Nivolumab plus relatlimab in patients with previously treated microsatellite instability-high/mismatch repair-deficient metastatic colorectal cancer: the phase II CheckMate 142 study.

BACKGROUND: Programmed death-1 (PD-1) inhibitors, including nivolumab, have demonstrated long-term survival benefit in previously treated patients with microsatellite instability-high/mismatch repair-deficient (MSI-H/dMMR) metastatic colorectal cancer (CRC). PD-1 and lymphocyte-activation gene 3 (LAG-3) are distinct immune checkpoints that are often co-expressed on tumor-infiltrating lymphocytes and contribute to tumor-mediated T-cell dysfunction. Relatlimab is a LAG-3 inhibitor that has demonstrated efficacy in combination with nivolumab in patients with melanoma. Here, we present the results from patients with MSI-H/dMMR metastatic CRC treated with nivolumab plus relatlimab in the CheckMate 142 study. METHODS: In this open-label, phase II study, previously treated patients with MSI-H/dMMR metastatic CRC received nivolumab 240 mg plus relatlimab 160 mg intravenously every 2 weeks. The primary end point was investigator-assessed objective response rate (ORR). RESULTS: A total of 50 previously treated patients received nivolumab plus relatlimab. With median follow-up of 47.4 (range 43.9-49.2) months, investigator-assessed ORR was 50% (95% CI 36% to 65%) and disease control rate was 70% (95% CI 55% to 82%). The median time to response per investigator was 2.8 (range 1.3-33.1) months, and median duration of response was 42.7 (range 2.8-47.0+) months. The median progression-free survival per investigator was 27.5 (95% CI 5.3 to 43.7) months with a progression-free survival rate at 3 years of 38%, and median overall survival was not reached (95% CI 17.2 months to not estimable), with a 56% overall survival rate at 3 years. The most common any-grade treatment-related adverse events (TRAEs) were diarrhea (24%), asthenia (16%), and hypothyroidism (12%). Grade 3 or 4 TRAEs were reported in 14% of patients, and TRAEs of any grade leading to discontinuation were observed in 8% of patients. No treatment-related deaths were reported. CONCLUSIONS: Nivolumab plus relatlimab provided durable clinical benefit and was well tolerated in previously treated patients with MSI-H/dMMR metastatic CRC. TRIAL REGISTRATION NUMBER: NCT02060188.

Assessment of therapeutic efficacy in seven cases of basal cell carcinoma in the ear and nose region treated with new surgical excision and immediate photodynamic therapy.

BACKGROUND: Basal cell carcinoma (BCC) is the most prevalent non-melanoma skin tumor. It commonly affects exposed areas. Currently, surgical resection is considered the primary approach for BCC treatment. However, BCC frequently affects exposed facial areas, leading to visible scars after surgery. PDT has garnered increasing recent attention, demonstrating superior efficacy and favorable cosmetic outcomes for superficial BCCs. However, it shows limited treatment effectiveness for deep-seated tumors. Most of the current literature focuses on the combination of surgery and postoperative PDT, while no studies have reported on the use of standard surgical excision with intraoperative margin pathological monitoring and immediate PDT. Therefore, we implemented a treatment protocol combining surgery and immediate PDT. Accordingly, this paper aimed to explore the effectiveness, cosmetic outcomes, and other relevant advantages of this therapeutic approach. METHODS: We aimed to evaluate this approach in seven patients with BCC on the nose and ears. Standard surgical excision of skin lesions was performed, with intraoperative frozen section examination of the margins, followed by immediate postoperative PDT for the wounds, and continued periodic PDT during the second phase of wound healing. RESULTS: All seven cases demonstrated significant improvement. The cosmetic rating was 100 % and no cases of recurrence existed among the seven patients. CONCLUSIONS: This approach effectively minimized the surgical wound, improved tumor clearance, achieved precise therapeutic effects, and reduced the recurrence rate. Moreover, it produced favorable cosmetic outcomes.

Terbinafine Induced Acute Generalized Exanthematous Pustulosis Treated with Adalimumab: Recalcitrant to Systemic Corticosteroid Therapy.

Acute generalized exanthematous pustulosis (AGEP) is generally caused by drugs and is characterized by the rapid development of numerous non-follicular sterile pustules on an erythematous base, fever, and neutrophilia. We report an association between terbinafine, with AGEP, and adalimumab treatment. A 24-year-old teenage female patient with a history of onychomycosis was treated with terbinafine. On the second day of the first dose, multiple edematous and erythematous lesions appear with pinhead pustules. Neutrophilia was observed in the blood report. The clinical history, lesions, and laboratory evaluations were consistent with AGEP. We discontinued the terbinafine therapy, and the systemic corticosteroid was initiated; however, the patient's condition worsened. Adalimumab subcutaneously was initiated, and the symptoms cleared up in weeks. The European Study of Severe Cutaneous Adverse Reactions (EuroSCAR) scoring system and Naranjo's algorithm scale were used to check the possibility of a drug-induced adverse reaction. The Association of AGEP with the terbinafine drug is not rare. However, there are no reports or literature of drug-related rash or exanthematous eruptions unresponsive to corticosteroids and treated with adalimumab.

SAPHO Syndrome with Palmoplantar Pustulosis as the First Manifestation Successfully Treated with Adalimumab.

Introduction: Synovitis-acne-pustulosis-hyperostosis-osteitis (SAPHO) syndrome is an acronym for synovitis, pustulosis, acne, hyperostosis, and osteitis, and clinically manifests as dermatological and musculoskeletal damage. Two major manifestations that co-occur in a single patient are rare. Methods/Results: This literature describes a 44-year-old male affected by SAPHO syndrome, whose first manifestation was palmoplantar pustulosis (PPP). Symptomatic treatments such as anti-inflammatory and analgesics did not work well for him. Adalimumab provided noteworthy improvement in the neck and thoracic back pain improvement after two weeks. The palmoplantar pustules were alleviated after four weeks. Conclusion: The literature on SAPHO syndrome therapy is increasing. Thus, adalimumab is a novel therapeutic agent. This report demonstrates the efficiency of adalimumab in SAPHO syndrome.

A rare case of condyloma acuminatum caused by HPV73 and HPV33 infection.

Condyloma acuminatum (CA) is a sexually transmitted disease caused by human papillomavirus (HPV) infection, mainly by HPV DNA types 6 and 11. Except for HPV16 and HPV18, CA caused by other intermediate or high-risk subtypes is rare in clinical settings. Here, we report a case that was positive for HPV73 and 33 and negative for other common subtypes. This case highlights that caution should be taken in cases that are negative for common HPV subtypes but have typical clinical manifestations. That the detection of other subtypes and tissue biopsy should not be ignored.

Mitochondrial-Targeted Antioxidant Peptide SS31 Prevents RPE Cell Death under Oxidative Stress.

This work aims at investigating the protective effects of the mitochondria-targeted peptide SS31, on mitochondria function, preventing human retinal pigment epithelial cell-19 (ARPE-19) cell apoptosis. The ARPE-19 cells were subjected to 24 h of intervention with H2O2 of various concentrations (0, 100, 150, 200, 250, 300, and 500 µmol/L). Various concentrations of SS31 (10 nM, 100 nM, and 1 µmol/L) pretreated the cells for 2 h. The MTT assay determined cell viability. ARPE-19 cell apoptosis was observed by 4',6-diamidino-2-phenylindole (DAPI) staining under fluorescence microscope and detected by Annexin-V/PI staining under flow cytometry. The measurement of reactive oxygen species (ROS) release level used MitoSOX Red (a mitochondrial superoxide indicator) and the probe 2'-7'dichlorofluorescin diacetate (DCFH-DA). And with the use of a JC-1 probe, the mitochondrial membrane potential (MMP; ΔΨm) was analyzed. Reverse transcription polymerase chain reaction (RT-PCR) and real-time PCR were responsible for measuring the levels of apoptosis related genes (Bcl-2, Bax, and Caspase-3). The cell viability increased significantly with SS31 pretreated (P < 0.05). In the SS31 + H2O2 group, the fluorescence of the cell nuclei with DAPI staining was weaker than H2O2 along group accordance with the decreased ratio of apoptotic cells (P < 0.05). The ROS generation decreased in SS31 pretreated group, with the increased ΔΨm. The RT-PCR result showed decreased Bax gene and Caspase-3 gene expression with SS31 pretreatment, while increased antiapoptotic gene Bcl-2 (P < 0.05). We provide evidence that SS31 promotes resilience of RPE cells to oxidative stress by stabilizing mitochondrial function.

Modified Trabeculectomy versus Glaucoma Drainage Implant Surgery: A Retrospective Comparative Study for Refractory Glaucoma Treatment.

Purpose: To observe and compare the efficacy of modified trabeculectomy (TE), Ahmed drainage valve implantation (AGV), and EX-PRESS glaucoma shunt for refractory glaucoma (RG). Methods: The study population of this retrospective study comprised 73 patients (76 eyes) who were suffering from RG and treated with modified TE, AGV, and EX-PRESS glaucoma shunt in our hospital from October 2012 to October 2020. The number of cases who underwent modified TE, AVG, and EX-PRESS glaucoma shunt was 36 (38 eyes). 19 (20 eyes), and 18 patients (18 eyes), respectively. The intraocular pressure (IOP), best-corrected visual acuity (BCVA), postoperative antiglaucoma medications, filter bubble morphology, anterior chamber depth (ACD), successful rate, and postoperative complications were recorded and statistically analyzed preoperative and 1 d, 1 w, 1 mon, 3 mon, 6 mon, and the end follow-up after operation. Results: The BCVA differed insignificantly among the three cohorts before and 6 months after surgery. Compared to preoperative BCVA, the postoperative BCVA of the three groups had no statistical significance. An obvious reduction in IOP was observed in all the three group after operation (P < 0.05). An obvious decrease in antiglaucoma medications was observed after surgery in all the three groups (P < 0.05). The AGV group showed deeper ACD postoperatively, while no marked difference was found in postoperative ACD in the other two groups. The total success rates in modified TE and AGV groups were slightly higher than those in the EX-PRESS group. The three groups differed insignificantly in filter bubble morphology after operation. Conclusion: Modified TE, AGV, and EX-PRESS glaucoma shunt showed equivalent efficacy for RG, which could validly reduce IOP and postoperative antiglaucoma medications. However, the success rates of modified TE and AGV were slightly higher than those of EX-PRESS glaucoma shunt in the last follow-up, and their complications were slightly less than those of the EX-PRESS glaucoma shunt.

Cryotherapy combined with photodynamic therapy for successful treatment of condyloma acuminatum in special sites such as the nipple and the nasal vestibule: A series of two case reports.

Condyloma acuminatum is a benign tumor principally resulting from a human papillomavirus type 6 or 11 infection. The lesions mostly damage the genital and perianal squamous epithelium and skin but occasionally emerge outside the perianal and genital regions. We studied the cases of a 29-year-old man with left nasal vestibule vegetation and a 22-year-old woman with left nipple vegetation. Each was diagnosed with condyloma acuminatum by histopathological examination and a human papillomavirus DNA test. The two patients received cryotherapy combined with 5-aminolevulinic acid photodynamic therapy and experienced no relapses during follow-up. These results suggest that physicians cannot ignore condyloma acuminatum outside the perianal and genital regions during diagnosis and treatment. Additionally, cryotherapy combined with 5-aminolevulinic acid photodynamic therapy is not only safe and effective for the treatment of condyloma acuminatum in special sites, but it is also less destructive to the affected regions. Thus, cryotherapy combined with 5-aminolevulinic acid photodynamic therapy may have more advantages than traditional therapy in the treatment of condyloma acuminatum in special sites.

A new option for the treatment of condyloma acuminatum in the male urethra: Multimodal ultrasound image-guided scraping and photodynamic therapy (USP).

OBJECTIVES: Condyloma acuminatum (CA) is a sexually transmitted disease with a high recurrence rate due to the rapid replication of human papillomavirus (HPV) and its subtle immune escape mechanism, which makes the diagnosis and treatment of CA in the male urethra particularly difficult. This study aims to evaluate the efficacy of comprehensive treatments for male urethral CA after accurate localization of warts under ultrasound guidance. METHODS: The study included 15 men with intraurethral CA. Before treatment, the urethra was examined by ultrasonography and HPV-PCR. After examination of the invisible urethral warts, wart curettage (penetrating operation with a special stainless steel medical curettage tool) combined with ALA-PDT was used for treatment. The ultrasound and HPV load were reviewed 1 week after treatment, and again at 1, 3, and 6 months after treatment. RESULTS: All patients achieved satisfactory results 1 week after the last treatment. The viral load of human papilloma was significantly reduced or turned negative, ultrasound imaging exploration showed no neoplasm in the urethra, and no obvious intraoperative or postoperative complications were observed. The side effects in patients included a mild burning or tingling sensation confined to the treated area. After a 6 month follow-up period, only 2 patient relapsed. CONCLUSION: The combined diagnosis and treatment of CA in the male urethra under the guidance of multi-mode ultrasound imaging is an effective, economical, safe, and well-tolerated treatment method.

Perioperative Management and Long-Term Outcomes in Ocular Cicatricial Pemphigoid Patients Undergoing Cataract Surgery.

Objective: To observe the outcomes of cataract surgery in ocular cicatricial pemphigoid (OCP) patients and explore routine perioperative medical treatments. Design: Retrospective case series. Methods: Fourteen eyes of 8 patients were included in the study. Foster's stage 1-4 OCP patients were given human intravenous immunoglobulin, whereas patients with active inflammation were treated with prednisone tablets and methotrexate. Those who were intolerant to methotrexate and had severe inflammatory symptoms were treated with cyclophosphamide. Cataract surgery was performed for all patients after three months of systemic treatment under stable conditions. The conjunctival biopsy was evaluated by immunofluorescence microscopy. Then, patients were divided into individuals with or without ankyloblepharon. Records were reviewed for OCP stage, type of surgery, best-corrected visual acuity (BCVA), Schirmer I test, corneal fluorescein sodium staining, meibomian gland coloboma range, and ocular surface disease index (OSDI) scores. Follow-up was for the duration of taking topical and systemic medication. Results: Nine female (64.29%) and 4 male (35.71%) eyes were diagnosed with OCP by biopsy. The mean follow-up time was 60.64 ± 35.62 months. Thirteen eyes (92.86%) of 7 patients underwent phacoemulsification. One eye underwent phacoemulsification combined with amniotic membrane transplantation. The intracapsular extraction of cataract was applied to one eye. The BCVA improved significantly in all the patients, which remained stable until the last follow-up. The Schirmer I test was higher than that before the surgery. Corneal fluorescein sodium staining after surgery showed a decrease in score compared to the preoperative score. The BCVA of the patients after surgery increased significantly. The OSDI scores of patients with ankyloblepharon were significantly higher than for those without it. Postoperative symblepharon showed no significant difference compared to the preoperative symblepharon. Conclusions: In this series, OCP patients with cataracts were able to undergo phacoemulsification surgery, whereas routine use of immunosuppression and closed postoperative follow-up were necessary.

Efficacy and safety of 177Lu­DOTATATE in patients with advanced pancreatic neuroendocrine tumours: data from the NETTER-R international, retrospective study.

PURPOSE: NETTER-R aimed to determine the efficacy, safety and tolerability of 177Lu-DOTATATE in patients with progressive, advanced pancreatic neuroendocrine tumours (panNETs) using retrospective real-world data from multiple sites. METHODS: This international study retrospectively included patients with panNETs treated with 177Lu-DOTATATE. The primary endpoint was progression-free survival (PFS) by Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1). Secondary endpoints included overall survival (OS), safety and tumour response. RESULTS: In total, 110 patients with panNETs were studied; 65.5% received a cumulative dose of 177Lu-DOTATATE 29.6 GBq ± 10% (median: 7.4 GBq). In 62 patients with available RECIST v1.1 tumour response, the median PFS was 24.8 months (95% confidence interval [CI]: 17.5-34.5), and the objective response rate was 40.3% (95% CI: 28.1-53.6); all responses were partial. With a median follow up of 24.5 months (range: 2.0-123.4 months) after the first cycle of 177Lu-DOTATATE, the median OS in the full analysis set (n = 110) was 41.4 months (95% CI: 28.6-50.2). PFS (hazard ratio [HR]: 3.672; p = 0.0009) and OS (HR: 3.360; p < 0.0001) were longer in patients who received no chemotherapy prior to 177Lu-DOTATATE than those who did. No treatment-emergent adverse events (TEAEs) led to treatment discontinuation. Grade 3 anaemia, lymphopenia and thrombocytopenia occurred in 0.9%, 5.4% and 0.9% of patients, respectively. No acute leukaemia or myelodysplastic syndrome was reported. Six patients (5.5%) had renal TEAEs. All renal grade ≥ 3 events were transient and did not lead to treatment modification. CONCLUSIONS: These results reinforce the role of 177Lu-DOTATATE for the treatment of patients with advanced, somatostatin receptor-positive panNETs.

Preparation of Targeted Mitochondrion Nanoscale-Release Peptides and Their Efficiency on Eukaryotic Cells.

We established a self-decomposable SiO2 encapsulated mitochondrial targeting short peptide SS31 drug loading system (SiO2@SS31) to determine its nano-sustained release characteristics in eukaryotic cells. We explored the protection of SiO2@SS31 on the 661W cells after oxidative injury by H2O2. After the drug loading, we detected the morphology of SiO2@SS31 by transmission electron microscopy (TEM). Moreover, high-pressure liquid chromatography (HPLC) was used to determine the drug capacity and encapsulation efficiency of the nanoparticles. Then, the release curve in vitro was drawn. The 661W cells were cultured in vitro to allow the detection of cytotoxicity by the MTT assay. The SS31loaded nanoscale microspheres labeled with fluorescein isothiocyanate (SiO2@FITC-SS31) were prepared, and their sustained release effect was detected with intracellular endocytosis, using confocal microscopy and flow cytometry. Within 15 days, the SiO2@SS31 nanoparticles were completely decomposed and simultaneously released the SS31 peptide in deionized water and normal saline. Nonetheless, the process was faster in simulated body fluid and serum. The MTT assay suggested that SiO2@SS31 has sustained protection compared with SS31 in the 661W cells at 48 h. Flow cytometry proved SiO2@FITC-SS31 could maintain a high level and last longer after 24 h. The SS31 peptide, which has excellent medical application prospects, can be slowly and continuously released from self-decomposable SiO2 and targeted to concentrate on mitochondria.

Safety of PSMA-Targeted Molecular Radioligand Therapy with 177Lu-PSMA-617: Results from the Prospective Multicenter Phase 2 Trial RESIST-PC (NCT03042312).

The purpose of this analysis was to report the safety evaluation of 177Lu-PSMA-617 derived from the cohort of 64 patients exposed to 177Lu-PSMA-617 in the RESIST-PC trial NCT03042312 Methods: RESIST-PC was a prospective multicenter phase 2 trial. Patients with progressive metastatic castration-resistant prostate cancer after ≥ 1 novel androgen-axis drug, either chemotherapy naïve or postchemotherapy, with sufficient bone marrow reserve, normal kidney function, sufficient PSMA expression by PSMA PET, and no PSMA-negative soft-tissue lesions were eligible. Patients were randomized (1:1) into 2 activity groups (6.0 or 7.4 GBq per cycle) and received up to 4 cycles every 8 wk. The primary safety endpoint was assessed by collecting and grading adverse events using the Common Terminology Criteria for Adverse Events. Patients were followed until disease progression, death, serious or intolerable adverse events, study termination by sponsor, patient withdrawal, lost to follow-up, or 24 mo after the first cycle. Results: The study was closed at enrollment of 71 of 200 planned patients because of sponsorship transfer. A total of 64 (90.1%) patients received at least 1 cycle of 177Lu-PSMA-617: 28 (36%) in arm 1 (6.0 GBq) and 41 (64%) in arm 2 (7.4 GBq). There were 10 (43.5%), 19 (46.5%), and 29 (45.3%) patients who completed 4 cycles of 177Lu-PSMA-617 in the 6.0-GBq arm, 7.4-GBq arm, and overall, respectively. The most common treatment-emergent adverse events (TEAEs) of any grade in the 6.0-GBq arm, the 7.4-GBq arm and overall, were dry mouth (47.8%; 63.4%; 57.8%, respectively), fatigue (56.5%; 51.2%; 53.1%, respectively), nausea (52.2%; 43.9%; 46.9%, respectively), and diarrhea (13.0%; 31.7%; 25.0%, respectively). Frequencies of all other TEAEs were comparable among the 2 groups (within 10% difference). Serious possibly drug-related TEAEs were reported for 5 (7.8%) patients overall (none were considered as probably or definitely related to treatment): 1 subdural hematoma grade 4, 1 anemia grade 3, 1 thrombocytopenia grade 4, 1 gastrointestinal hemorrhage grade 3, and 1 acute kidney injury grade 3. There were no clinically significant changes in vital signs in electrocardiograms in the 2 treatment groups. No trend to creatinine increase or increasing frequency of shifts from normal to abnormal over time for any hematologic parameter was noted. Conclusion:177Lu-PSMA-617 was safe and well-tolerated at 6.0 and 7.4 GBq per cycle given at 8-wk intervals with side effects easily managed with standard medical support. With established safety, further clinical trials applying individualized dosimetry and testing different 177Lu-PSMA-617 administration schemes (activity levels, time intervals) are needed to optimize tumor dose delivery and treatment efficacy.

Synthesis, Characterization, and Specific Localization of Mitochondrial-Targeted Antioxidant Peptide SS31 Probe.

The aim of this study is to investigate the targeting efficiency of FITC-SS31 to mitochondria in both normal and H2O2-induced oxidative damaged 661W cells, characterizing the properties of FITC-SS31 in the biological assays. The purity and molecular weight of FITC-SS31 were identified using HPLC and MS. MTT and LDH assays were used to evaluate the cytotoxicity and cell permeability. The binding ability of FITC-SS31 to cells was demonstrated by flow cytometry. The colocalization of FITC-SS31 and MitoTracker both in normal and oxidative cells was analyzed by a laser confocal microscope. We detected the DEGs between SS31+H2O2 and H2O2-alone-treated cells by RNA seq. GO and KEGG analyses were performed to predict the functional gene of SS31. The molecular weight of FITC-SS31 was 1142.2 with the 97.76% purity. The flow cytometry results showed that the MFI (mean fluorescence intensity) of FITC-SS31 in normal cells in the 4 h probe treatment group was higher than that in the 2 h and the 0 h group. The MFI in the 2 h probe treatment group was much higher than that in the 4 h and 0 h groups in damaged cells. The positive rate of 10 µM FITC-SS31 was higher than that of 1 µM and 5 µM. Fluorescein imaging analysis confirmed that FITC-SS31 was overlapped with MitoTracker. Through the analysis, DEGs were highly expressed in "localization, organelle, antioxidant activity, binding" functions and enriched in "AMPK signaling pathway, MAPK targets/nuclear events mediated by MAP kinase pathway and PI3K-Akt signaling pathway." It is speculated that SS31 exerts an antioxidant effect through one of these pathways. We hypothesized that SS31 could play a more efficient role in the pathological cells in the half-life period to avoid cell death due to oxidative damage. The functions of the DEGs in SS31+H2O2 and H2O2-alone samples are related to the localization and antioxidant activity of SS31. DEGs are mostly enriched in the AMPK signaling pathway, which needs further studies.

Protective Effect of Mitochondrially Targeted Peptide Against Oxidant Injury of Cone Photoreceptors Through Preventing Necroptosis Pathway.

Retinopathy is an eye disease caused by the death of retinal cells in the macular area and the surrounding choroid. As the retinal rod cell dysfunction and death lead to the loss of night vision, the disease will lead to visual dysfunction and blindness as the disease progresses. Because of the irreversible nature of cell death, gene therapy has become a research hotspot in the field of retinopathy. But the technology is still in animal studies or clinical trials, and more research is needed to prove its feasibility. In this study, oxidative damage cell model was established and divided into a control group, H2O2 group, SS31 +NEC1 group, SS31 +H2O2 group, and SS31 +NEC1 +H2O2 group, for different interventions. The cell survival rate of the H2O2 group was significantly increased compared with those of the SS31 + H2O2 group, SS31 +NEC1 +H2O2 group, and NEC1 +H2O2 group. Nec1 combined treatment significantly reduced reactive oxygen species (ROS) production compared with that in the H2O2 group. The level of MDA in the SS31 group, Nec-1 group and combined treatment of SS31 +NEC1 group decreased significantly compared with the H2O2 group. The proportion of cells with decreased mitochondrial membrane potential in the H2O2 group significantly increased, and the rate of positivity for propidium iodide (PI) of 661W cells in the H2O2 group and the control group significantly increased. Nine hours after H2O2 treatment of 661W cells, the RIP3 expression level began to increase, and peaked at 24 h. The level of RIP3 in the H2O2 group was significantly increased, while this level was downregulated in the SS31 and NEC1 treatment groups. Therefore, this study suggests that SS31 has a partial protective effect on 661W cells by inhibiting necrosis, which has certain guiding significance for the treatment of retinal diseases.

Clinical outcome of phacoemulsification combined with intraocular lens implantation for primary angle closure/glaucoma (PAC/PACG) with cataract.

OBJECTIVE: To evaluate the efficacy of phacoemulsification (Phaco) combined with intraocular lens implantation for treatment of primary angle-closure glaucoma (PACG) patients with cataract. METHODS: A total of 62 patients treated in our hospital meeting the inclusion criteria were included, including 62 eyes (26 PAC eyes and 36 PACG eyes). PACG patients were divided into early, middle, and advanced stages based on the HPA visual field staging system. The subjects were also grouped according to the extent of peripheral anterior synechia (PAS). Patients received topical medical treatment preoperatively and Phaco performed by the same surgeon. The visual acuity, intraocular pressure (IOP), anterior chamber depth (ACD), medication used, visual field and retinal nerve fiber layer (RNFL) were observed before and 6-24 months after surgery. RESULTS: The mean age of the patients was 68±8.91 years old, and postoperative follow-up was 13.1±5.5 months. Postoperative visual acuity was improved in all patients (P<0.001). Postoperatively, the IOP decreased significantly (P<0.001), the number of medications was reduced (P<0.001), and the ACD was deeper than that before operation (P<0.001). There was no significant difference in visual field (P=0.973) or RNFL (P=0.268) after surgery during the follow-up. There was no statistical difference in postoperative changes of various indexes between PAC and PACG patients. The decrease of IOP in patients with early stage PACG was significantly higher than that in patients in the middle and advanced stages (F=3.519, P=0.041), and the number of medications used in early-stage PACG patients was also significantly lower than that of advanced patients (P=0.020). There was no significant difference in postoperative visual acuity (X2=0.139, P=0.987) or IOP decline (F=0.260, P=0.854) among patients with different extents of preoperative PAS, nor was there any correlation between postoperative IOP control and preoperative PAS. No serious complications were observed in any subject. CONCLUSION: In PAC/PACG patients, Phaco can significantly control IOP, and prevent visual field defect and progressive loss of RNFL, indicating that the procedure has a protective effect on the optic nerve. Phaco is more effective in the treatment of early stage PACG than in middle or advanced stage, and can be used in PAC/PACG patients with different extents of PAS, but close follow-up is necessary.

The Mitochondrial-Targeted Peptide, SS31, Protects Murine 661W Cells from Oxidative Damage via Induction of Autophagy.

The goal of this study was to examine the impact of the mitochondrial-targeted antioxidant peptide, SS31, and its role in promoting autophagy in cone photoreceptor 661W cells that were subjected to oxidative damage. To do so, we examined the viability of 661W cells in the presence of increasing concentrations of H2O2 with or without SS31 pre-treatment using the MTT assay and by expression of autophagy and apoptosis-associated proteins LC3-II/I, P62, and caspase-3. Autophagy was evaluated by fluorescence microscopy in cells stained with monodansyl cadaverine (MDC). Autophagy was induced with rapamycin (Rap) and inhibited with bafamycin A1 (bafA1) followed by examination of Reactive oxygen species (ROS) levels in target 661W cells by fluorescence microscopy and flow cytometry. Annexin V/PI staining was used to evaluate the rate of apoptosis and mRNA sequencing (mRNA-seq) analysis (Illumina platform) was performed on H2O2-exposed 661W cells treated with SS31. Among our results, we observed a substantial and concentration-dependent decrease in 661W cell viability in response to H2O2-exposure; production of ROS, autophagy and apoptosis were induced at 8 h in response to exposure to 100 µM of H2O2. Pre-treatment with 100 nM SS31 resulted in significant attenuation of H2O2-mediated cytotoxicity, together with reduced ROS production and enhanced autophagy observed in response to oxidative stress. Both Rap and bafA1 were used to modulate SS31-mediated autophagy; the impact of Rap was similar to that of SS31. By contrast, administration of bafA1 counteracted autophagy induced by SS31. Furthermore, mRNAseq analysis revealed that SS31 promoted significant alterations in gene expression in 661W cells and suggested that autophagy was induced via the mTORC1-mediated signaling. In conclusion, our results indicate that exposure to H2O2 resulted in reduced 661W cell viability via mechanisms associated with oxidative damage, apoptosis, and autophagy. Notably, we demonstrated that pre-treatment with SS31 protects 661W cells from H2O2-induced oxidative damage that may result in part from induction of autophagy via mTORC1-mediated signaling pathways.

Impact of liver tumour burden, alkaline phosphatase elevation, and target lesion size on treatment outcomes with 177Lu-Dotatate: an analysis of the NETTER-1 study.

PURPOSE: To assess the impact of baseline liver tumour burden, alkaline phosphatase (ALP) elevation, and target lesion size on treatment outcomes with 177Lu-Dotatate. METHODS: In the phase 3 NETTER-1 trial, patients with advanced, progressive midgut neuroendocrine tumours (NET) were randomised to 177Lu-Dotatate (every 8 weeks, four cycles) plus octreotide long-acting release (LAR) or to octreotide LAR 60 mg. Primary endpoint was progression-free survival (PFS). Analyses of PFS by baseline factors, including liver tumour burden, ALP elevation, and target lesion size, were performed using Kaplan-Meier estimates; hazard ratios (HRs) with corresponding 95% CIs were estimated using Cox regression. RESULTS: Significantly prolonged median PFS occurred with 177Lu-Dotatate versus octreotide LAR 60 mg in patients with low (< 25%), moderate (25-50%), and high (> 50%) liver tumour burden (HR 0.187, 0.216, 0.145), and normal or elevated ALP (HR 0.153, 0.177), and in the presence or absence of a large target lesion (diameter > 30 mm; HR, 0.213, 0.063). Within the 177Lu-Dotatate arm, no significant difference in PFS was observed amongst patients with low/moderate/high liver tumour burden (P = 0.7225) or with normal/elevated baseline ALP (P = 0.3532), but absence of a large target lesion was associated with improved PFS (P = 0.0222). Grade 3 and 4 liver function abnormalities were rare and did not appear to be associated with high baseline liver tumour burden. CONCLUSIONS: 177Lu-Dotatate demonstrated significant prolongation in PFS versus high-dose octreotide LAR in patients with advanced, progressive midgut NET, regardless of baseline liver tumour burden, elevated ALP, or the presence of a large target lesion. Clinicaltrials.gov : NCT01578239, EudraCT: 2011-005049-11.

Integration of genomic, transcriptomic and proteomic data identifies two biologically distinct subtypes of invasive lobular breast cancer.

Invasive lobular carcinoma (ILC) is the second most frequently occurring histological breast cancer subtype after invasive ductal carcinoma (IDC), accounting for around 10% of all breast cancers. The molecular processes that drive the development of ILC are still largely unknown. We have performed a comprehensive genomic, transcriptomic and proteomic analysis of a large ILC patient cohort and present here an integrated molecular portrait of ILC. Mutations in CDH1 and in the PI3K pathway are the most frequent molecular alterations in ILC. We identified two main subtypes of ILCs: (i) an immune related subtype with mRNA up-regulation of PD-L1, PD-1 and CTLA-4 and greater sensitivity to DNA-damaging agents in representative cell line models; (ii) a hormone related subtype, associated with Epithelial to Mesenchymal Transition (EMT), and gain of chromosomes 1q and 8q and loss of chromosome 11q. Using the somatic mutation rate and eIF4B protein level, we identified three groups with different clinical outcomes, including a group with extremely good prognosis. We provide a comprehensive overview of the molecular alterations driving ILC and have explored links with therapy response. This molecular characterization may help to tailor treatment of ILC through the application of specific targeted, chemo- and/or immune-therapies.

NormaCurve: a SuperCurve-based method that simultaneously quantifies and normalizes reverse phase protein array data.

MOTIVATION: Reverse phase protein array (RPPA) is a powerful dot-blot technology that allows studying protein expression levels as well as post-translational modifications in a large number of samples simultaneously. Yet, correct interpretation of RPPA data has remained a major challenge for its broad-scale application and its translation into clinical research. Satisfying quantification tools are available to assess a relative protein expression level from a serial dilution curve. However, appropriate tools allowing the normalization of the data for external sources of variation are currently missing. RESULTS: Here we propose a new method, called NormaCurve, that allows simultaneous quantification and normalization of RPPA data. For this, we modified the quantification method SuperCurve in order to include normalization for (i) background fluorescence, (ii) variation in the total amount of spotted protein and (iii) spatial bias on the arrays. Using a spike-in design with a purified protein, we test the capacity of different models to properly estimate normalized relative expression levels. The best performing model, NormaCurve, takes into account a negative control array without primary antibody, an array stained with a total protein stain and spatial covariates. We show that this normalization is reproducible and we discuss the number of serial dilutions and the number of replicates that are required to obtain robust data. We thus provide a ready-to-use method for reliable and reproducible normalization of RPPA data, which should facilitate the interpretation and the development of this promising technology. AVAILABILITY: The raw data, the scripts and the normacurve package are available at the following web site: http://microarrays.curie.fr.