Targeting Both Autophagy and Immunotherapy in Breast Cancer Treatment.

As clinical efforts towards breast-conserving therapy and prolonging survival of those with metastatic breast cancer increase, innovative approaches with the use of biologics are on the rise. Two areas of current focus are cancer immunotherapy and autophagy, both of which have been well-studied independently but have recently been shown to have intertwining roles in cancer. An increased understanding of their interactions could provide new insights that result in novel diagnostic, prognostic, and therapeutic strategies. In this breast cancer-focused review, we explore the interactions between autophagy and two clinically relevant immune checkpoint pathways; the programmed cell death-1 receptor with its ligand (PD-L1)/PD-1 and the cytotoxic T-lymphocyte-associated protein 4 (CTLA-4)/CD80 and CD86 (B7-1 and B7-2). Furthermore, we discuss emerging preclinical and clinical data supporting targeting both immunotherapy and autophagy pathway manipulation as a promising approach in the treatment of breast cancer.

Alterations of the 70 kDa heat shock protein (HSP70) and sequestosome-1 (p62) in women with breast cancer.

Peripheral blood mononuclear cells (PBMCs) respond to altered physiological conditions to alleviate the threat. Production of the 70 kDa heat shock protein (HSP70) is up-regulated to protect proteins from degradation. Sequestosome-1 (p62) binds to altered proteins and the p62-protein complex is degraded by autophagy. P62 is also a regulator of intracellular kinase activity and cell differentiation. We hypothesized that the PBMC response to a malignant breast mass involves elevated production of HSP70 and a decrease in intracellular p62. In this study 46 women had their breast mass excised. PBMCs were isolated and intracellular levels of HSP70 and p62 were quantitated by ELISA. Differences between women with a benign or malignant breast mass were determined. A breast malignancy was diagnosed in 38 women (82.6%) while 8 had a benign lesion. Mean intracellular HSP70 levels were 79.3 ng/ml in PBMCs from women with a malignant lesion as opposed to 44.2 ng/ml in controls (p = 0.04). The mean PBMC p62 level was 2.3 ng/ml in women with a benign breast lesion as opposed to 0.6 ng/ml in those with breast cancer (p < 0.001). Mean p62 levels were lowest in women with invasive carcinoma and a positive lymph node biopsy when compared to those with in-situ carcinoma or absence of lymphadenopathy, respectively. Intracellular HSP70 and p62 levels in PBMCs differ between women with a malignant or benign breast lesion. These measurements may be of value in the preoperative triage of women with a breast mass.

Epidemiology, diagnostic approach and therapeutic management of tailgut cysts: A systematic review.

BACKGROUND: Tailgut cysts (TGCs) are benign congenital abnormalities that usually present with non-specific symptoms, constituting a diagnostic dilemma for physicians. The aim of this study was to systematically review the literature concerning clinical manifestations, diagnostic modalities and histologic findings of TGCs and highlight current knowledge on therapeutic management of this rare entity. METHODS: PubMed and Embase databases were systematically searched by two independent investigators (last search 18 February 2021) for studies concerning TGCs published in the past two decades. RESULTS: Totally, 144 articles, including 135 case reports and 9 case series, met our inclusion criteria. One hundred eighty-four patients were included (3:1/female:male) with an age of 42.3 ± 18.7 years (mean, SD), while 5 cases concerned new-born infants. Pain was the prevailing clinical manifestation (41.8%), whereas 16.8% were asymptomatic. MRI and CT were utilized for diagnosis in 58.7% and 54.7% of cases, respectively. The majority of cysts were multilocular, while ciliated columnar epithelium and smooth muscles of the cyst wall were the prevailed histological findings. Malignant degeneration of TGCs was reported in 32.1% of cases, while carcinoid tumours were the most frequent malignancies. Surgical resection was performed in 155 cases, while laparoscopic and robotic approach was preferred in 18 and 2 cases, respectively. A posterior approach was implemented in 80.9%, anterior technique in 9% and combined technique in 6.7% of cases. Postoperative complications and recurrence of the cystic lesion were reported in 17.4% and 7.6% of cases, respectively. CONCLUSIONS: TGCs constitute a dilemma for the physicians. Surgical resection comprises the ultimate treatment to avoid complications or malignant transformation of the cyst. Concrete follow-up strategies and optimal therapeutic options should be outlined through consensus guidelines and at the time being, such decisions can be made only on the basis of extrapolation and on a case-by-case approach.

Evaluation of molecular and genetic predisposing parameters at diverticular disease of the colon.

BACKGROUND: Diverticular disease (DD) refers to the presence of diverticula throughout the gastrointestinal (GI) tract, mainly along colon. DD might evolve into diverticulitis that is accompanied by severe clinical presentation, which includes abscess formation, perforation, stricture, obstruction and/or fistula. AIM: The aim of the present review is to summarize the role of molecular and genetic factors in DD development, as well as their possible contribution towards new prognostic indicators, diagnostic algorithms and new therapeutic approaches. METHODS AND RESULTS: Except from common predisposing parameters, several genetic mutations, immune factors, neurotransmitters, hormones and protein dysfunctions have been associated to the early onset of DD symptoms, pathogenesis and prognosis of the disease. Specific structural changes in the colonic wall, altered matrix composition and compromised motility have been verified as possible pathogenic factors for the development of DD. Dysregulation in peristaltic activity and reduced ability of the longitudinal muscle to relax following contraction has been also associated with DD evolution. In addition, it has been suspected that genetic defects combined with alterations in intestinal microbiota might play an important role in diverticulitis presentation.

Comprehensive expression analysis of TNF-related apoptosis-inducing ligand and its receptors in colorectal cancer: Correlation with MAPK alterations and clinicopathological associations.

TNF-related, apoptosis-inducing ligand (TRAIL) apoptotic pathway constitutes a promising therapeutic target due to high selectivity and low toxicity of TRAIL targeting agents when administered in combination therapies. 106 colorectal cancers were examined for: relative mRNA expression of TRAIL pathway genes, decoy receptors TRAIL-R3 and TRAIL-R4 promoter methylation and the presence of KRAS, NRAS, BRAF mutations. Elevated mRNA levels were observed in 26%, 15%, 13%, 12% and 10% of the cases for TRAIL-R4, TRAIL-R3, TRAIL-R2, TRAIL-R1 and TRAIL genes respectively. Reduced mRNA levels were detected in 77%, 65%, 64%, 60% and 37% of the cases for TRAIL, TRAIL-R2, TRAIL-R3, TRAIL-R1 and TRAIL-R4 genes respectively. TRAIL-R3 and TRAIL-R4 promoter methylation was detected in 55% and 16% of the analysed samples respectively. TRAIL-R1, TRAIL-R2 elevated relative mRNA levels inversely correlated with tumor stage (p = .036, p = .048). Strong linear correlations of TRAIL receptors' mRNA levels were found: TRAIL-R1/TRAIL-R2 (R = 0.653, p < .001), TRAIL-R2/TRAIL-R3 (R = 0.573, p < .001). Finally, relative expression of TRAIL was correlated with KRAS, BRAF and NRAS mutation status, defining an inverse correlation between increased TRAIL expression and the absence of mutations in Mitogen-activated protein kinase (MAPK) pathway. In conclusion, simultaneous analysis of TRAIL pathway membrane components, pointed towards a significant deregulation of mRNA expression in colorectal tumours. Death receptor overexpression was an indicator of a less aggressive phenotype. The multiple expression patterns of TRAIL pathway components in colorectal tumours underscore the importance of patient selection in order to achieve maximum efficiency with TRAIL targeted therapy.

Margin-free excision of small solid breast carcinomas using the Intact Breast Lesion Excision System®: is it feasible?

BACKGROUND: The Breast Lesion Excision System® (BLES®) is a stereotactic vacuum-assisted breast biopsy device that utilizes radiofrequency in order to excise non-palpable mammographic lesions for pathologic diagnosis. The purpose of this study was to evaluate the efficacy of BLES® in performing complete, margin-free excisions of small solid carcinomas. METHODS: Our retrospective study of prospectively enrolled patients included 50 cases of non-palpable, BIRADS ≥ 4, solid by means of mammography and sonography, lesions. All these patients underwent a BLES® breast biopsy procedure from June 2010 to June 2014 and had a malignant diagnosis. According to each patient's pathologic diagnosis, appropriate surgical treatment was recommended. Postoperatively, surgical specimens were histologically analyzed, aiming to determine whether residual malignant disease was present in the specimen cavity formatted by BLES®. RESULTS: Ductal carcinoma in situ (DCIS) was diagnosed in 5 patients and invasive carcinoma (IC) in 45 patients, at primary BLES® pathology report. Tumor-free resection margins (< 0.5 and < 1 mm) were accomplished in only 8/24 subcentimeter cases (33.3%). Absence of residual disease upon surgical excision was confirmed in 23/24 subcentimeter cases (95.8%) and 2/26 of the cases measuring > 1 cm (7.69%). Statistical analysis revealed that mammographic size was the only significant prognostic factor for complete excision (i.e., with no residual disease in the biopsy cavity) of a malignant lesion. CONCLUSIONS: Our results indicate that it is possible, when using the BLES® device, to completely excise small (≤ 10 mm) breast carcinomas that appear radiologically as solid lesions. This subset of patients should be investigated regarding the therapeutic potential of this method.