T-cell bispecific antibodies in node-positive breast cancer: novel therapeutic avenue for MHC class I loss variants

BackgroundTumor-infiltrating lymphocytes (TILs) represent a prognostic factor for survival in primary breast cancer (BC). Nonetheless, neoepitope load and TILs cytolytic activity are modest in BC, compromising the efficacy of immune-activating antibodies, which do not yet compete against immunogenic chemotherapy.Patients and methodsWe analyzed by functional flow cytometry the immune dynamics of primary and metastatic axillary nodes [metastatic lymph nodes (mLN)] in early BC (EBC) after exposure to T-cell bispecific antibodies (TCB) bridging CD3ε and human epidermal growth factor receptor 2 (HER2) or Carcinoembryonic Antigen-Related Cell Adhesion Molecule 5 (CEACAM5), before and after chemotherapy. Human leukocyte antigen (HLA) class I loss was assessed by whole exome sequencing and immunohistochemistry. One hundred primary BC, 64 surrounding ‘healthy tissue’ and 24 mLN-related parameters were analyzed.ResultsHLA loss of heterozygosity was observed in EBC, at a clonal and subclonal level and was associated with regulatory T cells and T-cell immunoglobulin and mucin-domain-3 expression restraining the immuno-stimulatory effects of neoadjuvant chemotherapy. TCB bridging CD3ε and HER2 or CEACAM5 could bypass major histocompatibility complex (MHC) class I loss, partially rescuing T-cell functions in mLN.ConclusionTCB should be developed in BC to circumvent low MHC/peptide complexes.     

Impact of molecular imaging on the diagnostic process in a memory clinic

Background[¹¹C]Pittsburgh compound B ([¹¹C]PIB) and [¹⁸F]-2-fluoro-2-deoxy-D-glucose ([¹⁸F]FDG) PET measure fibrillar amyloid-β load and glucose metabolism, respectively. We evaluated the impact of these tracers on the diagnostic process in a memory clinic population.MethodsOne hundred fifty-four patients underwent paired dynamic [¹¹C]PIB and static [¹⁸F]FDG PET scans shortly after completing a standard dementia screening. Two-year clinical follow-up data were available for 39 patients. Parametric PET images were assessed visually and results were reported to the neurologists responsible for the initial diagnosis. Outcome measures were (change in) clinical diagnosis and confidence in that diagnosis before and after disclosing PET results.Results[¹¹C]PIB scans were positive in 40 of 66 (61%) patients with a clinical diagnosis of Alzheimer’s disease (AD), 5 of 18 (28%) patients with frontotemporal dementia (FTD), 4 of 5 (80%) patients with Lewy body dementia, and 3 of 10 (30%) patients with other dementias. [¹⁸F]FDG uptake patterns matched the clinical diagnosis in 38 of 66 (58%) of AD patients, and in 6 of 18 (33%) FTD patients. PET results led to a change in diagnosis in 35 (23%) patients. This only occurred when prior diagnostic certainty was <90%. Diagnostic confidence increased from 71 ± 17% before to 87 ± 16% after PET (p < .001). Two-year clinical follow-up (n = 39) showed that [¹¹C]PIB and [¹⁸F]FDG predicted progression to AD for patients with mild cognitive impairment, and that the diagnosis of dementia established after PET remained unchanged in 96% of patients.ConclusionsIn a memory clinic setting, combined [¹¹C]PIB and [¹⁸F]FDG PET are of additional value on top of the standard diagnostic work-up, especially when prior diagnostic confidence is low.     

Bcl-2、 cyclin A2和P13K在激素受体阴性乳腺癌中的表达及意义

目的探讨激素受体阴性乳腺癌中B淋巴细胞瘤／白血病2基因（ B-cell lymphoma/leukemia-2, Bcl-2 ）、细胞周期素A2（cyclinA2）和磷酸肌醇3激酶（ phosphoinositide 3 -kinase, PI3K ）的表达及意义。方法采用实时聚合酶链反应（real time polymerase chain reaction,RT-PCR）方法检测Bcl-2、cyclinA2和P13K在激素受体阴性乳腺癌组织（58例）、乳腺正常组织（14例）中的表达水平,并采用Mann-WhitneyU检验分析其与临床病理特征的关系。结果与乳腺正常组织相比,激素受体阴性乳腺癌中Bel-2表达降低,而cyclinA2和P13K表达增高（P〈0．05）。在乳腺癌组织中,Bcl-2在TNM分期Ⅲ期、组织学分级Ⅲ级和出现转移复发的患者中表达水平降低（P〈0．05）,但其表达在不同年龄、肿瘤大小和淋巴结转移的组间差异无显著性（P〉0．05）;cyclinA2在转移复发的患者中显著高表达（P〈0．05）,但在不同的年龄、肿瘤大小、组织学分级、TNM分期和淋巴结状态的组间差异均无显著性（P〉0．05）;P13K在有淋巴结转移和TNM分期Ⅲ期的患者中高表达（P〈0．05）,但其表达在不同年龄、肿瘤大小、组织学分级以及是否转移复发的组间差异均无显著性（P〉0．05）。结论Bcl-2低表达、eyclinA2和P13K高表达可能与激素受体阴性乳腺癌的发生发展有关。     

Papilledema secondary to vestibular schwannoma: An atypical case without intracranial hypertension

In most cases, vestibular schwannomas with papilledema are associated with intracranial hypertension secondary to hydrocephalus (obstructive or communicating). We describe the atypical case of a 39-years-old man who presented with bilateral papilledema revealing a vestibular schwannoma, but without hydrocephalus and with normal intracranial pressure. Ophtalmologic signs were completely resolved after tumor removal. The pathophysiological mechanism generally described to explain bilateral papilledema in such cases is tumor-induced hyperproteinorachia. However, in the absence of hydrocephalus or intracranial hypertension, this case raises the question of the mechanisms involved in the visual impairment related to vestibular schwannoma.     

Comparison of aggressive versus standard intravenous hydration for clinical improvement among patients with mild acute pancreatitis: A randomized controlled trial

BackgroundControversy remains regarding fluid management strategy, optimal volume and rate of intravenous fluid in mild acute pancreatitis. We performed a randomized controlled trial to compare clinical improvement and inflammatory markers between aggressive and standard fluid management.MethodsA single center prospective randomized controlled trial was conducted in a tertiary care hospital. We randomized patients with a diagnosis of mild acute pancreatitis using revised Atlanta classification in two groups, the aggressive (20 ml/kg bolus followed by 3 ml/kg/hr) and standard (10 ml/kg bolus followed by 1.5 ml/kg/hr) intravenous hydration with Lactated Ringer's solution. Primary outcome was clinical improvement at 24 and 36 hours.ResultsThe mean age of patients was 46 years and 34 patients (77%) were male. The average volumes of fluid during the first 24 hours in aggressive and standard groups was 4886 ml (71 ml/kg) and 3985 ml (53 ml/kg), respectively; p-value 0.002. Aggressive intravenous hydration did not significantly improve clinical outcome compared with standard intravenous hydration (45.45% vs. 31.82%, respectively; p-value 0.353). However, subgroup analysis between patients with obese and non-obese status, revealed aggressive intravenous hydration significantly improved clinical outcome within the first 24 hours in obese group.ConclusionAggressive intravenous hydration with Lactated Ringer's solution did not improve clinical outcome in mild acute pancreatitis but showed statistically significant improvement only in patients with obese status. Future studies should include a larger sample size to confirm these findings.     

乙型、丁型肝炎病毒诊断基因芯片制备的初步实验研究

目的 制备联合检测乙型、丁型肝炎病毒基因芯片并进行杂交验证。方法利用Primer 5.0软件分别针对乙型、丁型肝炎病毒基因保守区域设计多对PCR引物，纯化PCR扩增产物，扩增后的产物克隆至pMD18-T载体，提取阳性克隆质粒进行测序分析及鉴定。用芯片点样仪将PCR产物点到玻片上制备成基因芯片。样品标记采用限制性显示技术，样品标记后进行杂交。结果运用PCR技术，得到多个乙型、丁型肝炎病毒特异性基因片段。序列分析表明，所扩增的片段均属于HBV、HDV特异基因。杂交结果显示，样品和乙型、丁型肝炎诊断基因芯片杂交的敏感性和特异性均佳。结论利用PCR扩增产物制备乙型、丁型诊断基因芯片是一种快速、简便的实用方法，有着广阔的应用前景。另外，利用限制性显示技术标记样品可为进一步更多种肝炎病毒的混和检测奠定基础。     

Long-term safety and efficacy of the PI3K inhibitor copanlisib in patients with relapsed or refractory indolent lymphoma: 2-year follow-up of the CHRONOS-1 study

Safety profiles of oral PI3K inhibitors have resulted in US FDA black box warnings regarding fatal/serious toxicities. The approved intravenous PI3K inhibitor copanlisib has low incidence of severe toxicities and no black box warnings, but chronic treatment effects were unknown. We provide an update on safety and efficacy of copanlisib with a minimum 2-year follow-up of the CHRONOS-1 study. A total of 142 patients with histologically confirmed indolent B-cell lymphoma who had relapsed after or were refractory to ≥2 prior treatments received intravenous copanlisib 60 mg on days 1, 8, and 15 (28-day cycle). The primary efficacy endpoint was objective response rate (ORR) after ≥4 cycles (independent assessment). The predominant histology was follicular lymphoma (n = 104). The ORR was 60.6% (seven additional complete responses since primary analysis). Secondary endpoints of median duration of response, progression-free survival, and overall survival were 14.1 months (median follow-up, 16.1 months), 12.5 months (median follow-up, 14.0 months), and 42.6 months (median follow-up, 31.5 months), respectively. Median safety follow-up was 6.7 months; 26% of patients received treatment for >1 year. Common treatment-emergent adverse events (TEAEs) (all grade/grade 3/grade 4) were transient hyperglycemia (50.0%/33.1%/7.0%), diarrhea (35.2%/8.5%/0%), transient hypertension (29.6%/23.9%/0%), and neutropenia (28.9%/9.2%/14.8%). Serious AEs were largely unchanged, with no new cases of pneumonitis (4.2%), diarrhea (2.8%), or grade 5 events. Note, TEAEs showed no evidence for increased incidence or worsening following longer exposure in patients treated >1 year. Long-term follow-up of patients with relapsed/refractory indolent B-cell lymphoma treated with intravenous copanlisib demonstrated durable, enhanced responses without evidence of worsening TEAEs, as reported for orally administered PI3K inhibitors.