Salvage Therapy Research Articles

Safety and efficacy of the yellow sub-threshold micropulse laser for uveitic macular edema: A pilot study.

To assess the safety and efficacy of the yellow sub-threshold micropulse laser (YSML) in eyes with uveitic macula edema (UME). A prospective interventional study. Eyes with non-infectious UME and an unsatisfactory response to prior conventional treatments underwent navigated YSML (NAVILAS®). The treatment was planned on an imported macular OCT scan. The central macular thickness (CMT) and best-corrected visual acuity (BCVA) were recorded immediately before the treatment (baseline) and again after 1 and 3 months. The end of the follow up (FU) was the last available evaluation in the case of no UME recurrence; or when the CMT increase required rescue therapy. Eight eyes of as many patients were included. The mean duration of the FU was 252 days (range: 170-398 days). No adverse events were observed. In the whole cohort the mean values improvement over time was significant for both CMT (p = 0.011) and BCVA (p < 0.001). The indication for a new treatment was stated in 4 eyes (50%) after a mean FU of 277 ± 43 days. This time was statistically comparable with the mean FU of eyes without UME recurrence. At the baseline the non-UME recurrence eyes had a significantly lower mean CMT (326 ± 80 vs 485 ± 112 μm, p = 0.03). The application of YSLM for UME has not previously been mentioned in literature. Our results were promising in terms of both safety and efficacy. This would authorize further studies on the procedure, also as a first line treatment in naif UME cases.

Outcomes of children and young adults with B-cell acute lymphoblastic leukemia given blinatumomab as last consolidation treatment before allogeneic hematopoietic stem cell transplantation.

Blinatumomab has remarkable efficacy in patients with relapsed/refractory (r/r) or measurable residual disease (MRD)-positive B-cell acute lymphoblastic leukemia (B-ALL). In many patients, blinatumomab treatment is followed by allogeneic hematopoietic stem cell transplantation (HSCT). However, the influence of blinatumomab on HSCT outcomes in children and young adults (YA) remains to be fully elucidated. We conducted a single-center, retrospective analysis on patients given blinatumomab as last treatment before HSCT. Seventy-eight pediatric and YA patients were evaluated. With a median follow-up of 23.23 months, the 2-year disease-free (DFS) and overall survival (OS) probability were 72.2% and 89.2%, respectively, with a 2-year cumulative incidence (CI) of non-relapse mortality (NRM) of 2.6%. A trend toward improved 2-year DFS, but not OS, was noted in patients transplanted in first complete remission (CR1) (92.9%) compared to those in second or greater remission (CR2/3) (68.5%, p=0.18) due to a lower CI of relapse (0% vs. 29.9%, p=0.05). Among CR2/3 patients, those receiving the sequential combination of inotuzumab and blinatumomab had a significantly lower CI of relapse as compared to those who did not receive inotuzumab (9.5% vs. 40.4%, p=0.023). Relapse after HSCT occurred in 16 patients, all exhibiting CD19-positive blasts; 10 of them received anti-CD19 chimeric antigen receptor T-cell (CAR-T) therapy and 2 inotuzumab as salvage therapy, leading to a 2-year post-relapse OS of 52.7%. Our results indicate that HSCT following blinatumomab in children and YA with B-ALL is highly effective, being associated with low NRM and not affecting the efficacy of subsequent salvage immunotherapies, including CAR-T cells.

Sustained Remission in an Elderly Patient with Acute Myeloid Leukemia Following Gilteritinib Treatment as Third-Line Salvage Therapy.

Limited data are available on the effectiveness of gilteritinib as a third-line salvage therapy in patients with acute myeloid leukemia (AML). We present an elderly patient who achieved sustained remission following gilteritinib monotherapy as a third-line treatment after failing two prior regimens.

US Clinical Practice Experience with Eculizumab in Myasthenia Gravis: Acute Clinical Events and Healthcare Resource Utilization.

The terminal complement inhibitor eculizumab is approved in the USA for the treatment of patients with acetylcholine receptor antibody-positive generalized myasthenia gravis (MG). The ELEVATE study aimed to examine clinical-practice outcome data on eculizumab effectiveness in US adults with MG (generalized or ocular). This paper reports the findings on MG exacerbations and crises and associated healthcare resource utilization, and the use of rescue therapy. A retrospective chart review was conducted of US adults with MG who initiated eculizumab. Outcomes assessed for up to 2 years before and after eculizumab initiation included percentages and rates per patient per year (PPPY) of exacerbations and crises (the latter defined as intubation/impending intubation), healthcare resource utilization, and rescue therapy administration. A total of 119 patients diagnosed with MG were enrolled in the study; 92 patients had ≥3 months of data both before and during eculizumab therapy and were included in the analyses. The mean rate of MG exacerbations decreased from 0.385 PPPY before eculizumab initiation to 0.152 PPPY during eculizumab treatment (p = 0.0034); the mean rate of MG crises decreased from 0.411 to 0.056 PPPY (p = 0.0018). Rates of healthcare resource utilization and rescue therapy use also decreased significantly during eculizumab treatment. This retrospective chart review analysis provides evidence for a beneficial impact of eculizumab treatment on the incidence of MG exacerbations and crises and associated healthcare resource utilization in clinical practice, and on rescue therapy use. These data further support the therapeutic benefits of eculizumab in patients with MG.

Usefulness of Upfront Neck Dissection Before Chemoradiation Therapy for Head and Neck Squamous Cell Carcinoma.

Locally advanced squamous cell carcinoma of the head and neck (L/A SCCHN) is typically treated with surgery or chemoradiation therapy (CRT), whereas salvage surgery is considered for residual disease post-CRT. However, salvage surgery after radiation therapy presents challenges due to tissue fibrosis. Planned neck dissection (ND) combined with CRT, as well as positron emission tomography after CRT, have been proposed strategies, but no definitive consensus has been reached. Therefore, this study aimed to investigate the utility of "upfront ND" performed prior to CRT to enhance local control and reduce complications. We retrospectively reviewed 121 patients who underwent primary CRT for oropharyngeal, hypopharyngeal, or laryngeal cancer at Tokyo Medical University Hospital from January 2015 to September 2021. Patients without cervical lymph node metastasis or with unresectable nodes were excluded. All patients underwent pre-treatment imaging and staging. CRT consisted of intensity-modulated radiation therapy (IMRT) and cisplatin-based chemotherapy. Selective ND or modified radical neck dissection was performed based on lymph node involvement. Overall, 35 patients underwent upfront ND, whereas 54 did not. The upfront ND group exhibited significantly better 2-year locoregional recurrence-free survival than the group without upfront ND (93.7% vs. 71.0%). No significant differences were noted in adverse events between groups. The findings highlight upfront ND before CRT as a viable option for locally advanced head and neck cancer, particularly beneficial in cases with extranodal extension. This approach enhances local control and may reduce the need for salvage surgery, thus improving patient outcomes.

Long-Term Survey of Japanese Children with Recurrent Nephroblastoma: A Report from Japan Children’s Cancer Group

In prospective Japanese studies of pediatric renal tumors, 5-year event-free survival and overall survival (OS) for patients with nephroblastoma ranges from 75–90% and 89–97%, respectively. However, treatments strategies for recurrent nephroblastoma in Japanese patients remain unclear. This retrospective study aimed to inform the development of treatment strategies by analyzing the long-term results and side effects of salvage therapies for recurrent nephroblastoma in Japan. A questionnaire survey involving 41 institutions (74 patients) collected clinical data on recurrent cases reported to the Renal Tumor Committee of the Japan Children’s Cancer Group. Survey forms from 54 cases were evaluated. Median time to recurrence was 9.5 months among 51 patients without underlying disorders. Recurrence occurred at lung-only in 18 patients and at other sites in 33. The 5-year OS for all 51 patients was 70.6%, with recurrent disease causing death in 15 patients and one patient dying from treatment-related complications. Patients with lung-only recurrence had higher 5-year OS rates than those with other-site recurrence. Initial chemotherapy intensity also affected prognosis, with lower intensity associated with higher 5-year OS. In 17 survivors with lung-only recurrence, the most frequent treatment approach combined chemotherapy, surgery and radiotherapy. Conventional chemotherapy included platinum-containing regimens and/or Regimen I-based treatment containing cyclophosphamide and etoposide. Salvage therapies showed remarkable effectiveness for patients with lung-only recurrence or low intensity of the initial chemotherapy, highlighting the need to standardize prospective studies for post-recurrence treatment and identify risks of late complications for long-term survivors.

Use of corticosteroids and antibiotics for the treatment of asthma exacerbations at a quaternary care respiratory institute: A descriptive cohort study

Rationale The Global Initiative for Asthma guidelines recommend 50 mg prednisone for 5-7 days for asthma exacerbations and avoiding antibiotics. Management following failed home action plans is not addressed. Objectives The objectives of this study were to describe management of asthma exacerbations at the Montreal Chest Institute - Day Hospital (MCI-DH). Methods We retrospectively reviewed patients presenting to the MCI-DH for asthma exacerbations from January 2019 to June 2020. Data pertaining to demographics, treatments, and adverse events were collected and presented descriptively without statistical comparison. Measurements and Main Results Most patients present to the MCI-DH with an asthma exacerbation following a failed home action plan. A total of 107 patients (130 visits) were included in the analysis. Systemic corticosteroids were initiated in 119/130 (91.5%) visits, with 30 (25.2%) patients receiving the full course as oral therapy, whereas 89 (74.8%) were transitioned to oral therapy from intravenous. A daily dose of 50 mg of prednisone was observed in 34/119 (28.6%) treatment courses. The mean total corticosteroid duration was 12 days (SD 8), with only 18/119 (15.1%) treatment courses prescribed for 5-7 days. Corticosteroids were tapered over a mean of 14 days (SD 15) in 66 (55.5%) patients. Antibiotics were initiated in 18/130 (13.9%) visits, and 5/18 (27.8%) had no documented rationale. No adverse drug events were recorded in the 90 days following treatments. Conclusions The MCI-DH serves a complex population of patients often presenting following a failed action plan. Clinical judgment appears to have led to longer course high dose corticosteroids for many. Salvage therapy following a failed action plan requires further study.

Pediatric B-cell Non-Hodgkin Lymphoma: The Impact of Therapy Response and Relapse on Outcome. A Single-center Analysis.

Pediatric patients with primary refractory or relapsed B-cell non-Hodgkin lymphoma (B-NHL) have highly unfavorable prognosis. In this study, we retrospectively analyzed outcomes in pediatric B-NHL patients treated in a single center in Poland from 1995 to 2022, with emphasis on therapy results in patients with progression or relapse. The primary objectives were a 5-year probability of overall survival (pOS) and a 5-year probability of event-free survival (pEFS). The secondary objectives involved the assessment of prognostic factors. A total of 76 children were eligible for the analysis. The 5-year pOS was 76.7%, and the 5-year pEFS was 72.9%. At diagnosis, elevated lactate dehydrogenase activity, the presence of B symptoms, bone marrow, skeletal or mediastinal involvement, and stage IV disease were associated with inferior outcomes. Nine children experienced progression and four relapse. The 5-year pOS for patients with progression was 38.1%. Two patients treated with hematopoietic stem cell transplantation (HSCT) as part of salvage therapy survived. However, only one out of seven patients who were treated without HSCT survived. The 5-year pOS was 0.0% in patients with relapsed disease. The most significant factor related to outcomes in pediatric B-NHL is therapy response, with a high mortality rate in children with refractory disease and relapse. There is no consensus on the salvage therapy approach; however, HSCT appears to be the optimal choice.

Bactericidal versus bacteriostatic antibacterials: clinical significance, differences and synergistic potential in clinical practice.

Antibacterial activity can be classified as either bactericidal or bacteriostatic, using methods such as the MBC/MIC ratio and time-kill curves. However, such categorization has proven challenging in clinical practice, as these definitions only apply under specific laboratory conditions, which may differ from clinical settings. Several factors, such as the specific bacteria or infectious medium, can affect the action of antibiotics, with many antibacterials exerting both activities. These definitions have also led to the belief that bactericidal antibacterials are superior to bacteriostatic, especially in more severe cases, such as endocarditis, neutropenia and bacteraemia. Additionally, current dogma dictates against the combination of bactericidal and bacteriostatic antibacterials in clinical practice, due to potential antagonism. This review aimed to assess the differences in antibacterial activity of bactericidal and bacteriostatic antibacterials based on in vitro and in vivo studies and examine their antagonistic or synergistic effects. Our findings show that specific bacteriostatic agents, such as linezolid and tigecycline, are clinically non-inferior to bactericidals in multiple infections, including pneumonia, intra-abdominal infections, and skin and soft tissue infections. Studies also support using several bacteriostatic agents as salvage therapies in severe infections, such as neutropenic fever and endocarditis. Additionally, not all combinations of bacteriostatic and bactericidal agents appear to be antagonistic, with many combinations, such as linezolid and rifampicin, already being used. The findings should be interpreted with caution, as most evidence is from observational studies and there is a need for randomized controlled trials to assess their effectiveness and combinations, especially within the context of rising antimicrobial resistance.

Oncological and Surgical Outcomes of Oncoplastic Reduction Mammoplasty: A Single-centre Retrospective Study.

Breast-conserving surgery is the preferred treatment for early-stage breast cancer but can often result in unsatisfactory cosmetic outcomes. Oncoplastic surgery aims to improve both oncologic and aesthetic outcomes by combining local excision with plastic surgery techniques. Using breast reduction techniques in breast cancer treatment has been shown to allow for wider margins of excision, leading to enhanced oncological safety and reduced recurrence rates without causing significant asymmetry. This study aimed to analyze the surgical and oncological outcomes of a large cohort of patients undergoing oncoplastic reduction mammoplasty (ORM). A retrospective analysis of postoperative surgical and oncological outcomes of all patients who underwent ORM at a single center between January 2018 and December 2023 was performed. Preoperative patient characteristics, operative and post-operative outcomes were recorded and analyzed. A total of 67 patients that underwent oncologic breast reduction were included in the final analysis - representing a total of 71 ORM, with a mean (SD) age of 53.1 (10.5) years and a mean (SD) BMI of 28.8 (5.9) kg/m2 A superomedial pedicle-based technique was the most frequently used (36.6%), followed by inferior pedicle-based technique (28.1%). A complication rate of 18.3% on the ipsilateral side was observed. Salvage surgery was necessary in five cases (7.0%) due to positive margins - with one patient (1.4%) requiring margin expansion surgery and four (5.6%) a completion mastectomy. This monocentric retrospective study shows that ORM is safe, with a complication rate on par with conventional breast reduction and offers satisfactory oncological outcomes.

Long-term survival after coronary artery bypass grafting comparing bilateral versus single internal mammary artery in a women cohort

Abstract Introduction Although neutral results from the ART randomized controlled trial, observational studies have been supporting better survival after bilateral internal mammary artery (BIMA) vs single internal mammary artery (SIMA) coronary artery bypass grafting (CABG). However, for some specific subgroups, like women patients, more doubts remain about BIMA benefits. Aim To compare long-term survival and early results in women after SIMA vs BIMA. Methods Longitudinal, retrospective, single-center study including consecutive women with at least 2 left-coronary system (LCS) vessel disease who underwent primary isolated CABG with at least 1 internal mammary artery (IMA) conduit and a minimum of 2 conduits targeting the LCS, between 2004-2014. Emergent or salvage surgeries, on-pump beating-heart, BIMA in which 1 IMA targeted the right coronary artery territory were excluded. The primary outcome was all-causes mortality (checked on February 2023). Time-to-event outcomes were studied using Kaplan-Meier Curves, Log-Rank test and multivariable Cox Regression. Median follow-up was 11 years, maximum of 19 years. Results From 539 women selected for this study, BIMA CABG was performed in 30%. SIMA patient’s were older (mean age 68.95±8.39 vs 62.75±9.82 years, p&amp;lt;0.001), but the prevalence of cardiovascular risk factors were similar between groups (arterial hypertension, p=0.693; dyslipidemia, p=0.111; diabetes mellitus, p=0.462 and obesity, p=0.109). Peripheral artery disease (p=0.707), left ventricular dysfunction (p=0.727), cerebrovascular disease (p=0.730), active smoking habits (p=0.05) and chronic obstrutive pulmonary disease (p=0.537) were also similar. Severe chronic kidney disease (27% vs 14%, p&amp;lt;0.001) and Canadian Coronary Society - grade IV (74% vs 63%, p=0.011) were more frequent in SIMA group. In the univariable survival analysis, SIMA had worse survival results than BIMA (Log Rank test p&amp;lt;0.01). At 5-, 10- and 15- years of follow-up, cumulative survival for SIMA vs BIMA were 88% vs 90%, 68% vs 75%, 42% vs 58%, respectively. However, the multivariable Cox regression showed that BIMA was not associated with long-term survival (HR [95%CI]: 1.09 [0.75-1.59], p=0.6). Most of post-operative outcomes were similar between groups, with the exception of atrial fibrilation (25% vs 16%, p=0.031) and time to discharge (median days [min-max]: 7 [4-128] vs 7 [4-59]) that were higher in SIMA. No differences were found in immediate reexploration of thorax (sternal infection – 0.3% SIMA vs 1.2% BIMA, p=0.219; bleeding- 1.6% SIMA vs 0.6% BIMA, p=0.681). Redo CABG occurred in 1 SIMA and 1 BIMA women, at 41 and 84 months of follow-up, respectively. Conclusion In this study, revascularization with BIMA seems to be safe in women and provides similar results than SIMA. More studies in women are needed to establish the better approach for this specific subgroup.

Optimizing aldosterone receptor antagonist therapy by sodium zirconium cyclosilicate in heart failure - OPRA-HF trial

Abstract Background Heart failure remains a significant health burden, characterized by disabling symptoms and mortality rates comparable to cancer. Mineralocorticoid antagonists (MRAs), pivotal in treating heart failure with reduced ejection fraction (HFrEF), are underutilized due to concerns of hyperkalemia. Sodium Zirconium Cyclosilicate (SZC) enables optimized MRA therapy by reducing hyperkalemia. However, prospective studies on the efficacy and safety of SZC in patients with HFrEF and high hyperkalemia risk are lacking, particularly in the context of contemporary heart failure quadruple-therapy including angiotensin receptor neprilysin inhibitor (ARNI) and Sodium-Glucose Transport Protein 2 (SGLT2) Inhibitors. Purpose The OPRA-HF trial aims to assess the efficacy and safety of SZC in optimizing MRA treatment in symptomatic patients with HFrEF with risk for hyperkalemia on top of optimal guideline-directed medical therapy including ARNI and SGLT2 Inhibitors. Methods This investigator-initiated multicentred, randomized, placebo-controlled, and double-blinded trial include patients with HFrEF on suboptimal MRA treatment due to (1) history of hyperkalemia due to MRA, or (2) risk of hyperkalemia due to reduced renal function (eGFR 30-45 ml/min/m2) and current potassium 4.5-5-0 mmol/L. Patients undergo a Run-In phase with SZC, initiating or up-titrating MRA to target doses for 4-7 weeks and SZC was initiated in those patients that became hyperkalemic (K+&amp;gt;5 mEq/L. Those normokalemic and tolerating MRA ≥ 25 mg daily or at least 25 mg dose increase vs before run-in were randomized to SZC (5g or 10g) or placebo for 6 months. Study is powered to randomize 110 patients. Primary outcomes include maintaining daily MRA dose ≥ 25 mg or dose increase by 25 mg with normal potassium levels without rescue therapy. Secondary outcomes include evaluating the safety and tolerability of SZC as well as impact of SZC on quality of life. Results In this ongoing trial, so far 40 patients have been randomized. Of these, mean age was 74.3 years, 88.9% men. Most patients had ischemic etiology (54.2%), 36.1% had diabetes mellitus, 52.8% had hypertension.n. At screening 94.4% had beta-blockers, 35% ACEI/ARB, 60% ARNI and 72.2% had SGLT2 inhibitors, 33.3% had no MRAs and 35,6% of patients had less than 25 mg MRA daily,62,2% had 25 mg MRA daily, mean p-potassium was 4.7+0.4 mmol/L, and eGFR was 57.3 ml/min/1.73m². After run-in, 85.2% were on 50 mg MRA daily. A substantial number (51.2%) of eligible patients with previous hyperkalemia had Run-In failure as they now successfully tolerated target dose of MRA at 50 mg daily without recurrent hyperkalemia. SZC dosing was 5g once daily in 78.9% of patients. Conclusion This ongoing trial will provide evidence for the use of SZC to optimize MRA treatment in contemporary HFrEF patients. Preliminary findings suggest SZC effectively maintains normokalemia, enabling MRA optimization, potentially improving patients’ otcome.

Pemetrexed-carboplatin salvage therapy in advanced thyroid cancers.

The overall survival of patients with advanced thyroid cancers that have progressed following targeted therapies is limited, indicating a strong need for salvage treatments. We retrospectively analyzed patients with refractory advanced thyroid cancer treated with pemetrexed-carboplatin (PC) at Mayo Clinic since 2019. Eleven patients, three with anaplastic thyroid cancer (ATC), seven with differentiated or poorly differentiated thyroid cancer (DTC), and one with oncocytic carcinoma of the thyroid, were treated with novel salvage PC. Patients with DTC (n = 7) had durable responses with a median progression-free survival of 29 months. One responder included a patient with ATC whose disease progressed following pembrolizumab/axitinib, lenvatinib, and dabrafenib/trametinib. On this fourth line treatment, the patient remains on therapy to date, over 12 months after initial response. This case series reinforces prior published phase I clinical trial data and shows that pemetrexed can have potent efficacy in the treatment of the most advanced thyroid cancers.

Is extended resection for locally advanced thoracic cancer with cardiopulmonary bypass justified?

BackgroundResection of intrathoracic tumor with cardiopulmonary bypass (CPB) remains a relatively under-reported intervention in literature, and its role in managing locally advanced mediastinal and lung cancers is a topic of ongoing debate. Our aim was to review our experience and assess the role of CPB for treating locally advanced mediastinal and lung cancers.MethodsBetween 2015 and 2020, this study initially included 10 patients with primary locally advanced thoracic malignancies with apparent adjacent cardiovascular invasion demonstrated by thoracic imaging scans. Operation was performed based on a multidisciplinary tumor board consensus. Eventually, 8 patients (3 primary lung cancers and 5 mediastinal cancers) received either salvage or elective resection with CPB; two completed surgery without requiring CPB.ResultsRegarding the extent of adjacent structure involvement, 4 patients presented with involvement of the superior vena cava (SVC), 1 involved the right atrium (RA), 2 involved the SVC and RA, and 1 involved the SVC, the origin of main pulmonary artery, and the ascending aorta. Thirty-day mortality occurred in two of three patients receiving salvage surgery due to respiratory insufficiency. With the long-term follow-up, one patient died of recurrence 25 months postoperatively, one survived with recurrence 30 months postoperatively, and four were alive without recurrence for 35, 36, 49, and 107 months after operations.ConclusionIn certain patients, particularly for elective surgical candidates rather than salvage resection, CPB allows for extended resection of locally advanced thoracic cancers with acceptable perioperative safety and survival.

Effectiveness, Safety, and Patterns of Real-World Isavuconazole Use in Europe (2015-2019).

Real-world data from multinational observational studies are required to better understand the role and performance of isavuconazole in real-world practice in Europe. A retrospective medical record review was conducted at 16 sites in Europe (France, Germany, Italy, Spain, and the United Kingdom). Eligible records were from patients aged ≥ 18years at the time of isavuconazole initiation and received at least one dose of isavuconazole for suspected or confirmed invasive aspergillosis (IA) or invasive mucormycosis (IM) during the eligibility period (October 15, 2015 to June 30, 2019). Data were descriptively analysed. Success rates, overall survival, and times to these events were descriptively analysed. Data were abstracted from 218 patients (201, IA; 17, IM) who received isavuconazole as monotherapy (initiated as infusion, 52%; oral, 46%). Isavuconazole was initiated as primary therapy in 92 patients (42.2%) and salvage therapy in 121 patients (55.5%) (unknown for five patients). Mean (standard deviation) age was 56.8 (15.6) years, 66% were men and 62% had at least three comorbidities, most frequently haematologic malignancy (62%). Estimated clinical response rate at week 24 was 54.5% (95% confidence interval [CI], 38.2-66.5%) for primary treatment and 73.5% (95% CI, 62.7-81.1%) for salvage therapy. Overall, 45 patients (21%) experienced at least one adverse event (AE). Serious AEs were experienced by 37 patients (17%), with seven related to isavuconazole; five patients (2.3%) discontinued isavuconazole monotherapy due to the serious AE. A total of 137 patients (63%) died, with 17 deaths (12.4%) related to their invasive fungal infection, 11 of whom initiated isavuconazole as salvage therapy. This study adds to the growing body of evidence that whether used as first-line therapy or after the failure of other antifungal therapies, isavuconazole appears to have a promising clinical response and a good safety profile as an antifungal agent in patients with varied underlying conditions.

Efficacy and safety of dual blockade of HER2 and PD-1 in patients with HER2-positive gastric cancer: a retrospective, multicentre study

Human epidermal growth factor receptor 2 (HER2) expression is one of the most important pathological characteristics of gastric cancer. The positive rate of HER2 expression in patients with gastric cancer is approximately 20%. The phase III Keynote-811 study revealed that anti-HER2 and anti-PD-1 therapy combined with chemotherapy could significantly improve the objective response rate as first-line treatment in patients with HER2-positive advanced gastric cancer. In the present study, we aimed to evaluate the efficacy of combination therapy with trastuzumab and PD-1 inhibitors in patients with advanced HER2-positive gastric cancer in a real-world setting. Seventy-two HER2-positive gastric cancer patients from three hospitals in China were retrospectively reviewed. These patients were treated with trastuzumab plus one anti-PD-1 agent with or without chemotherapy. The overall response rate, progression-free survival and overall survival were assessed according to the Response Evaluation Criteria in Solid Tumours (RECIST 1.1). From January 2018 to October 2021, 72 patients with HER2-positive gastric cancer received trastuzumab and a PD-1 inhibitor with or without chemotherapy as neoadjuvant chemotherapy, first-line therapy, second-line therapy or salvage therapy. The ORR was 54.2% for all patients and 79.4% for previously untreated patients. The median PFS and median OS were 10 months (95% CI: 8–13 months) and 26.1 months (95% CI: 18.5-NA months), respectively, for all patients. Grade 3 adverse effects occurred in approximately 25% of patients. Immune-related adverse effects occurred in approximately 12.5% of patients. Trastuzumab and PD-1 inhibitor combination therapy with or without chemotherapy achieved satisfactory survival outcomes in patients with HER2-positive gastric cancer with acceptable safety.

Modelling post-chemotherapy stem cell dynamics in the bone marrow niche of AML patients

Acute myeloid leukemia (AML) is a stem cell-driven malignancy of the blood forming (hematopoietic) system. Despite of high dose chemotherapy with toxic side effects, many patients eventually relapse. The “7+3 regimen”, which consists of 7 days of cytarabine in combination with daunorubicin during the first 3 days, is a widely used therapy protocol. Since peripheral blood cells are easily accessible to longitudinal sampling, significant research efforts have been undertaken to characterize and reduce adverse effects on circulating blood cells. However, much less is known about the impact of the 7+3 regimen on human hematopoietic stem cells and their physiological micro-environments, the so-called stem cell niches. One reason for this is the technical inability to observe human stem cells in vivo and the discomfort related to bone marrow biopsies. To better understand the treatment effects on human stem cells, we consider a mechanistic mathematical model of the stem cell niche before, during and after chemotherapy. The model accounts for different maturation stages of leukemic and hematopoietic cells and considers key processes such as cell proliferation, self-renewal, differentiation and therapy-induced cell death. In the model, hematopoietic (HSCs) and leukemic stem cells (LSCs) compete for a joint niche and respond to both systemic and niche-derived signals. We relate the model to clinical trial data from literature which longitudinally quantifies the counts of hematopoietic stem like (CD34+CD38-ALDH+) cells at diagnosis and after therapy. The proposed model can capture the clinically observed interindividual heterogeneity and reproduce the non-monotonous dynamics of the hematopoietic stem like cells observed in relapsing patients. Our model allows to simulate different scenarios proposed in literature such as therapy-related impairment of the stem cell niche or niche-mediated resistance. Model simulations suggest that during the post-therapy phase a more than 10-fold increase of hematopoietic stem-like cell proliferation rates is required to recapitulate the measured cell dynamics in patients achieving complete remission. We fit the model to data of 7 individual patients and simulate variations of the treatment protocol. These simulations are in line with the clinical finding that G-CSF priming can improve the treatment outcome. Furthermore, our model suggests that a decline of HSC counts during remission might serve as an indication for salvage therapy in patients lacking MRD (minimal residual disease) markers.

Mechanisms and salvage treatments in patients with multiple myeloma relapsed post-BCMA CAR-T cell therapy.

Chimeric antigen receptor T-cell (CAR-T) therapy has ushered in a new era for the treatment of multiple myeloma (MM). Numerous clinical studies, especially those involving B-cell maturation antigen (BCMA)-directed CAR-T, have shown remarkable efficacy in patients with relapsed or refractory multiple myeloma (R/R MM). However, a considerable number of patients still experience disease recurrence or progression after BCMA CAR-T treatment, which is attributed to various factors, including antigen escape, CAR-T manufacturing factors, T cell exhaustion, inhibitory effects of tumor microenvironment and impact of prior treatments. The scarcity of effective treatment options following post-CAR-T disease recurrence, coupled with the lack of well-established salvage regimens, leaves patients who do relapse facing a bleak prognosis. In recent years, some academic institutions have achieved certain results in salvage treatments of patients with relapse after BCMA CAR-T treatment through secondary infusion of BCMA CAR-T, changing to non-BCMA-directed CAR-T, double-target CAR-T, bispecific antibodies or other novel therapies. This review summarizes the mechanisms of resistance or relapse after BCMA CAR-T administration and the available data on current salvage treatments, hoping to provide ideas for optimizing clinical salvage therapies.

Inadvertent Detachment of Stent Retrievers: Report of 2 Cases.

Mechanical thrombectomy using a stent retriever is a widely-used technique for recanalizing occluded cerebral arteries in acute ischemic stroke. Although rare, inadvertent stent detachment has primarily been reported with earlier stent retriever designs. We present 2 cases of inadvertent stent detachment with the pRESET stent. In the first case, an elderly patient presented with right middle cerebral artery occlusion and experienced stent detachment during the second retrieval. Despite this, successful recanalization was achieved through balloon angioplasty. In the second case, an elderly patient experienced stent detachment after the third retrieval, and recanalization of the M1 segment was unsuccessful due to the inability to pass the microcatheter. The first patient had a modified Rankin scale (mRS) score of 3, while the second had a poor prognosis with an mRS score of 5. These cases highlight that inadvertent stent detachment can impact outcomes, and balloon angioplasty may serve as a useful salvage therapy.

The activated caveolin-3/μ-opioid receptor complex drives morphine-induced rescue therapy in failing hearts.

Opioid analgesics can alleviate ischaemia/reperfusion (I/R) injury in chronic heart failure. However, the underlying mechanisms and targets remain unknown. Here, we investigate if caveolin-3 (Cav3) interacts with μ opioid receptors and if Cav3-μ receptor interactions play a role in morphine-induced cardioprotection in failing hearts. Cav3 and μ receptor proteins in human and rat heart tissue were determined by western blot, immunofluorescence and co-immunoprecipitation. Methyl-β-cyclodextrin (MβCD), a destroyer of caveolae, and AAV-Cav3 shRNA were used to reduce Cav3 expression in failing rat hearts. CTOP, a specific μ antagonist, was administrated before morphine preconditioning in perfused failing heart models of myocardial I/R injury. Levels of Cav3 and μ receptor proteins were significantly higher in human and rat myocardial tissues with heart failure than in control tissues. Cav3 and μ receptor expression levels were positively correlated with disease severity. The signal of the cardiac Cav3 protein was colocalized with μ receptor in both the human and rat heart sections. Disruption of caveolae in the failing heart by either MβCD or AAV-Cav3 shRNA significantly inhibits morphine-induced phosphorylation of ERK1/2 and cardioprotection. Administration of CTOP substantially reduced Cav3 expression and morphine-induced cardioprotective effect in heart failure. Our data suggest that up-regulation of the Cav3/μ receptor complex is critical for morphine protection of the failing heart against I/R injury by regulating the ERK1/2 pathway. The activated Cav3/μ receptor complex is an understudied therapeutic target for opioid treatment of heart failure and ischaemic insult.