Prolonged Chemotherapy Research Articles

Experience with Minimal Invasive Conversion Surgery after Prolonged Chemotherapy: Two Case Reports

Experience with Minimal Invasive Conversion Surgery after Prolonged Chemotherapy: Two Case Reports

Prevalence and impact of multidrug-resistant bacteria in solid cancer patients with bloodstream infection: a 25-year trend analysis.

Multidrug-resistant (MDR) bacteria pose a global public health threat as they are more challenging to treat, and they are on the rise. Solid cancer patients are often immunocompromised due to their disease and cancer treatments, making them more susceptible to infections. Understanding the changes and trends in bloodstream infections in solid cancer patients is crucial, to help physicians make informed decisions about appropriate antibiotic therapies, manage infections in this vulnerable population, and prevent infection. Solid cancer patients often require intensive and prolonged treatments, including surgery, chemotherapy, and radiation therapy. Infections can complicate these treatments, leading to treatment delays, increased healthcare costs, and poorer patient outcomes. Investigating new strategies to combat MDR infections and researching novel antibiotics in these patients is of paramount importance to avoid these negative impacts.

Intra-abdominal infection and sepsis in immunocompromised intensive care unit patients: Disease expression, microbial aetiology, and clinical outcomes

We compared epidemiology of intra-abdominal infection (IAI) between immunocompromised and non-immunocompromised ICU patients and identified risk factors for mortality.We performed a secondary analysis on the “AbSeS” database, a prospective, observational study with IAI patients from 309 ICUs in 42 countries. Immunocompromised status was defined as either neutropenia or prolonged corticosteroids use, chemotherapy or radiotherapy in the past year, bone marrow or solid organ transplantation, congenital immunodeficiency, or immunosuppressive drugs use. Mortality was defined as ICU mortality at any time or 28-day mortality for those discharged earlier. Associations with mortality were assessed by logistic regression.The cohort included 2589 patients of which 239 immunocompromised (9.2 %), most with secondary peritonitis. Among immunocompromised patients, biliary tract infections were less frequent, typhlitis more frequent, and IAIs were more frequently healthcare-associated or early-onset hospital-acquired compared with immunocompetent patients. No difference existed in grade of anatomical disruption, disease severity, organ failure, pathogens, and resistance patterns. Septic shock was significantly more frequent in the immunocompromised population. Mortality was similar in both groups (31.1% vs. 28.9 %; p = 0.468). Immunocompromise was not a risk factor for mortality (OR 0.98, 95 % CI 0.66–1.43). Independent risk factors for mortality among immunocompromised patients included septic shock at presentation (OR 6.64, 95 % CI 1.27–55.72), and unsuccessful source control with persistent inflammation (OR 5.48, 95 % CI 2.29–12.57). In immunocompromised ICU patients with IAI, short-term mortality was similar to immunocompetent patients, despite the former presented more frequently with septic shock, and septic shock and persistent inflammation after source control were independent risk factors for death.

Multi-stimuli-responsive Hydrogels for Therapeutic Systems: An Overview on Emerging Materials, Devices, and Drugs.

The rising interest in hydrogels nowadays is due to their usefulness in physiological conditions as multi-stimuli-responsive hydrogels. To reply to the prearranged stimuli, including chemical triggers, light, magnetic field, electric field, ionic strength, temperature, pH, and glucose levels, dual/multi-stimuli-sensitive gels/hydrogels display controllable variations in mechanical characteristics and swelling. Recent attention has focused on injectable hydrogel-based drug delivery systems (DDS) because of its promise to offer regulated, controlled, and targeted medication release to the tumor site. These technologies have great potential to improve treatment outcomes and lessen side effects from prolonged chemotherapy exposure.

Association Between Time From Surgery to Radiation Therapy and Multimodality Treatment Outcomes in HPV+ Head and Neck Cancer: A Multi-Institutional Cohort Experience

Oropharyngeal squamous cell cancers (OPSCCs) are traditionally managed with surgery and, if indicated, adjuvant radiation therapy (RT) with or without chemotherapy. NCCN recommends keeping the time from surgery to the start of RT (TSRT) within 6 weeks to avoid possibly compromising patient outcomes. HPV+ OPSCCs behave more favorably than HPV- OPSCCs. We hypothesized that TSRT beyond 6 weeks may not portend poorer outcomes for the former. We identified nonmetastatic, high-risk HPV+ OPSCCs treated with multimodal therapy at 2 institutions. Prolonged TSRT was defined as >6 weeks and was evaluated for association with recurrence-free survival (RFS). Radiation treatment time (RTT; time from the first to the last day of RT), total treatment package time (TTPT; time from surgery to the end of adjuvant treatments), de-escalated RT (dose ≤56 Gy), concurrent chemotherapy, smoking history, and treatment institution were evaluated as possible confounders. In total, 96 patients were included. The median follow-up time was 62 months (4-123 months); 69 patients underwent transoral robotic surgeries, and 27 received open surgeries. The median postoperative RT dose was 60 Gy (50-70.8 Gy). The median TSRT, RTT, and TTPT were 38 days (11-208), 43 days (26-56 days), and 81 days (40-255 days), respectively. Ten patients failed treatment at a median of 8 months (4-64 months). Two locoregional and 4 distant failures occurred in the group without prolonged TSRT, whereas 2 locoregional and 2 distant failures were recorded in the prolonged TSRT group. Prolonged TTPT, de-escalated RT, chemotherapy, smoking history, and treatment institution were not associated with treatment failure. RTT was dropped from our analyses as no events appeared in the prolonged RTT group, and no reliable hazard ratio could be computed. TSRT > 6 weeks was not significantly associated with inferior outcomes in the postoperative management of HPV+ OPSCCs. Longer TSRT may facilitate better recovery from surgical toxicity, as needed, without compromising oncologic outcomes. The TSRT goal for these cancers should be investigated in future studies.

Four-year clinical update and treatment switching-adjusted outcomes with first-line nivolumab plus ipilimumab with chemotherapy for metastatic non-small cell lung cancer in the CheckMate 9LA randomized trial

BackgroundIn CheckMate 9LA, nivolumab plus ipilimumab with chemotherapy prolonged overall survival (OS) versus chemotherapy regardless of tumor PD-L1 expression or histology. We report updated efficacy and safety in all randomized...

The Apoptotic Property of Nymphaea Caerulea Flower Extract on Acute Myeloid Leukaemia Cell Line, THP-1.

Acute Myeloid Leukaemia (AML) is considered to be an extremely heterogeneous malignancy of bone marrow and blood. The first line of therapy for AML is prolonged chemotherapy. Due to the presence of molecular heterogeneity in AML as confirmed by next-generation sequencing, researchers are planning to develop newer strategies of therapy. In the present study we have explored the anti-cancer potentiality of the hydro-ethanolic extract (50% and 70%) of the whole flower of Nymphaea caerulea against the Acute Myeloid Leukaemia cell line, THP-1 with control of normal human kidney epithelial cell line (HEK 293). The present study is a novel contribution to the existing scientific knowledge as at present no study as an anti-leukaemic agent is available on N. caerulea (blue lotus) extract and exploring its action mechanism on in-vitro cell line model. Some targeted cytokine and apoptotic genes genes to deduce the anti-cancer mechanism of action of the crude extract (hydro-ethanolic extract (50% and 70%) of the whole flower) were selected as Interferon (IFN) γ, Interleukins - IL-6, IL-8, IL- 10, IL-1β, Transforming Growth Factor (TGF β1), Tumor Necrosis Factor (TNF α), Caspase 3(CAS 3), Caspase 9 (CAS 9), CD95 (Fas), Tumor Necrosis Factor Receptor 1 (TNFRSF1A) to observe relative fold changes of the expression using Real-Time PCR with housekeeping gene β-actin. Cellular cytopathic effect (CPE), cell viability assay by methylene blue assay, and cell cytotoxicity of the crude extract against the THP-1 cell line were also studied along with it's bio-active compositional analysis of the extract was explored using ultra-performance liquid chromatography followed by mass spectra. The N. caerulea flower extract is capable of inducing apoptosis in AML and it can balance cytokine alterations in such diseases. Nymphaea caerulea flower extract appears to be a good anti-leukemia agent.

A Specialized CD4+ T-Cell Subset Protects Residual Leukemic Cells from Immune Surveillance, Enabling Relapse

Outcomes for patients with acute lymphoblastic leukemia (ALL) continue to improve in the era of immune- therapies. Despite this, measurable residual disease (MRD) frequently persists after frontline treatment, necessitating allogeneic hematopoietic stem cell transplantation or prolonged chemotherapy lasting multiple years. Relapse remains common and is associated with long-term survival rates of <25%. This emphasizes the need for research into fundamental mechanisms that enable the persistence of leukemic blasts. We previously showed that adding anti-PDL1 therapy to the tyrosine kinase inhibitor nilotinib improved survival from 10% to 70% in a murine model of BCR-ABL+ ALL. This effect was abrogated in the absence of CD4 T cells, suggesting a key role for CD4 T cells in anti-leukemia immunity. Persisting MRD in the absence of PDL1 blockade was associated with the polyclonal expansion of FOXP3- CD4 T-cells. These CD4s expressed high levels of the suppressive cytokine IL10, and loss of key helper molecules such as CD40L. In contrast, successful treatment with PDL1 blockade correlated with oligoclonal expansion of a CD4+ T-cell subset with preserved CD40L expression and diminished IL10. The observed IL10+ FOXP3- CD4 T-cell phenotype implies a T-regulatory type 1 (Tr1) identity. Importantly, a specialized Tr1 subset has been shown to eliminate mutation-harboring hematopoietic stem cells (HSCs), demonstrating a role for surveillance and leukemia prevention by Tr1s in the HSC niche. Tr1s convey pro-proliferative and differentiation signals towards mutation-harboring HSCs, driving their development into short-lived myeloid blasts. Tr1s in the HSC niche secrete high levels of IL10, apparently to minimize excess inflammation while eliminating mutated HSCs. In our current proposal, we hypothesize that the pro-proliferative and immunosuppressive signals of Tr1s are co-opted by residual acute lymphoblastic leukemia cells, maladaptively protecting them from immune attack and eradication. To investigate this hypothesis, we made a novel transgenic mouse (HV1) that harbors CD4 T-cells with a fixed TCR derived from the oligoclonally expanded CD4+ T-cells that we observed during treatment with anti-PDL1 blockade. HV1 CD4 T-cells specifically recognized and expanded in response to BCR-ABL+ ALL cells. HV1 cells remained largely FOXP3-negative and demonstrated an increase in IL10 expression with concordant loss of CD40L during leukemia progression. scATACSeq studies revealed that naïve HV1 cells develop into 5 distinct subsets during leukemia challenge in vivo (Fig. 1). Accessible chromatin regions (ACRs) of IL10, EOMES and other Tr1-like genes were high in clusters 1,2, and 5. Interestingly, clusters 1 and 5 did not have a loss of ACRs in genes associated with helper/effector function (CD40L, IFNγ, TNF). Functional studies verified that co-culture of CD4 T-cells with BCR-ABL+ ALL cells induced CD4s to suppress bystander CD8+ T-cells. Adoptive transfer of HV1 cells prolonged survival of mice bearing BCR-ABL+ ALL, but was non-curative, consistent with reprogramming of HV1 cells to an IL10+ suppressive phenotype. These findings imply that anti-leukemia CD4 T-cells in the presence of leukemia initially develop into heterogenous pro-helper/cytotoxic subsets. Chronic exposure to leukemia drives most of these early subsets to terminally differentiate into IL10+/FOXP3- suppressive Tr1s. These Tr1s do not bear classic hallmarks of exhaustion (e.g. epigenetic silencing of effector cytokines) but instead phenocopy a class of CD4s that normally guards the HSC niche. Anti-PDL1 blockade may function in this context by clonally expanding progenitor helper/cytotoxic leukemia-specific CD4s, tilting the local balance away from IL10+ populations. This mechanism is distinct from rescue of early-exhausted T-cell populations, which is a well-accepted explanation for the effects of checkpoint blockade on CD8+ T-cells in solid tumor settings. Our results imply a novel mechanism underlying anti-PDL1 checkpoint blockade clinical efficacy, which may be therapeutically exploited to eradicate measurable residual disease.

One-Stop No-Edited Allogenic CAR-T Therapy Bridging HSCT to Treat Children with Relapse and Refractory Acute Lymphoblastic Leukemia: A Prospective Clinical Study from a Single Center

Object: Chimeric Antigen Receptor T-Cell (CAR-T) therapy has been developed to be the most effective treatment for relapse and refractory(R/R) B-cell acute lymphoblastic leukemia(B-ALL). However, in some patients prolonged chemotherapy and previous autologous-CAR-T(auto-CAR-T) therapy severely impaired lymphocyte function leading to inability in vitro expansion for effective CAR-T therapy. To address this challenge, we designed this clinical trail to use one-stop no-edited allogenic CAR-T（allo-CART）bridging to same donor conditioning free HSCT to treat children with R/R B-ALL. Methods: Myeloablative conditioning was given to reducing the leukemia burden and clearing lymphatic function for these active ALL. After that allo-CART was used to regain the immune killing effect and clear leukemia cells. Same donor seamless conditioning free HSCT were performed to rapid reconstruction of hematopoietic cells to overcome Immune effector cell associated hematologic toxicity post CAR-T therapy. Ex vivo TCRαβ+ T-cell depleted hematopoietic stem cell were transplanted for haplo-identical donor (HID) to minimize allogeneic reactivation and only macophenolate mofetil (MMF) were given for GHVD prophylaxis and to avoid more immunosuppressive to injury CART effect. Results: From October 2020 to April 2023, 16 extremely R/R B-ALL children with the median age of 10y (1.5-17) were recruited in this study, all patients relapsed 2-5 times and failure of 1-3 times auto-CART therapy with mean blast 70.6%±28.8%. Myeloablative conditioning with total body irradiation (12GY，-7d to -5d),Flu (160mg/m2, -5 to -2d) and CTX (120mg/kg，-4d to -3d) were given. After conditioning all patients received no-edited family donor allo-CAR-T therapy with the average cart (5.29±2.92)×10 6/kg, 3 from matched sibling donor (MSD) and 13 from haplo identical donor(HID). 6 patients received CD22-targeted CAR-T therapy due to loss of CD19 after previous auto-CART and another 10 received bispecific CD19/CD22-targeted CAR-T therapy. Immediately after the peak of cytokine release syndrome (CRS), median 11 days (range: 8-34 days), same allo-CART donor hematopoietic stem cell were transplanted with the median CD34+cells(6.88±2.77)×10 6 /kg and TCRαβ+T cells(18.65±16.10)×10 4 /kg for TCRαβ+depleted HSCT. After median follow-up of 8 (range 3 to 34) months for the surviving patients. Out of the 16 patients, 6 (37.5%) achieved CR after conditioning, 13 (81.3%) achieved CR after CAR-T therapy and 15 (93.8%) got CR at one month post HSCT. Among the 16 patients, 15 experienced CRS (above grade 1) and one accompanied by immune effector cell-associated neurotoxicity syndrome (ICANS), but no one died of CRS. 13(81.2%) patients developed acute graft-versus-host disease (aGvHD) before transplant mainly presented with skin GVHD except 3(18.9%) had a grade III GVHD which easily be resolved. Before HSCT, all patients achieved complete chimerism with donor T-cells. Almost every one experienced several episode infection during these therapy. Until the last follow-up, 2 cases relapsed and 5 died (2 died of infections, 1 died of relapse and 2 died of GvHD combined thrombotic microangiopathy and infection). Despite being a cohort of R/R patients with non-CR, the estimated overall survival (OS) at 1 year was 58.7%±16.0%, event-free survival (EFS) was 44.4%±14.2%. Conclusion: For children with repeated relapsed B-ALL failure of previous auto-CART, Allo-CART treat can be considered as long as CART targets still presented. One-stop no-edited same donor allo-CART bridging to conditioning free HSCT provides a chance of survival for these extremely refractory/relapsed B-ALL with manageable CRS and GVHD, but more serious infection.

Pembrolizumab versus methotrexate, docetaxel, or cetuximab in recurrent or metastatic head and neck squamous cell carcinoma (KEYNOTE-040): Subgroup analysis by pattern of disease recurrence

BackgroundIn the phase 3 KEYNOTE-040 study, pembrolizumab prolonged OS versus chemotherapy in previously treated recurrent or metastatic (R/M) HNSCC. We present a post hoc subgroup analysis by disease recurrence pattern: recurrent-only, recurrent and metastatic (recurrent-metastatic), and metastatic-only HNSCC. Materials and MethodsPatients had HNSCC that progressed during or after platinum-containing treatment for R/M disease or had recurrence or progression within 3–6 months of previous platinum-containing definitive therapy for locally advanced disease. Patients were randomly assigned (1:1) to pembrolizumab 200 mg Q3W or investigator’s choice of standards of care (SOC): methotrexate, docetaxel, or cetuximab. Outcomes included OS, PFS, ORR, and DOR. The data cutoff was May 15, 2017. ResultsThere were 125 patients (pembrolizumab, 53; SOC, 72) in the recurrent-only subgroup, 204 in the recurrent-metastatic subgroup (pembrolizumab, 108; SOC, 96), and 166 in the metastatic-only subgroup (pembrolizumab, 86; SOC, 80). The hazard ratio (95% CI) for death for pembrolizumab versus SOC was 0.83 (0.55–1.25) in the recurrent-only, 0.78 (0.58–1.06) in the recurrent-metastatic, and 0.74 (0.52–1.05) in the metastatic-only subgroups. PFS was similar between treatment arms in all subgroups. ORR was 22.6% for pembrolizumab versus 16.7% for SOC in the recurrent-only, 10.2% versus 6.3% in the recurrent-metastatic, and 15.1% versus 8.8% in the metastatic-only subgroups. DOR was numerically longer with pembrolizumab in all subgroups. ConclusionPembrolizumab provided numerically longer OS and durable responses in all subgroups compared with SOC, suggesting that patients with previously treated R/M HNSCC benefit from pembrolizumab regardless of recurrence pattern.

CAR T-Cells for the Treatment of B-Cell Acute Lymphoblastic Leukemia

B-cell acute lymphoblastic leukemia (B-ALL) is the most common subtype of acute leukemia in the pediatric population. The prognosis and treatment of B-ALL have dramatically improved over the past decade with the adoption of intensive and prolonged combination chemotherapy regimens. The advent of novel immunologic agents such as blinatumomab and inotuzumab has changed the treatment landscape of B-ALL. However, patients have continued to relapse, raising the need for novel therapies. Chimeric antigen receptor (CAR) T-cells have achieved a milestone in the treatment of B-ALL. Two CD19-targeting CAR T-cells were approved by the Food and Drug Administration and the European Medicines Agency for the treatment of relapsed and/or refractory B-ALL. In this review, we review the available data regarding CD19-targeting CAR T-cells with their safety profile as well as the mechanism of resistance to these agents and the way to overcome this resistance.

Combinatorial efficacy of Manuka honey and antibiotics in the in vitro control of staphylococci and their small colony variants

IntroductionStaphylococci are among the list of problematic bacteria contributing to the global antibiotic resistance (ABR) crisis. Their ability to adopt the small colony variant (SCV) phenotype, induced by prolonged antibiotic chemotherapy, complicates staphylococcal infection control options. Novel and alternative approaches are needed to tackle staphylococcal infections and curb ABR. Manuka honey (MH), a non-antibiotic alternative is recognized for its unique antibacterial activity based on its methylglyoxal (MGO) component.MethodsIn this study, MH (MGO 830+) was tested in combination with gentamicin (GEN), rifampicin (RIF), or vancomycin (VA) against staphylococcal wildtype (WT) and SCVs. To our knowledge, there are no current studies in the literature documenting the effects of MH on staphylococcal SCVs. While Staphylococcus aureus is well-studied for its international ABR burden, limited data exists demonstrating the effects of MH on S. epidermidis and S. lugdunensis whose pathogenic relevance and contribution to ABR is also rising.Results & discussionThe three staphylococci were most susceptible to RIF (0.06-0.24 μg/ml), then GEN (0.12-0.49 μg/ml), and lastly VA (0.49-0.96 μg/ml). The MICs of MH were 7%, 7-8%, and 6-7% (w/v), respectively. Fractional inhibitory concentration (FIC) evaluations showed that the combined MH + antibiotic effect was either additive (FICI 1-2), or partially synergistic (FICI >0.5-1). While all three antibiotics induced SCVs in vitro, stable SCVs were observed in GEN treatments only. The addition of MH to these GEN-SCV-induction analyses resulted in complete suppression of SCVs (p<0.001) in all three staphylococci, suggesting that MH’s antibacterial properties interfered with GEN’s SCV induction mechanisms. Moreover, the addition of MH to growth cultures of recovered stable SCVs resulted in the inhibition of SCV growth by at least 99%, indicating MH’s ability to prevent subsequent SCV growth. These in vitro analyses demonstrated MH’s broad-spectrum capabilities not only in improving WT staphylococci susceptibility to the three antibiotics, but also mitigated the development and subsequent growth of their SCV phenotypes. MH in combination with antibiotics has the potential to not only resensitize staphylococci to antibiotics and consequently require less antibiotic usage, but in instances where prolonged chemotherapy is employed, the development and growth of SCVs would be hampered, providing a better clinical outcome, all of which mitigate ABR.

Comprehensive Clinical Characterization of Decade-Long Survivors of Metastatic Breast Cancer.

Elucidating the clinical features of metastatic breast cancer (MBC) patients with an exceptionally favorable prognosis may offer insights to improve the survival of more typical patients. We collected comprehensive real-world data on clinicopathologic characteristics, treatments, and outcomes of 110 consecutive MBC patients who survived for over ten years from the clinical data warehouse of Samsung Medical Center. The cohort included 54 hormone receptor (HR)-positive/HER2-negative (HR+/HER2-), 21 HR+/HER2+, 16 HR-/HER2+, and 14 triple-negative breast cancer (TNBC) patients. The median age at MBC diagnosis was 48.5 years. Approximately 70% of patients initially had a single-organ metastasis. The most common site of metastasis was the lung (46.4%), followed by distant lymph nodes (37.3%). During a median follow-up of 14.6 years, the median duration of systemic therapy was 11, 8.4, 7.3, and 0.8 years in the HR+/HER2-, HR+/HER2+, HR-/HER2+, and TNBC subgroups, respectively. Seven HER2+ and ten TNBC patients received systemic treatment for less than two years and remained treatment-free for most of the follow-up period, suggesting a potential chance of cure. The TNBC subtype (p < 0.001) and local treatment with curative intent within 1 year of MBC diagnosis (p = 0.002) were significantly associated with long-term treatment-free survival. The survival of HER2+ MBC and TNBC patients, but not that of HR+/HER2- patients, plateaued approximately 13 years after MBC diagnosis. A small subset of patients with HER2+ MBC and metastatic TNBC may be curable with multimodality therapy. Prospective studies integrating clinical and genomic data may identify unique clinicogenomic features of MBC patients who can achieve durable disease control without prolonged chemotherapy.

Microbiological evaluation of probiotic therapy in patients with pulmonary tuberculosis

Patients with pulmonary tuberculosis and multiple pathogen resistance (MDR) develop persistent disorders of the intestinal microbiome during prolonged multicomponent chemotherapy requiring correction. However, there is limited data on the use of bacterial drugs in patients with tuberculosis followed by assessing their effectiveness. The aim of the study was to evaluate changes in the intestinal microbiome after a course of probiotics along with anti-tuberculosis chemotherapy in patients with MDR tuberculosis.&#x0D; Materials and methods. The design a prospective small-cohort study (n = 30). Patients with pulmonary tuberculosis received anti-tuberculosis drugs according to the IV or V regimen, the median of the doses taken was 34.5 (30; 57.5); gastrointestinal syndrome was recorded in all study subjects. Probiotic therapy was applied by using a preparation containing Bifidobacterium bifidum and B. animalis and Lactobacillus casei, L. plantarum, L. delbrueckii subsp.bulgaricus, L. acidophilus. The course of therapy comprised 21 days,1 capsule twice a day. Before and 7 days after probiotics therapy, studies on composition of the intestinal microbiota were carried out, the frequency of virulence factors Enterococcus spp., Staphylococcus spp., Candida spp. was examined; fatty acid composition and activity of enterococcal organic acid production were studied.&#x0D; Results. After a course of probiotics, a significant increase in lactobacillus titers was recorded from 5.2 (4.0; 6.0) to 6.1 (6.0; 8.0) lg CFU/g (p = 0.05). The frequency of mucosal colonization by Candida fungi and lactose-negative Escherichia decreased by 2-fold (p = 0.001) and 3-fold (p = 0.05), respectively. The frequency of detected virulent strains significantly decreased: hemolysin-producing staphylococci by 9 times (p = 0.009), enterococci with gelatinase activity by 6 times. E. faecalis membrane oleic acid level significantly increased (C9-C18:1) (p = 0.03). In E. faecium, cis-7-palmitoleic acid (C7-C16:1) and oleic (C9-C18:1) fatty acid level increased by 2-fold (p = 0.05), and for linoleic acid (C18:2) by 4 time (p = 0.04) accompanied by elevated acid formation by 1.5 times.&#x0D; Conclusion. A single course of probiotic therapy in patients with pulmonary tuberculosis leads to qualitative microbiome changes, which are characterized by decreased levels of conditionally pathogenic microorganisms with virulent properties and altered composition of the enterococcal cell membrane accompanied by their increased biochemical activity.

Prolonged hyperthermic intraperitoneal chemotherapy duration with 90 minutes cisplatin might increase overall survival in gastric cancer patients with peritoneal metastases.

Advanced gastric cancer with synchronous peritoneal metastases (GC-PM) is associated with a poor prognosis. Although cytoreductive surgery with hyperthermic intraperitoneal chemotherapy (CRS-HIPEC) is a promising approach, only a limited number of Western studies exist. To investigate the clinicopathological outcomes of patients who underwent CRS-HIPEC for GC-PM. A retrospective analysis of patients with GC-PM was conducted. All patients were seen at the Department of General and Visceral Surgery, Hospital Barmherzige Brüder, Regensburg, Germany between January 2011 and July 2021 and underwent CRS-HIPEC. Preoperative laboratory results, the use of neoadjuvant trastuzumab, and the details of CRS-HIPEC, including peritoneal carcinomatosis index, completeness of cytoreduction, and surgical procedures were recorded. Disease-specific (DSS), and overall survival (OS) of patients were calculated. A total of 73 patients were included in the study. Patients treated with neoadjuvant trastuzumab (n = 5) showed longer DSS (P = 0.0482). Higher white blood cell counts (DSS: P = 0.0433) and carcinoembryonic antigen levels (OS and DSS: P < 0.01), and lower hemoglobin (OS and DSS: P < 0.05) and serum total protein (OS: P = 0.0368) levels were associated with shorter survival. Longer HIPEC duration was associated with more advantageous median survival times [60-min (n = 59): 12.86 mo; 90-min (n = 14): 27.30 mo], but without statistical difference. To obtain additional data from this observation, further separation of the study population was performed. First, propensity score-matched patient pairs (n = 14 in each group) were created. Statistically different DSS was found between patient pairs (hazard ratio = 0.2843; 95% confidence interval: 0.1119-0.7222; P = 0.0082). Second, those patients who were treated with trastuzumab and/or had human epidermal growth factor receptor 2 positivity (median survival: 12.68 mo vs 24.02 mo), or had to undergo the procedure before 2016 (median survival: 12.68 mo vs 27.30 mo; P = 0.0493) were removed from the original study population. Based on our experience, CRS-HIPEC is a safe and secure method to improve the survival of advanced GC-PM patients. Prolonged HIPEC duration may serve as a good therapy for these patients.

Systemic and Intracranial Outcomes With First-Line Nivolumab Plus Ipilimumab in Patients With Metastatic NSCLC and Baseline Brain Metastases From CheckMate 227 Part 1

IntroductionIn CheckMate 227 Part 1, nivolumab plus ipilimumab prolonged overall survival (OS) versus chemotherapy in patients with metastatic NSCLC, regardless of tumor programmed death-ligand 1 (PD-L1) expression. Here, we report post hoc exploratory systemic and intracranial efficacy outcomes and safety by baseline brain metastasis status at 5 years’ minimum follow-up. MethodsTreatment-naive adults with stage IV or recurrent NSCLC without EGFR or ALK alterations, including asymptomatic patients with treated brain metastases, were enrolled. Patients with tumor PD-L1 greater than or equal to 1% were randomized to nivolumab plus ipilimumab, nivolumab, or chemotherapy; patients with tumor PD-L1 less than 1% were randomized to nivolumab plus ipilimumab, nivolumab plus chemotherapy, or chemotherapy groups. Assessments included OS, systemic and intracranial progression-free survival per blinded independent central review, new brain lesion development, and safety. Brain imaging was performed at baseline (all randomized patients) and approximately every 12 weeks thereafter (patients with baseline brain metastases only). ResultsOverall, 202 of 1739 randomized patients had baseline brain metastases (nivolumab plus ipilimumab: 68; chemotherapy: 66). At 61.3 months’ minimum follow-up, nivolumab plus ipilimumab prolonged OS versus chemotherapy in patients with baseline brain metastases (hazard ratio = 0.63; 95% confidence interval: 0.43–0.92) and in those without (hazard ratio = 0.76; 95% confidence interval: 0.66–0.87). In patients with baseline brain metastases, 5-year systemic and intracranial progression-free survival rates were higher with nivolumab plus ipilimumab (12% and 16%, respectively) than chemotherapy (0% and 6%). Fewer patients with baseline brain metastases developed new brain lesions with nivolumab plus ipilimumab (4%) versus chemotherapy (20%). No new safety signals were observed. ConclusionsWith all patients off immunotherapy for more than or equal to 3 years, nivolumab plus ipilimumab continued to provide a long-term, durable survival benefit in patients with or without brain metastases. Intracranial efficacy outcomes favored nivolumab plus ipilimumab versus chemotherapy. These results further support nivolumab plus ipilimumab as an efficacious first-line treatment for patients with metastatic NSCLC, regardless of baseline brain metastasis status.

203P Clinical effectiveness of olaparib in BRCA-mutated, HER2-negative metastatic breast cancer (mBC) by ER expression level: Subgroup analysis from phase IIIb LUCY trial

In the OlympiAD phase III trial, olaparib significantly prolonged progression-free survival (PFS) vs chemotherapy in patients (pts) with germline-BRCA-mutated (gBRCAm), HER2-negative mBC regardless of hormone receptor (HR) status. In a study population that reflects clinical practice, the phase IIIb LUCY trial similarly showed clinical effectiveness of olaparib regardless of HR status. ASCO/CAP guidelines highlight the lack of data on the best treatment approach for breast tumors that are estrogen receptor (ER)-low (1–10% ER+ stained cells). We examined olaparib clinical effectiveness by ER expression in pts with HER2-negative gBRCAm mBC from the LUCY trial. In this open-label trial, pts with germline or somatic BRCAm, HER2-negative mBC received olaparib (300 mg BID). Pts had received ≤2 chemotherapy lines for mBC and a taxane and/or anthracycline in the (neo)adjuvant or mBC setting. Pts with ER+ BC had received endocrine therapy. In this post hoc subgroup analysis (data cut-off Sept 1, 2021), pts with gBRCAm were grouped by ER expression (ER <1%; 1–10%; >10% by IHC) and analysed for PFS, overall survival, clinical response rate (CRR; i.e. the proportion of pts assessed as responding by the investigator [radiological or symptomatic] at ≥1 visit), and duration of clinical response. 251/252 pts in the gBRCAm cohort were included (ER <1% n=117; 1–10% n=29; >10% n=105). At baseline, pts in the ER <1% group had shorter median times from their original diagnosis (29.7 vs 52.0 vs 58.6 mo) and from diagnosis of mBC (4.8 vs 11.1 vs 12.5 mo) vs pts in the ER 1–10% and >10% groups, respectively. Efficacy outcomes with olaparib were consistent across ER expression subgroups (Table).Table: 203PEfficacy results by ER expressionER <1%ER 1–10%ER >10%Median PFS, months (95% CI)92/117*6.8 (5.5–9.0)24/29*8.3 (4.5–12.6)89/105*8.4 (7.6–11.0)Median OS, months (95% CI)67/117*20.1 (16.5–26.9)20/29*22.9 (13.0–35.1)54/105*27.4 (23.0–NR)CRR, % (95% CI)59/116*50.9 (41.4–60.3)12/28*42.9 (24.5–62.8)51/104*49.0 (39.1–59.0)Median DOCR, months (IQR)59/116*8.3 (3.8–26.5)12/28*7.2 (5.3–14.1)51/104*7.4 (4.3–17.7)∗number of events or responses/number of evaluable pts.CI, confidence interval; CRR, clinical response rate; DOCR, duration of clinical response; IQR, interquartile range; NR, not reached; OS, overall survival; PFS, progression-free survival. Open table in a new tab ∗number of events or responses/number of evaluable pts. CI, confidence interval; CRR, clinical response rate; DOCR, duration of clinical response; IQR, interquartile range; NR, not reached; OS, overall survival; PFS, progression-free survival. Real-world results of the phase IIIb LUCY trial support the clinical effectiveness of olaparib in pts with gBRCAm, HER2-negative mBC, regardless of ER expression level.

A concise review on breast cancer in pregnancy

Breast cancer is major serious cancer in the women, it can be easily treated with chemotherapy drugs or by breast conservation surgery if it is diagnosed earlier. However the condition become even worse in those pregnant women, because chemotherapy is the most common first line prophylaxis treatment for breast cancer. In pregnancy diagnosed with breast cancer reveals a complicated chemotherapy because it affect the fetus and eventually produce fetal abnormalities and decreases the survival chances of fetus. The 50% survival chances of breast cancer patient is increased with the early diagnosis. Hormonal factors like estrogen, inheritance of BRCA1 and BRCA2 are the foremost responsible for breast cancer, it can get even worsen due to life style adaptations. Multi-drug resistance is eventually happen due to prolonged chemotherapy.

Total steroidal saponins from black nightshade (Solanum nigrum L.) overcome tumor multidrug resistance by inducing autophagy-mediated cell death in vivo and in vitro.

Multiple drug resistance (MDR) often occurs after prolonged chemotherapy, leading to refractory tumors and cancer recurrence. In this study, we demonstrated that the total steroidal saponins from Solanum nigrum L. (SN) had broad-spectrum cytotoxic activity against various human leukemia cancer cell lines, especially in adriamycin (ADR)-sensitive and resistant K562 cell lines. Moreover, SN could effectively inhibit the expression of ABC transporter in K562/ADR cells in vivo and in vitro. In vivo, by establishing K562/ADR xenograft tumor model, we demonstrated that SN might overcome drug resistance and inhibit the proliferation of tumors by regulating autophagy. In vitro, the increased LC3 puncta, the expression of LC3-II and Beclin-1, and the decreased expression of p62/SQSTM1 in SN-treated K562/ADR and K562 cells demonstrated autophagy induced by SN. Moreover, using the autophagy inhibitors or transfecting the ATG5 shRNA, we confirmed that autophagy induced by SN was a key factor in overcoming MDR thereby promoting cell death in K562/ADR cells. More importantly, SN-induced autophagy through the mTOR signaling pathway to overcome drug resistance and ultimately induced autophagy-mediated cell death in K562/ADR cells. Taken together, our findings suggest that SN has the potential to treat multidrug-resistant leukemia.

OlympiAD extended follow-up for overall survival and safety: Olaparib versus chemotherapy treatment of physician's choice in patients with a germline BRCA mutation and HER2-negative metastatic breast cancer

BackgroundIn the Phase III OlympiAD study, olaparib significantly prolonged progression-free survival versus chemotherapy treatment of physician's choice (TPC) in patients with germline BRCA-mutated (gBRCAm), human epidermal growth factor receptor 2-negative metastatic breast cancer (mBC). In the final pre-specified analysis (64% maturity), median overall survival (OS) was 19.3 months for olaparib and 17.1 months for TPC (P = 0.513). Post-hoc extended follow-up, 25.7 months longer than previously reported for OS, is reported. Patients and methodsPatients with gBRCAm, human epidermal growth factor receptor 2-negative mBC, who had received ≤2 lines of chemotherapy for metastatic disease, were randomised 2:1 to olaparib (300 mg bid) or TPC. During extended follow-up, OS was analysed every 6 months using the stratified log-rank test (overall population) and Cox proportional hazards model (pre-specified subgroups). ResultsIn the overall population (302 patients; 76.8% maturity), median OS was 19.3 months for olaparib and 17.1 months for TPC (hazard ratio 0.89, 95% confidence interval 0.67–1.18); median follow-up was 18.9 and 15.5 months, respectively. Three-year survival was 27.9% for olaparib versus 21.2% for TPC. With olaparib, 8.8% of patients received study treatment for ≥3 years versus none with TPC. In first-line mBC, median OS was longer for olaparib than TPC (22.6 versus 14.7 months; hazard ratio 0.55, 95% confidence interval 0.33–0.95) and 3-year survival was 40.8% for olaparib versus 12.8% for TPC. No new serious adverse events related to olaparib were observed. ConclusionsOS was consistent with previous analyses from OlympiAD. These findings support the possibility of meaningful long-term survival benefit with olaparib, particularly in first-line mBC.