ovarian tumors in the future. Full article

Background/Objectives: Helicobacter pylori (H. pylori) infection remains highly prevalent in Vietnam, associated with chronic gastritis, peptic ulcers, and gastric cancer. This study aimed to evaluate the real-world eradication rate of levofloxacin-based bismuth quadruple therapy (PALB) as second-line treatment, assess adherence, and identify associated factors with treatment success. Methods: We conducted a prospective cohort study including 225 patients with confirmed failure of classical bismuth-based quadruple therapy. All received a 14-day PALB regimen. H. pylori eradication was assessed using 13C-urea breath test and/or rapid urease test 4–12 weeks after treatment. Results: Eradication rates were 78.2% (mITT) and 78.6% (PP), with 95% CIs overlapping the 80% benchmark. Adherence was high (91.6%) and significantly associated with success (OR = 2.93; 95% CI: 1.11–7.74; p = 0.039). No other factors were significantly associated. Conclusions: While PALB remains a valid second-line therapy, its efficacy may be declining, though not statistically inferior to 80%. Improving adherence and strengthening stewardship are essential. Full article

The treatment landscape for EGFR-mutated metastatic non-small cell lung cancer (mNSCLC) has evolved significantly with multiple combination regimens demonstrating superiority over single agent Osimertinib over the past two years. Recent trials such as FLAURA2 and MARIPOSA have explored intensified front-line regimens, with FLAURA2 demonstrating improvement in PFS with the addition of chemotherapy to Osimertinib and MARIPOSA, showing both a PFS and OS benefit with a novel combination regimen of Amivantamab and Lazertinib. However, these regimens are associated with significantly higher toxicity to patients and pose a huge financial and logistical burden to the health care system; therefore, treatment selection must therefore be individualized, considering disease biology, patient fitness, and toxicity burden. Post-progression strategies remain challenging due to resistance mechanisms like EGFR C797S mutations and MET amplification and the lack of data post-progression on novel first-line combinations. Ongoing trials are investigating fourth-generation EGFR TKIs, MET inhibitors, antibody–drug conjugates, and bispecific antibodies in subsequent lines. While regimens like Amivantamab-Lazertinib show promise even in second-line settings, toxicity, cost, and access remain barriers. As therapeutic options expand, biomarker-driven sequencing and personalized care will be critical to optimizing long-term outcomes in EGFR-mutated mNSCLC. Full article

Background/Objectives: This study compared overall survival (OS) associated with common real-world treatment sequences in patients with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) in the United States. Methods: Utilizing the nationwide Flatiron Health electronic health record-derived de-identified database, adult CLL/SLL patients who initiated systemic therapy (JAN2016-NOV2023) and received at least two lines of therapy (LoTs) were analyzed. Treatment regimens were categorized based on drug class, and most frequent (n ≥ 50) sequences (first LoT followed by [→] second LoT) were compared. OS from initiation of the first LoT was compared using multivariable Cox proportional hazard models, and adjusted hazard ratios with 95% CIs were reported. Results: Among 2354 eligible patients, n = 1711 (73%) received the 16 most frequent treatment sequences. Sequencing chemoimmunotherapy (CIT) → CIT (HR: 2.29 [1.23–4.28]), anti-CD20 monoclonal antibody (anti-CD20mab) monotherapy → CIT (1.95 [1.03–3.69]), and covalent Bruton tyrosine kinase inhibitor (cBTKi) monotherapy → anti-CD20mab monotherapy (2.00 [1.07–3.74]) were associated with worse OS compared to patients treated with cBTKi monotherapy → B-cell lymphoma 2 inhibitors (BCL2i) + anti-CD20mab (reference). Conclusions: OS associated with other sequences were not significantly different from the reference sequence in adjusted analyses, suggesting a lack of evidence for the optimal standard of care for sequencing the first two LoTs in real-world settings. Future research should reassess sequencing outcomes as novel treatments become adopted into clinical practice. Full article

Background/Objectives: The TOPAZ-1 phase III trial reported a survival benefit of using durvalumab, an anti-programmed death ligand 1 (anti-PD-L1) antibody, in combination with gemcitabine and cisplatin (GCD) treatment in patients with advanced biliary tract cancer. This retrospective study investigated the efficacy and safety of GCD treatment for advanced biliary tract cancer in real-world conditions. Methods: The study subjects were 52 patients with biliary tract cancer who received GCD therapy between January 2023 and May 2024. The observation parameters included the modified Glasgow Prognostic Score (mGPS), neutrophil–lymphocyte ratio (NLR), platelet–lymphocyte ratio (PLR), tumor markers (CEA, CA19-9), overall response rate (ORR), disease control rate (DCR), progression-free survival (PFS), overall survival (OS), and adverse events. Results: The cohort included 36 men and 16 women, with a median age of 73.0 years. There were 36 cases of cholangiocarcinoma (distal: 10, perihilar: 19, intrahepatic: 7), 13 cases of gallbladder cancer, and 3 cases of ampullary carcinoma. The stages were locally advanced in 30 cases and metastatic in 22 cases. Biliary drainage was performed in 30 cases. There were 38 cases receiving first-line therapy and 14 cases receiving second-line or later treatments. The median values at the start of GCD therapy were ALB 3.7 g/dL, CRP 0.39 mg/dL, NLR 2.4, PLR 162.5, CEA 4.8 ng/mL, and CA19-9 255.9 U/mL. The mGPS distribution was 0:23 cases, 1:18 cases, and 2:11 cases. The treatment outcomes were ORR 25.0% (CR 2 cases, PR 11 cases), DCR 78.8% (SD 28 cases, PD 10 cases, NE 1 case), median PFS 8.6 months, and median OS 13.9 months. The PLR was suggested to be useful for predicting PFS. A decrease in CEA at six weeks after the start of treatment was a significant predictor of PFS and OS. Gallbladder cancer had a significantly poorer prognosis compared to other cancers. The immune-related adverse events included hypothyroidism in two cases, cholangitis in one case, and colitis in one case. Conclusions: The ORR, DCR, and PFS were comparable to those in the TOPAZ-1 trial. Although limited by its retrospective design and small sample size, this study suggests that GCD therapy is an effective treatment regimen for unresectable biliary tract cancer in real-world clinical practice. Full article