Management of granulomatous lobular mastitis: an international multidisciplinary consensus (2021 edition).

Granulomatous lobular mastitis (GLM) is a rare and chronic benign inflammatory disease of the breast. Difficulties exist in the management of GLM for many front-line surgeons and medical specialists who care for patients with inflammatory disorders of the breast. This consensus is summarized to establish evidence-based recommendations for the management of GLM. Literature was reviewed using PubMed from January 1, 1971 to July 31, 2020. Sixty-six international experienced multidisciplinary experts from 11 countries or regions were invited to review the evidence. Levels of evidence were determined using the American College of Physicians grading system, and recommendations were discussed until consensus. Experts discussed and concluded 30 recommendations on historical definitions, etiology and predisposing factors, diagnosis criteria, treatment, clinical stages, relapse and recurrence of GLM. GLM was recommended as a widely accepted definition. In addition, this consensus introduced a new clinical stages and management algorithm for GLM to provide individual treatment strategies. In conclusion, diagnosis of GLM depends on a combination of history, clinical manifestations, imaging examinations, laboratory examinations and pathology. The approach to treatment of GLM should be applied according to the different clinical stage of GLM. This evidence-based consensus would be valuable to assist front-line surgeons and medical specialists in the optimal management of GLM.

Effect of different rehabilitation training timelines to prevent shoulder dysfunction among postoperative breast cancer patients: study protocol for a randomized controlled trial.

INTRODUCTION: Due to advancements in treatment, the survival of breast cancer (BC) patients has significantly improved. Improving the postoperative quality of life has become a widespread concern for patients and doctors. At present, the staged rehabilitation training program for postoperative BC patients has been recognized. However, there is not yet a consensus about the optimal time to initiate rehabilitation training. We designed this study to investigate the optimal intervention times for postoperative BC patients to begin different stages of rehabilitation. DESIGN: This is a randomized controlled trial. Female participants with BC who are scheduled to undergo mastectomy, including unilateral total breast or breast-conserving surgery plus axillary lymph node dissection, will be enrolled in this study. The intervention includes the following: 200 participants will be allocated using a 1:1:1:1 ratio to the A, B, C, and D groups, which have four different rehabilitation timelines for four phases of rehabilitation exercises. A therapist will evaluate the patient's overall health and then adjust the training intensity before initiating training. The assessments include upper limb mobility, grip, limb circumference, postoperative drainage volume (PDV), and pain. The training will last for 12 weeks, and patients will undergo follow-up twice within 6 weeks after discharge. Outcomes include the following: Constant-Murley Score (CMS) is the primary parameter. European Organization Research and Treatment of Cancer Quality of Life Questionnaire-BR23 (EORTC QLQ-BR23), SF-36, range of motion (ROM), strength, grip, circumference, PDV, and pain are the secondary parameters. All enrolled subjects will be assessed at 1 day, 3 days, 1 week, and 2, 3, 6, 9, 12, and 18 weeks after the surgery. DISCUSSION: This is a randomized controlled trial to evaluate the effect of different rehabilitation training timelines to prevent shoulder dysfunction among postoperative patients with BC. If the results are confirmed, this study will establish an optimal timeline for postoperative BC rehabilitation. TRIAL REGISTRATION: ClinicalTrials.gov NCT03658265 . Registered on September 2018.

Long noncoding RNA HULC promotes colorectal carcinoma progression through epigenetically repressing NKD2 expression.

Recently, long noncoding RNAs (lncRNAs) have been emerged as crucial regulators of human diseases and prognostic markers in numerous of cancers, including colorectal carcinoma (CRC). Here, we identified an oncogenetic lncRNA HULC, which may promote colorectal tumorigenesis. HULC has been found to be up-regulated and acts as oncogene in gastric cancer and hepatocellular carcinoma, but its expression pattern, biological function and underlying mechanism in CRC is still undetermined. Here, we reported that HULC expression is also over-expressed in CRC, and its increased level is associated with poor prognosis and shorter survival. Knockdown of HULC impaired CRC cells proliferation, migration and invasion, and facilitated cell apoptosis in vitro, and inhibited tumorigenicity of CRC cells in vivo. Mechanistically, RNA immunoprecipitation (RIP) and RNA pull-down experiment demonstrated that HULC could simultaneously interact with EZH2 to repress underlying targets NKD2 transcription. In addition, rescue experiments determined that HULC oncogenic function is partly dependent on repressing NKD2. Taken together, our findings expound how HULC over-expression endows an oncogenic function in CRC.

Cathepsin B cleavable novel prodrug Ac-Phe-Lys-PABC-ADM enhances efficacy at reduced toxicity in treating gastric cancer peritoneal carcinomatosis: an experimental study.

BACKGROUND: Doxorubicin (Adriamycin) is effective in gastric cancer treatment, but with severe dose-dependent toxicities. A novel prodrug of doxorubicin (Ac-Phe-Lys-PABC-ADM) is designed to deliver free doxorubicin relying on cathepsin B and reduce side effects. The authors examined the antitumor effect and toxicities of Ac-Phe-Lys-PABC-ADM against gastric cancer peritoneal carcinomatosis. METHODS: SGC-7901 gastric cancer cell line was used for the study. The in vitro study investigated the effects of doxorubicin and Ac-Phe-Lys-PABC-ADM on cell growth dynamics and cell cycle. The in vivo study investigated the efficacy and toxicity of Ac-Phe-Lys-PABC-ADM on a nude mice model of peritoneal carcinomatosis, with doxorubicin as positive control. RESULTS: In the in vitro study, Ac-Phe-Lys-PABC-ADM had a lower dose-dependent inhibitory effect on SGC-7901 cells. In the in vivo study of control, doxorubicin, and Ac-Phe-Lys-PABC-ADM groups, the median experimental peritoneal carcinomatosis indexes were 6, 1.5, and 1, respectively (P = .004); the body weights were 24.32 ± 1.40 g, 18.40 ± 2.97 g, and 23.61 ± 0.80 g, respectively (P = .000). Biochemical studies showed that Ac-Phe-Lys-PABC-ADM had significantly lower toxicities on the bone marrow, liver, kidney, and particularly heart. Histopathological studies of the control, doxorubicin, and Ac-Phe-Lys-PABC-ADM groups found significant myocardium toxicities in 3, 7, and 4 animals, respectively. CONCLUSIONS: Ac-Phe-Lys-PABC-ADM could be an effective molecular targeting drug to treat gastric cancer peritoneal carcinomatosis with enhanced efficacy and reduced toxicity.

Quantum dot-based quantitative immunofluorescence detection and spectrum analysis of epidermal growth factor receptor in breast cancer tissue arrays.

BACKGROUND: The epidermal growth factor receptor (EGFR) is a promising therapeutic target in cancer, but its clinical value in breast cancer remains controversial. Our previous studies have found that quantitative analysis of biomarkers with quantum dot-based nanotechnology had better detection performance than conventional immunohistochemistry. The present study was undertaken to investigate the prognostic value of EGFR in breast cancer using quantum dot-based quantitative spectral analysis. METHODS: EGFR expression in 65 breast cancer specimens was detected by immunohistochemistry and quantum dot-immunohistochemistry, and comparisons were made between the two methods. EGFR expression in tissue microarrays of 240 breast cancer patients was then detected by quantum dot-immunohistochemistry and spectral analysis. The prognostic value of EGFR immunofluorescence area (EGFR area) for five-year recurrence-free survival was investigated. RESULTS: The same antigen localization, high correlation of staining rates (r = 0.914), and high agreement of measurement (κ = 0.848) of EGFR expression in breast cancer were found by quantum dot-immunohistochemistry and immunohistochemistry. The EGFR area showed significant differences by tumor grade, lymph node status, HER2 status, and hormone receptor status (all P < 0.05). Patients in the large EGFR area (≥ 30.51) group had a significantly higher five-year recurrence rate (47.2% versus 27.4%, P = 0.002) and worse five-year recurrence-free survival (log-rank test, P = 0.0015) than those in the small EGFR area (<30.51) group. In the subgroups, EGFR area was an independent prognosticator in the HER2-positive and lymph node-positive subgroups. CONCLUSION: Quantum dot-based quantitative detection demonstrates the prognostic value of EGFR area in the HER2-positive and lymph node-positive subgroups of invasive breast cancer.

Hepatocellular carcinoma: insight from animal models.

Hepatocellular carcinoma (HCC) ranks as the third most common cause of death from cancer worldwide. Although major risk factors for the development of HCC have been defined, many aspects of the evolution of hepatocellular carcinogenesis and metastasis are still unknown. Suitable animal models are, therefore, essential to promote our understanding of the molecular, cellular and pathophysiological mechanisms of HCC and for the development of new therapeutic strategies. This Review provides an overview of animal models that are relevant to HCC development, metastasis and treatment. For HCC development, this Review focuses on transgenic mouse models of HBV and HCV infection, which provide experimental evidence that viral genes could initiate or promote liver carcinogenesis. Animal models of HCC metastasis provide platforms to elucidate the mechanisms of HCC metastasis, to study the interaction between the microenvironment and HCC invasion and to conduct intervention studies. In addition, animal models have been developed to investigate the effects of new treatment modalities. The criteria for establishing ideal HCC animal models are also discussed.

Preoperative serum carbohydrate antigen 242 is a useful predictive and prognostic marker in colorectal cancer.

BACKGROUND/AIMS: Tumor markers (TM) play an important role in the management of colorectal cancer (CRC). This study evaluates the predictive and prognostic value of preoperative serum carbohydrate antigen 242 (CA242) in CRC. METHODOLOGY: Preoperative serum CA242 level was detected by C12 protein-chip diagnostic system in 185 CRC patients, and the predictive value of CA242 in stage, lymph node metastasis and tumor invasion depth was assessed. The prognostic value of CA242 for 5-year overall survival (OS) was analyzed. RESULTS: CA242 positive rate elevated with stage advancing, lymph node metastasis and tumor invasion depth, the differences between stage III+IV and stage I+II, between positive lymph node and negative lymph node, between T3+T4 and T1+T2, reached statistical significance (all p<0.05). Receiver operating characteristic analysis demonstrated that the area under the curve of CA242 in stage, lymph node metastasis and tumor invasion depth were 0.677, 0.631 and 0.744, respectively. Patients with higher CA242 had worse 5-year OS compared to those with normal CA242 (p=0.0002). Multivariate analysis showed stage (p=0.000) and preoperative serum CA242 (p=0.026) as independent prognostic factors for 5-year OS of CRC patients. CONCLUSIONS: The preoperative serum CA242 can predict stage, lymph node metastasis and tumor invasion depth, and can be used as an independent prognostic factor for OS of CRC.

Screening the gastric cancer related tumor markers from multi-tumor markers protein chip with kappa coefficient and cost-effectiveness analysis.

BACKGROUND/AIMS: To retrospectively evaluate the clinical values of C12 multi-tumor markers protein chip system in gastric cancer (GC) and screen for GC related tumor markers so as to provide a theoretical base for the establishment of GC diagnostic biochips. METHODOLOGY: The sera of 156 GC patients were detected for 12 common tumor markers using the C12 tumor markers protein chip. GC related parameters were analyzed by Kappa test and cost-effectiveness analysis to find the most optimal tumor marker combination. RESULTS: Carbohydrate antigen (CA) 19-9 (20.5%), CA242 (19.9%), carcinoembryonic antigen (CEA, 17.3%), CA125 (7.1%) were major tumor markers increased among the 156 GC patients. Kappa test revealed 6 tumor marker combinations having strong consistency with the detection results of C12 tumor markers proteinchip, and CA19-9 plus CEA proved to be the best combination by cost-effectiveness analysis. CONCLUSIONS: C12 tumor markers protein chip system had limited value in the diagnosis of GC, and the design of chip was too complicated and costly for widespread screening among the high risk populations. Searching for new GC biomarkers and designing small diagnostic chip could significantly enhance the clinical value of tumor markers in terms of diagnostic rate and practical utility.

[Increased coronin-1C expression is related to hepatocellular carcinoma invasion and metastasis].

OBJECTIVE: To search for hepatocellular carcinoma (HCC) invasion related biomarkers using the cell membrane proteomics approaches, and to validate the markers using experimental and clinical specimens. METHODS: The HCCLM9 and MHCC97L cells with a similar genetic background and remarkably different metastasis behaviors were used for comparative membrane proteome profiling using sodium dodecyl sulfate polyacrylamide gel electrophoresis and electrospray ionization mass spectrometry technologies. Candidate protein makers were further validated by western blot on cells, immunohistochemistry (IHC) on animal tumor tissues, and tissue micro-array on clinical specimens. RESULTS: The membrane proteins of MHCC97L and HCCLM9 cells were compared by sodium dodecyl sulfate polyacrylamide gel electrophoresis analyses. 14 proteins were identified by ESI-MS/MS among the differential bands. Coronin-1C was overexpressed in HCCLM9 (7.31+/-0.73) versus MHCC97L (2.84+/-0.99) validated by western blot. Elevated coronin-1C expression was observed in liver cancer tissues of HCCLM9 nude mice. IHC study in 115 human HCC specimens demonstrated that patients with higher coronin-1C expression had more advanced stage. CONCLUSION: The study suggests that coronin-1C could be a potential molecule to predict HCC invasive behavior.

Coronin-1C is a novel biomarker for hepatocellular carcinoma invasive progression identified by proteomics analysis and clinical validation.

BACKGROUND: To better search for potential markers for hepatocellular carcinoma (HCC) invasion and metastasis, proteomic approach was applied to identify potential metastasis biomarkers associated with HCC. METHODS: Membrane proteins were extracted from MHCC97L and HCCLM9 cells, with a similar genetic background and remarkably different metastasis potential, and compared by SDS-PAGE and identified by ESI-MS/MS. The results were further validated by western blot analysis, immunohistochemistry (IHC) of tumor tissues from HCCLM9- and MHCC97L-nude mice, and clinical specimens. RESULTS: Membrane proteins were extracted from MHCC97L and HCCLM9 cell and compared by SDS-PAGE analyses. A total of 14 differentially expressed proteins were identified by ESI-MS/MS. Coronin-1C, a promising candidate, was found to be overexpressed in HCCLM9 cells as compared with MHCC97L cells, and validated by western blot and IHC from both nude mice tumor tissues and clinical specimens. Coronin-1C level showed an abrupt upsurge when pulmonary metastasis occurred. Increasing coronin-1C expression was found in liver cancer tissues of HCCLM9-nude mice with spontaneous pulmonary metastasis. IHC study on human HCC specimens revealed that more patients in the higher coronin-1C group had overt larger tumor and more advanced stage. CONCLUSIONS: Coronin-1C could be a candidate biomarker to predict HCC invasive behavior.

Application of C12 multi-tumor marker protein chip in the diagnosis of gastrointestinal cancer: results of 329 surgical patients and suggestions for improvement.

BACKGROUND/AIMS: Gastrointestinal (GI) cancer remains number one cancer killer in China. Serum tumor markers (TMs) are frequently used in the diagnosis of GI cancer. This study was to assess value of C12 multi-tumor marker protein chip diagnostic system developed in China in GI cancer. METHODOLOGY: Sera from 329 GI cancer patients were detected by the C12 protein chip diagnostic system which consisted of 12 TMs including CEA, AFP, CA19-9, CA242, CA15-3, CA125, PSA, fPSA, NSE, B-HCG, HGH and Ferritin. The contribution of various TMs to the improvement of diagnosis was analyzed. The relationship between its positive rate and clinical stage, pathological type, and gender were explored. RESULTS: The diagnostic rates were 13.73%, 33.33%, 38.30%, 58.03%, respectively, for stage I, II, III and IV patients, and the overall diagnostic rate was 39.21%. There were statistically significant differences in stage I versus stage III, stage I versus stage IV, and stage II versus stage IV (p < 0.01). The other stage comparisons did not reach statistical significance (p > 0.05). Among the 12 TMs of the protein chip, the top 3 positive rates of 27.36%, 19.76% and 19.45% were obtained from CEA, CA242 and CA19-9, respectively, which were correlated with stage of GI cancer. The combinations of 5 most relevant TMs (3, 4 or 5 markers combined) improve the diagnostic rate significantly comparison to CEA (p < 0.05 or p < 0.01)). The combination of CEA+CA19-9+f-PSA (35.71%) for male patients, and CEA+CA19-9+ CA125 (40.95%) for female patients almost got the same diagnostic value as the C12 protein chip diagnostic system did (38.39% for male, 40.95% for female). CONCLUSIONS: The C12 system is of some value in the diagnosis of GI cancer, but new markers are needed to improve the early diagnosis. In GI cancer, the most rational combination way was CEA+CA19-9+f-PSA for male patient and CEA+CA19-9 +CA125 for female patient.