Pegylated liposomal doxorubicin (PLD) in daily practice—A single center experience of treatment with PLD in patients with comorbidities and older patients with metastatic breast cancer

Abstract Purpose Real‐world data about pegylated liposomal doxorubicin (PLD) in patients with metastatic breast cancer (MBC) are limited. We have aimed to highlight the role of PLD in daily practice focusing on older patients and patients with comorbidities with MBC. Methods We analyzed electronic records of all patients with advanced/metastatic breast cancer treated with single‐agent PLD at the University Hospital Basel between 2003 and 2021. Primary endpoint was time to next chemotherapy or death (TTNC). Secondary endpoints were overall survival (OS), progression‐free survival (PFS), and overall response rate (ORR). We performed univariate and multivariate analysis for clinical variables. Results 112 patients with MBC having received single‐agent PLD in any treatment line were analyzed, including 34 patient who were older than 70 years and 61 patients with relevant comorbidities. Median TTNC, OS, and PFS for treatment with PLD were 4.6, 11.9, and 4.4 months, respectively. ORR was 13.6%. Age >70 years predicted shorter OS (median 11.2 months) in multivariate analysis (hazard ratio [HR] 1.83, 95% CI 1.07–3.11, p = 0.026). Age and comorbidities did not significantly affect other endpoints. Unexpectedly, hypertension predicted longer TTNC (8.3 months, p = 0.04) in univariate analysis, maintained in multivariate analysis as a trend for both TTNC (HR 0.62, p = 0.07) and OS (HR 0.63, p = 0.1). Conclusion Age predicted shorter OS significantly but median OS was not relevantly shorter in older patients. PLD remains a treatment option in patients with comorbidities and older patients with MBC. However, our real‐world results of PLD appear underwhelming compared to relevant phase II trials through all age groups, pointing to an efficacy‐effectiveness gap, possibly due to sampling bias

Corticosteroid-resistant immune-related adverse events: a systematic review

Immune checkpoint inhibitor (ICI) treatment has become an important therapeutic option for various cancer types. Although the treatment is effective, ICI can overstimulate the patient’s immune system, leading to potentially severe immune-related adverse events (irAEs), including hepatitis, colitis, pneumonitis and myocarditis. The initial mainstay of treatments includes the administration of corticosteroids. There is little evidence how to treat steroid-resistant (sr) irAEs. It is mainly based on small case series or single case reports. This systematic review summarizes available evidence about sr-irAEs. We conducted a systematic literature search in PubMed. Additionally, we included European Society for Medical Oncology, Society for Immunotherapy of Cancer, National Comprehensive Cancer Network and American Society of Clinical Oncology Guidelines for irAEs in our assessment. The study population of all selected publications had to include patients with cancer who developed hepatitis, colitis, pneumonitis or myocarditis during or after an immunotherapy treatment and for whom corticosteroid therapy was not sufficient. Our literature search was not restricted to any specific cancer diagnosis. Case reports were also included. There is limited data regarding life-threatening sr-irAEs of colon/liver/lung/heart and the majority of publications are single case reports. Most publications investigated sr colitis (n=26), followed by hepatitis (n=21), pneumonitis (n=17) and myocarditis (n=15). There is most data for mycophenolate mofetil (MMF) to treat sr hepatitis and for infliximab, followed by vedolizumab, to treat sr colitis. Regarding sr pneumonitis there is most data for MMF and intravenous immunoglobulins (IVIG) while data regarding infliximab are conflicting. In sr myocarditis, most evidence is available for the use of abatacept or anti-thymocyte globulin (ATG) (both with or without MMF) or ruxolitinib with abatacept. This review highlights the need for prompt recognition and treatment of sr hepatitis, colitis, pneumonitis and myocarditis. Guideline recommendations for sr situations are not defined precisely. Based on our search, we recommend—as first line treatment—(1) MMF for sr hepatitis, (2) infliximab for sr colitis, followed by vedolizumab, (3) MMF and IVIG for sr pneumonitis and (4) abatacept or ATG (both with or without MMF) or ruxolitinib with abatacept for sr myocarditis. These additional immunosuppressive agents should be initiated promptly if there is no sufficient response to corticosteroids within 3 days

Benzoate Fermentation by the Anaerobic Bacterium Syntrophus aciditrophicus in the Absence of Hydrogen-Using Microorganisms

The anaerobic bacterium Syntrophus aciditrophicus metabolized benzoate in pure culture in the absence of hydrogen-utilizing partners or terminal electron acceptors. The pure culture of S. aciditrophicus produced approximately 0.5 mol of cyclohexane carboxylate and 1.5 mol of acetate per mol of benzoate, while a coculture of S. aciditrophicus with the hydrogen-using methanogen Methanospirillum hungatei produced 3 mol of acetate and 0.75 mol of methane per mol of benzoate. The growth yield of the S. aciditrophicus pure culture was 6.9 g (dry weight) per mol of benzoate metabolized, whereas the growth yield of the S. aciditrophicus-M. hungatei coculture was 11.8 g (dry weight) per mol of benzoate. Cyclohexane carboxylate was metabolized by S. aciditrophicus only in a coculture with a hydrogen user and was not metabolized by S. aciditrophicus pure cultures. Cyclohex-1-ene carboxylate was incompletely degraded by S. aciditrophicus pure cultures until a free energy change (ΔG′) of −9.2 kJ/mol was reached (−4.7 kJ/mol for the hydrogen-producing reaction). Cyclohex-1-ene carboxylate, pimelate, and glutarate transiently accumulated at micromolar levels during growth of an S. aciditrophicus pure culture with benzoate. High hydrogen (10.1 kPa) and acetate (60 mM) levels inhibited benzoate metabolism by S. aciditrophicus pure cultures. These results suggest that benzoate fermentation by S. aciditrophicus in the absence of hydrogen users proceeds via a dismutation reaction in which the reducing equivalents produced during oxidation of one benzoate molecule to acetate and carbon dioxide are used to reduce another benzoate molecule to cyclohexane carboxylate, which is not metabolized further. Benzoate fermentation to acetate, CO(2), and cyclohexane carboxylate is thermodynamically favorable and can proceed at free energy values more positive than −20 kJ/mol, the postulated minimum free energy value for substrate metabolism