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Introduction Neoadjuvant endocrine therapy (NET) has demonstrated efficacy in post-menopausal patients with hormone-responsive breast cancer. This trial was designed to compare the efficacy of neoadjuvant chemotherapy (NCT) with NET in pre-menopausal breast cancer. Patients and methods In this prospective, randomised, phase III study, oestrogen receptor (ER)-positive, HER2-negative, and lymph node-positive pre-menopausal breast cancer patients were recruited from 7 hospitals in South Korea. Enrolled patients were randomly assigned (1:1) to receive 24 weeks of either NCT or NET with goserelin and tamoxifen. The primary purpose was to evaluate the non-inferiority of NET compared to NCT using clinical response, assessed by MRI. Besides, pathological complete response rate (pCR), changes in Ki-67 expression, breast conservation surgery (BCS) rate, and quality of life were included as secondary endpoints. Results A total of 187 patients were assigned to receive NCT ( n  = 95) or NET ( n  = 92), and 87 patients in each group completed treatments. More NCT patients had complete response or partial response than NET patients using MRI (NCT 83.7% vs. NET 52.9%, 95% CI 17.6–44.0, p  < 0.001) and callipers (NCT 83.9% vs. NET 71.3%, 95% CI 0.4–24.9, p  = 0.046). Three NCT patients (3.4%) and one NET patient (1.2%) showed pCR ( p  < 0.005). No difference existed in the conversion rate of BCS (13.8% for NCT vs. 11.5% for NET, p  = 0.531) and Ki-67 change ( p  = 0.114) between the two groups. Nineteen NCT patients had treatment-related grade 3 or worse events compared with none in the NET group. Conclusions Better clinical responses were observed in pre-menopausal patients after 24 weeks of NCT compared to those observed after NET. Trial registration Clinicaltrials.gov , NCT01622361 . Registration June 19, 2012.

The ARTemis trial was developed to assess the efficacy and safety of adding bevacizumab to standard neoadjuvant chemotherapy in HER2-negative early breast cancer. In this randomised, open-label, phase 3 trial, we enrolled women (≥18 years) with newly diagnosed HER2-negative early invasive breast cancer (radiological tumour size >20 mm, with or without axillary involvement), at 66 centres in the UK. Patients were randomly assigned via a central computerised minimisation procedure to three cycles of docetaxel (100 mg/m2 once every 21 days) followed by three cycles of fluorouracil (500 mg/m2), epirubicin (100 mg/m2), and cyclophosphamide (500 mg/m2) once every 21 days (D-FEC), without or with four cycles of bevacizumab (15 mg/kg) (Bev+D-FEC). The primary endpoint was pathological complete response, defined as the absence of invasive disease in the breast and axillary lymph nodes, analysed by intention to treat. The trial has completed and follow-up is ongoing. This trial is registered with EudraCT (2008-002322-11), ISRCTN (68502941), and ClinicalTrials.gov (NCT01093235). Between May 7, 2009, and Jan 9, 2013, we randomly allocated 800 participants to D-FEC (n=401) and Bev+D-FEC (n=399). 781 patients were available for the primary endpoint analysis. Significantly more patients in the bevacizumab group achieved a pathological complete response compared with those treated with chemotherapy alone: 87 (22%, 95% CI 18–27) of 388 patients in the Bev+D-FEC group compared with 66 (17%, 13–21) of 393 patients in the D-FEC group (p=0·03). Grade 3 and 4 toxicities were reported at expected levels in both groups, although more patients had grade 4 neutropenia in the Bev+D-FEC group than in the D-FEC group (85 [22%] vs 68 [17%]). Addition of four cycles of bevacizumab to D-FEC in HER2-negative early breast cancer significantly improved pathological complete response. However, whether the improvement in pathological complete response will lead to improved disease-free and overall survival outcomes is unknown and will be reported after longer follow-up. Meta-analysis of available neoadjuvant trials is likely to be the only way to define subgroups of early breast cancer that would have clinically significant long-term benefit from bevacizumab treatment. Cancer Research UK, Roche, Sanofi-Aventis.

Lymph node and adipose tissue fibrosis may limit CD4+ T-cell recovery and contribute to comorbidities in treated human immunodeficiency virus (HIV) infection. We demonstrate that fibrosis decreases with continued suppressive antiretroviral therapy; telmisartan, an angiotensin receptor blocker and peroxisome proliferator-activated receptor γ agonist, confers no additional benefit. Abstract Background Fibrosis in lymph nodes may limit CD4+ T-cell recovery, and lymph node and adipose tissue fibrosis may contribute to inflammation and comorbidities despite antiretroviral therapy (ART). We hypothesized that the angiotensin receptor blocker and peroxisome proliferator-activated receptor γ agonist telmisartan would decrease lymph node or adipose tissue fibrosis in treated human immunodeficiency virus type 1 (HIV) infection. Methods In this 48-week, randomized, controlled trial, adults continued HIV–suppressive ART and received telmisartan or no drug. Collagen I, fibronectin, and phosphorylated SMAD3 (pSMAD3) deposition in lymph nodes, as well as collagen I, collagen VI, and fibronectin deposition in adipose tissue, were quantified by immunohistochemical analysis at weeks 0 and 48. Two-sided rank sum and signed rank tests compared changes over 48 weeks. Results Forty-four participants enrolled; 35 had paired adipose tissue specimens, and 29 had paired lymph node specimens. The median change overall in the percentage of the area throughout which collagen I was deposited was −2.6 percentage points (P = 0.08) in lymph node specimens and −1.3 percentage points (P = .001) in adipose tissue specimens, with no between-arm differences. In lymph node specimens, pSMAD3 deposition changed by −0.5 percentage points overall (P = .04), with no between-arm differences. Telmisartan attenuated increases in fibronectin deposition (P = .06). In adipose tissue, changes in collagen VI deposition (−1.0 percentage point; P = .001) and fibronectin deposition (−2.4 percentage points; P < .001) were observed, with no between-arm differences. Conclusions In adults with treated HIV infection, lymph node and adipose tissue fibrosis decreased with continued ART alone, with no additional fibrosis reduction with telmisartan therapy.

Purpose Establishing breast MRI imaging patterns associated with neoadjuvant immunotherapy is needed to monitor response. We analyzed serial breast MRIs in patients receiving neoadjuvant chemo-immunotherapy on the I-SPY2 clinical trial. Methods Patients with stage 2–3 HER2-negative breast cancer were randomized to weekly paclitaxel (control), weekly paclitaxel and pembrolizumab, or weekly paclitaxel, pembrolizumab and intra-tumoral injection of SD-101, a TLR9 agonist. All patients received AC. Regional lymph nodes were retrospectively evaluated on breast MRI at baseline, 3, 12 and 20 weeks by a single blinded radiologist. MRIs were assessed for development of new regional lymphadenopathy, or increase in the longest diameter or cortical thickness of the largest abnormal regional lymph node. Results Between 12/2015 and 4/2021, a total of 43 patients enrolled in the control ( n  = 16) and paclitaxel + pembrolizumab ± SD-101 ( n  = 27) arms. 12 of 27 patients (44.4%) receiving chemo-immunotherapy experienced increased lymphadenopathy within the first 12 weeks compared to 1 of 16 patients (6.3%) in the control group ( p  = 0.014). Most patients with increased lymphadenopathy were in the SD101/pembro arm ( n  = 10, p  = 0.002). Increased lymphadenopathy was observed despite concomitant decrease in breast tumor size at all time points. 11 of 12 patients with increased lymphadenopathy had pathologically negative nodes at surgery. There was no association between lymphadenopathy and lower residual cancer burden or immune-related toxicity. Conclusions The combination of neoadjuvant paclitaxel and pembrolizumab ± SD101 intratumoral injection was associated with early increases in regional lymphadenopathy on MRI despite decreased breast tumor size. Increased lymphadenopathy was not associated with node positive disease at surgery.

A clinical trial in patients with glioblastoma shows increased immune and anti-tumour responses to dendritic cell vaccination after pre-conditioning the site of vaccination with tetanus toxoid (Td); similar results are also seen in mice in part due to the actions of the chemokine CCL3, and the findings may represent new ways to improve the efficacy of anti-cancer vaccines. A novel anti-tumour immunotherapy strategy John Sampson and colleagues report on a small clinical trial in glioblastoma patients that shows that the immune and anti-tumour response to dendritic cell vaccination is increased by pre-conditioning the site of vaccination with tetanus/diptheria toxoid (Td). Experiments in mice showed similar effects and demonstrated that pre-conditioning with Td enhanced migration of dendritic cells to the tumours, at least in part due to the action of the cytokine CCL3. Although the clinical trial reported is small, these findings may pave the way for new ways of improving the efficacy of anti-cancer vaccines. After stimulation, dendritic cells (DCs) mature and migrate to draining lymph nodes to induce immune responses 1 . As such, autologous DCs generated ex vivo have been pulsed with tumour antigens and injected back into patients as immunotherapy. While DC vaccines have shown limited promise in the treatment of patients with advanced cancers 2 , 3 , 4 including glioblastoma 5 , 6 , 7 , the factors dictating DC vaccine efficacy remain poorly understood. Here we show that pre-conditioning the vaccine site with a potent recall antigen such as tetanus/diphtheria (Td) toxoid can significantly improve the lymph node homing and efficacy of tumour-antigen-specific DCs. To assess the effect of vaccine site pre-conditioning in humans, we randomized patients with glioblastoma to pre-conditioning with either mature DCs 8 or Td unilaterally before bilateral vaccination with DCs pulsed with Cytomegalovirus phosphoprotein 65 (pp65) RNA. We and other laboratories have shown that pp65 is expressed in more than 90% of glioblastoma specimens but not in surrounding normal brain 9 , 10 , 11 , 12 , providing an unparalleled opportunity to subvert this viral protein as a tumour-specific target. Patients given Td had enhanced DC migration bilaterally and significantly improved survival. In mice, Td pre-conditioning also enhanced bilateral DC migration and suppressed tumour growth in a manner dependent on the chemokine CCL3. Our clinical studies and corroborating investigations in mice suggest that pre-conditioning with a potent recall antigen may represent a viable strategy to improve anti-tumour immunotherapy.

To investigate the targeting effect of toluidine blue-dextran-40 (TB-Dex-40) on the head and neck lymphatic system. Thirty healthy adult New Zealand white rabbits were randomly divided into two groups: the experimental group (TB-Dex-40 group, n = 15) and the control group (TB group, n = 15). In the experimental group, 1.0% TB-Dex-40 (0.14 mOsm/L) was submucosally injected at the lingual margin (1 cm from the tip of the tongue), while in the control group, 1.0% toluidine blue (32.60 mOsm/L) was administered under the same conditions. The time required for the dye to reach and stain the sentinel lymph node (SLN) was recorded, and the diffusion range of the dyes in the tongue was measured. SLN samples were collected at 30 min and 2 h post-injection for histopathological examination. SLN staining persistence was observed at 1 day, 2 days, and 4 weeks post-injection. Routine blood and biochemical tests were conducted before and 2 weeks after the experiment to evaluate systemic safety. Additionally, in two separate rabbits, the two dyes were injected into the common carotid artery to observe their effects on cervical lymph nodes, submandibular glands, and tongue tissue. A sucrose preference test was performed during animal rearing to assess potential neurotoxicity induced by the dyes. In the experimental group, it took (21.67 ± 0.19) seconds for the dye to reach the SLN and stain lymphatic vessels, which was significantly longer than that in the control group [(3.22 ± 0.34) seconds] ( P  < 0.01). The SLN stained in the experimental group remained clearly visible even after 4 weeks, whereas the SLN stained in the control group had completely faded by 2 days. The diffusion range of the dye in the tongue was significantly smaller in the experimental group [(10.53 ± 1.09) mm] compared with the control group [(20.04 ± 1.06) mm] ( P  < 0.01). No abnormalities were detected in the blood parameters of the experimental animals. Neither group exhibited neurological abnormalities. After injection via the common carotid artery, significant staining was observed in the lymph nodes of the TB group but not in the TB-Dex-40 group. TB-Dex-40 demonstrates superior targeting capabilities within the lymphatic system and holds substantial potential for clinical translation. Clinical relevance: TB-Dex-40 exhibits specificity for lymphatic vessels and serves as an effective tracer with significant clinical potential. Its molecular structure provides a robust theoretical foundation for the development of future imaging agents.

Impaired immune effector functions in the melanoma sentinel lymph node (SLN) may allow for early metastatic events. In an effort to determine the optimal way to strengthen immune defenses, 28 clinical stage I–II melanoma patients were randomized in a 3-arm Phase II study to receive, prior to excision and sampling of the SLN, i.d. injections of saline or low-dose CpG-B (CpG), alone or combined with GM-CSF (GM), around the melanoma excision site. We previously described the combined administration of these DC-targeting agents to result in activation and recruitment of potentially cross-presenting BDCA3 + DCs to the SLN. In this report we describe the effects on effector and regulatory T and NK cell subsets. Local low-dose CpG administration resulted in lower CD4/CD8 ratios, Th1 skewing, increased frequencies of melanoma-specific CD8 + T cells and possible recruitment of effector NK cells, irrespective of GM co-administration. These immune-potentiating effects were counterbalanced by increased IL-10 production by T cells and significantly higher levels of FoxP3 and CTLA4 in regulatory T cells (Tregs) with correspondingly higher suppressive activity in the SLN. Notably, CpG ± GM-administered patients showed significantly lower numbers of SLN metastases (saline: 4/9, CpG + GM: 1/9, CpG: 0/10, p  = 0.04). These findings indicate that i.d. delivery of low-dose CpG ± GM potentially arms the SLN of early-stage melanoma patients against metastatic spread, but that antitumor efficacy may be further boosted by counteracting the collateral activation of Tregs.

Background In the phase III SOLE trial, the extended use of intermittent versus continuous letrozole for 5 years did not improve disease-free survival in postmenopausal women with hormone receptor-positive breast cancer. Intermittent therapy with 3-month breaks may be beneficial for patients’ quality of life (QoL). Methods In the SOLE QoL sub-study, 956 patients completed the Breast Cancer Prevention Trial (BCPT) symptom and further QoL scales up to 24 months after randomisation. Differences in change of QoL from baseline between the two administration schedules were tested at 12 and 24 months using repeated measures mixed-models. The primary outcome was change in hot flushes at 12 months. Results There was no difference in hot flushes at 12 months between the two schedules, but patients receiving intermittent letrozole reported significantly more improvement at 24 months. They also indicated less worsening in vaginal problems, musculoskeletal pain, sleep disturbance, physical well-being and mood at 12 months. Overall, 25–30% of patients reported a clinically relevant worsening in key symptoms and global QoL. Conclusion Less symptom worsening was observed during the first year of extended treatment with the intermittent administration. For women experiencing an increased symptom burden of extended adjuvant endocrine therapy, an intermittent administration is a safe alternative. Clinical trial information Clinical trial information: NCT00553410.

Purpose: To evaluate the efficacy of neoadjuvant chemotherapy in combination with regional inductive moderate hyperthermia for patients with locally advanced breast cancer. Patients and Methods: 200 patients with stage IIB-IIIA breast cancer received neoadjuvant chemotherapy (control group, n = 97) or chemotherapy combined with hyperthermia (experimental group, n = 103). Inductive hyperthermia was set at 27.12 ± 0.16 MHz and the 50 W output power. Results: Thermal and color Doppler ultrasound imaging demonstrated that hyperthermia increased the surface temperature on the breasts to < 4°С while the mean values for systolic blood flow were 3.5 times as high as those prior to treatment. Assessment of tumor size and response found a (31.24 ± 3.85)% reduction in the size of the primary tumor in patients receiving chemotherapy + hyperthermia, while chemotherapy alone showed a (22.95 ± 3.61)% decrease on average (p = 0.034). The rate of objective response increased by 15.9% in the experimental group (р = 0.034) compared with the control group. The patients in the experimental group also had axillary lymph node regression of 14.17% greater than in the control group (p = 0.011). Moreover, the combination treatment allowed to increase the proportion of women eligible for breast-conserving and reconstructive surgery by 13.63% in the experimental group. The viable tumor volume was lower in patients receiving neoadjuvant chemotherapy + hyperthermia (24.4 ± 0.2)% compared with those given chemotherapy alone (30.4 ± 0.25)%. The 10-year overall survival rates were higher (log-rank: p = 0.009) in breast cancer patients who underwent chemotherapy combined with hyperthermia than in patients receiving chemotherapy only. Conclusion: The combination neoadjuvant chemotherapy and the technology of regional inductive moderate hyperthermia improved the efficacy of treatment for patients with locally advanced breast cancer staged IIB-IIIA.

The purpose of this study was to understand the short-term therapeutic effects of an activated carbon nanoparticle–epirubicin suspension for regional lymphatic chemotherapy in patients with breast cancer. One hundred and twenty patients with stage I, II, or III primary breast cancer were randomly divided into three groups: the lymphatic chemotherapy group using the activated carbon nanoparticle–epirubicin suspension, the epirubicin control group, and the activated carbon control group. Each group of 40 patients was further divided into two subgroups with the drug injected either 24 or 48 h before surgery. The terminal deoxynucleotidyl transferase–mediated deoxyuridine triphosphate–biotin nick end labeling (TUNEL) assay was used to determine cancer cell apoptotic indices in metastatic lymph nodes. The epirubicin concentration in the black-stained lymph nodes in the lymphatic chemotherapy treatment group was 4,144.64 ± 2,426.44 ng/g, which is significantly higher than in the epirubicin control group (335.87 ± 212.82 ng/g, P  < 0.001). The plasma epirubicin concentrations at 0.5, 1.5, and 24 h postinjection in the regional lymphatic chemotherapy treatment group were significantly lower than in the epirubicin control group ( P  < 0.001). Tolerable mild pain was observed at the injection area after administration of the epirubicin–activated carbon nanoparticle suspension. No regional necrosis or adverse effects were found. The TUNEL assay demonstrated that there was no significant difference in the apoptotic indices in the metastatic lymph nodes from the three groups. Performing lymphatic chemotherapy by regionally injecting the epirubicin–activated carbon nanoparticle suspension could significantly enhance the drug concentration in the stained lymph nodes and lower the plasma drug concentration. The epirubicin–activated carbon nanoparticle suspension has the ability to release the drug slowly in the lymph nodes and, as a result, can prolong the chemotherapeutic effects.