Self-Assembly of the Porphyrin Monomer on the Surface of Fe/Graphene Material: a Novel Sensing Material for the Detection of Chloramphenicol Antibiotic in Aqueous solution.

Currently, electrochemical sensors are being developed and widely used in various fields, and new materials are being explored to enhance the precision and selectivity of the sensors. The present investigation involved the fabrication of a Fe/graphene/porphyrin nanocomposite through self-assembly, wherein the individual porphyrin molecules were arranged on the Fe/graphene nanomaterials' surface. The Fe/graphene nanoparticles were synthesized utilizing a green approach, wherein leaf extract was employed as the reducing agent. The resulting materials underwent comprehensive characterization using a range of contemporary techniques, including scanning electron microscopy (SEM), X-ray diffraction (XRD), Fourier-transform infrared spectroscopy (FTIR), and Raman spectroscopy. The study's findings revealed that the nanocomposites of Fe/graphene/porphyrin comprised zero-valent iron nanoparticles, exhibiting an average particle size ranging from 15 to 60 nm. These nanoparticles were seen to be evenly dispersed across the graphene sheets. The presence of nanostructure porphyrin nanofibers, measuring 20 nm in diameter, was also shown to exhibit strong integration with the surface of the Fe/graphene nanomaterials. The electrochemical properties of the Fe/graphene/porphyrin nanocomposite were also investigated, demonstrating that the prepared material could be effectively employed as a sensing electrode in the electrochemical sensor for detecting Chloramphenicol (CAP) through CV, EIS, and DPV techniques using a three-electrode electrochemical system. Under optimal conditions, Fe/graphene/porphyrin exhibited a high current response when detecting CAPs. Electrochemical sensors created using Fe/graphene/porphyrin nanocomposite have high stability and repeatability, and they hold promise in developing sensors capable of identifying other antibiotic residues in agriculture.

A Phase II Trial of Selinexor (KPT-330) for Metastatic Triple-Negative Breast Cancer.

LESSONS LEARNED: Single-agent selinexor has limited activity in heavily pretreated patients with metastatic triple-negative breast cancer.Selinexor 60 mg by mouth twice weekly was generally well tolerated with a side-effect profile consistent with previous clinical trials.Future studies of selinexor in this population should focus on combination approaches and a biomarker-driven strategy to identify patients most likely to benefit. BACKGROUND: This phase II trial evaluated the safety, pharmacodynamics, and efficacy of selinexor (KPT-330), an oral selective inhibitor of nuclear export (SINE) in patients with advanced triple-negative breast cancer (TNBC). METHODS: This phase II trial was designed to enroll 30 patients with metastatic TNBC. Selinexor was given at 60 mg orally twice weekly on days 1 and 3 of each week, three of each 4-week cycle. The primary objective of this study was to determine the clinical benefit rate (CBR), defined as complete response + partial response + stable disease (SD) ≥12 weeks. RESULTS: Ten patients with a median age of 60 years (range 44-71 years) were enrolled between July 2015 and January 2016. The median number of prior chemotherapy lines was 2 (range 1-5). A planned interim analysis for the first stage per protocol was performed. Three patients had SD and seven had progressive disease. On the basis of these results and predefined stoppage rules, the study was halted. CONCLUSION: Selinexor was fairly well tolerated in patients with advanced TNBC but did not result in objective responses. However, clinical benefit rate was 30%, and further investigation of selinexor in this patient population should focus on combination therapies.

Rigor prophylaxis in stage IV melanoma and renal cell carcinoma patients treated with high dose IL-2.

BACKGROUND: Rigors are a significant adverse event during interleukin-2 (IL2) therapy for metastatic melanoma and renal cell carcinoma. Meperidine has been a mainstay for rigor prophylaxis but there is a paucity of data regarding possible alternatives. METHODS: Ninety one patients receiving IL2 therapy for metastatic renal cell carcinoma and melanoma at Huntsman Cancer institute (HCI), Utah from May 2009 to October 2016 were retrospectively evaluated for rigor prophylaxis. Forty two patients received meperidine and 49 received tramadol. Rigors were tabulated using the proxy of number of doses of as needed (PRN) rigor medications and normalized by IL2 doses. Other outcomes of fever, hypotension, and renal insufficiency were noted on a binary scale and normalized by cycles. Statistical analysis was performed utilizing univariate and multivariate negative binomial models. RESULTS: Ninety one patients were identified with metastatic melanoma or RCC who received high dose IL2 therapy. Forty two received meperidine and 49 received tramadol prophylaxis for rigors. Univariate negative binomial analysis shows incidence rate ratios (IRR): fever 0.41 (95% CI 0.28-0.62, p-value < 0.001), hypotension 1.7 (95% CI 1.11-2.61, p-value 0.015), renal insufficiency 0.58 (95% CI 0.35-0.98, p-value 0.041), rigors per all PRN meds 1.01 (95% CI 0.79-1.28, p-value 0.964), and rigors via opioid PRN meds 0.85 (95% CI 0.67-1.07, p-value 0.168). Multivariate negative binomial analysis shows IRR: fever 0.59 (95% CI 0.28-1.24, p-value 0.163), hypotension 0.93 (95% CI 0.43-2.03, p-value 0.864), renal insufficiency 1.1 (95% CI 0.52-2.32, p-value 0.807), rigors per al PRN meds 0.92 (95% CI 0.67-1.26, p-value 0.604), and rigors via opioid PRN 0.9 (95% CI 0.65-1.26, p-value 0.554). CONCLUSION: Univariate models indicated meperidine pre-treatment was associated with significantly lower rates of fever and renal insufficiency whereas tramadol was associated with significantly lower rate of hypotension. However, when controlled for demographics and other treatment differences, these differences were no longer significant.

miR-125b functions as a key mediator for snail-induced stem cell propagation and chemoresistance.

Chemoresistance is a major obstacle in cancer treatment. Our previous studies have shown that miR-125b plays an important role in chemoresistance. Here we report a novel mechanism that up-regulation of miR-125b through Wnt signaling by Snail enriches cancer stem cells. Overexpression of Snail dramatically increases the expression of miR-125b through the Snail-activated Wnt/ß-catenin/TCF4 axis. Snail confers chemoresistance by repressing Bak1 through up-regulation of miR-125b. Restoring the expression of Bak1 or depleting miR-125b re-sensitizes Snail-expressing cancer cells to Taxol, indicating that miR-125b is critical in Snail-induced chemoresistance. Moreover, overexpression of miR-125b significantly increases the cancer stem cell population (CD24-CD44+), while depletion of miR-125b or rescue of the expression of Bak1 increases the non-stem cell population (CD24+CD44+) in Snail-overexpressing cells. These findings strongly support that miR-125b functions as a key mediator in Snail-induced cancer stem cell enrichment and chemoresistance. This novel mechanism for Snail-induced stem cell propagation and chemoresistance may have important implications in the development of strategies for overcoming cancer cell resistance to chemotherapy.

Sentinel lymph node biopsy for melanoma in pregnant women.

BACKGROUND: The incidence of melanoma is rising in young women of childbearing age. Melanoma diagnosed during pregnancy presents unique challenges. This study was conducted to determine the effect of sentinel lymph node biopsy (SLNB) for melanoma on maternal and fetal outcomes in pregnant women. METHODS: A prospective melanoma database was retrospectively queried for women diagnosed with melanoma during or immediately before pregnancy as well as SLNB in pregnant women. The outcomes of SLNB for the mothers and fetuses were evaluated. RESULTS: Fifteen pregnant women underwent wide local excision (WLE) and SLNB for melanoma from 1997 to 2012. The median gestational age was 20 weeks. More than half of the women noticed changes in the primary melanoma lesion during the pregnancy. The median Breslow thickness was 1.00 mm. Lymphatic mapping and SLNB were performed with some combination of radiocolloid or vital blue dye without adverse effects. Three patients had micrometastatic disease and underwent a completion lymphadenectomy. Sixteen children were born at a median gestational age of 39 weeks. The median 1- and 5-minute Apgar scores were 8 and 9, respectively. At a median follow-up of 54.4, months none of the patients had experienced recurrence, and all children were healthy and free of melanoma. CONCLUSIONS: In this series of pregnant women with melanoma, SLNB was performed safely during pregnancy without adverse effects to the mothers and fetuses. We recommend that clinicians explain the risks and benefits of the SLNB procedure to pregnant women so an informed decision can be made about the procedure.

Oncolytic T-VEC virotherapy plus neoadjuvant chemotherapy in nonmetastatic triple-negative breast cancer: a phase 2 trial.

Talimogene laherparepvec (T-VEC) is an oncolytic virus hypothesized to enhance triple-negative breast cancer (TNBC) responses to neoadjuvant chemotherapy (NAC). This article describes the phase 2 trial of T-VEC plus NAC (ClinicalTrials.gov ID: NCT02779855 ). Patients with stage 2-3 TNBC received five intratumoral T-VEC injections with paclitaxel followed by doxorubicin and cyclophosphamide and surgery to assess residual cancer burden index (RCB). The primary end point was RCB0 rate. Secondary end points were RCB0-1 rate, recurrence rate, toxicity and immune correlates. Thirty-seven patients were evaluated. Common T-VEC toxicities were fevers, chills, headache, fatigue and injection site pain. NAC toxicities were as expected. Four thromboembolic events occurred. The primary end point was met with an estimated RCB0 rate = 45.9% and RCB0-1 descriptive rate = 65%. The 2-year disease-free rate is equal to 89% with no recurrences in RCB0-1 patients. Immune activation during treatment correlated with response. T-VEC plus NAC in TNBC may increase RCB0-1 rates. These results support continued investigation of T-VEC plus NAC for TNBC.

A Real-World Data Retrospective Cohort Study of Low Estrogen Receptor-Positive Early Breast Cancer: Natural History and Treatment Outcomes.

Purpose: Estrogen receptor-positive (ER+) breast cancer (BC) is a heterogeneous disease, and there is an ongoing debate regarding the optimal cut point for clinically relevant ER expression. We used a real-world database to assess the prognostic and predictive values of lower ER expression levels on treatment outcomes with endocrine therapy. Methods: We used a nationwide electronic health record database. Descriptive statistics were used to evaluate the association between ER expression, tumor characteristics, and treatment patterns among patients with early-stage BC. We used Kaplan-Meier survival curves to estimate recurrence-free survival (RFS) and overall survival (OS). We assessed associations between an alternative ER expression-level cut point and clinical outcomes. Results: Among 4697 patients with early-stage HER2-negative BC, 83 (2.04%) had ER+-low BC (ER expression, 1-9.99%) and 36 (0.88%) had ER+-intermediate BC (10-19.9%). ER+-low tumors were associated with higher tumor grade, larger size, and higher axillary tumor burden than ER+-high tumors (≥20% ER expression). African Americans had a higher prevalence of both triple-negative BC (TNBC) and ER+-low BC than ER+-high BC. Patients with ER+-low and ER+-intermediate tumors had survival outcomes similar to patients with TNBC and worse survival outcomes than patients with ER+-high tumors (P < 0.001). Tumors with <20% ER expression were associated with worse outcomes. Conclusion: In our cohort, patients with BCs with ER expression levels <20% had poor clinical outcomes similar to those of patients with TNBC.

Fatal Allograft Rejection and Cardiac Allograft Vasculopathy After Treatment With Pembrolizumab for Metastatic Melanoma in a Heart Transplant Recipient: A Case Report.

Checkpoint inhibitors decrease the progression of many cancers. However, the experience in immunosuppressed patients is limited, with reports of possible serious adverse events. We present a heart transplant recipient treated with pembrolizumab for metastatic melanoma who developed fatal rejection. The patient was a 29 year-old man who underwent heart transplantation at the age of 10 years for congenital heart disease. Seventeen years after transplant, he was diagnosed with scalp melanoma pT3a, N2a, M0, Stage IIIA, positive for BRAF V600E mutation treated with excision, which metastasized to his lungs and brain a year later. Dabrafenib and trametinib were started with transient response. Additional options and their risks were discussed, and pembrolizumab was started 4 months later due to the incomplete response to previous therapy. Five days after initiation the patient presented with moderate cellular rejection and possible antibody mediated rejection (ISHLT Grade 2R, pAMR 1H). Pembrolizumab was discontinued, and he was treated with steroids. Seven months later he presented in cardiogenic shock and severe coronary allograft vasculopathy. Biopsy was negative for cellular rejection, but suspicious for antibody mediated rejection (ISHLT Grade 0R, pAMR 1H), and he had a new serum alloantibody. Despite steroids and plasmapheresis he remained in refractory cardiogenic shock and died of cardiac arrest.

Elacestrant (oral selective estrogen receptor degrader) Versus Standard Endocrine Therapy for Estrogen Receptor-Positive, Human Epidermal Growth Factor Receptor 2-Negative Advanced Breast Cancer: Results From the Randomized Phase III EMERALD Trial.

PURPOSE: Patients with pretreated estrogen receptor (ER)-positive/human epidermal growth factor receptor 2 (HER2)-negative advanced breast cancer have poor prognosis. Elacestrant is a novel, oral selective ER degrader that demonstrated activity in early studies. METHODS: This randomized, open-label, phase III trial enrolled patients with ER-positive/HER2-negative advanced breast cancer who had one-two lines of endocrine therapy, required pretreatment with a cyclin-dependent kinase 4/6 inhibitor, and ≤ 1 chemotherapy. Patients were randomly assigned to elacestrant 400 mg orally once daily or standard-of-care (SOC) endocrine monotherapy. Primary end points were progression-free survival (PFS) by blinded independent central review in all patients and patients with detectable ESR1 mutations. RESULTS: Patients were randomly assigned to elacestrant (n = 239) or SOC (n = 238). ESR1 mutation was detected in 47.8% of patients, and 43.4% received two prior endocrine therapies. PFS was prolonged in all patients (hazard ratio = 0.70; 95% CI, 0.55 to 0.88; P = .002) and patients with ESR1 mutation (hazard ratio = 0.55; 95% CI, 0.39 to 0.77; P = .0005). Treatment-related grade 3/4 adverse events occurred in 7.2% receiving elacestrant and 3.1% receiving SOC. Treatment-related adverse events leading to treatment discontinuations were 3.4% in the elacestrant arm versus 0.9% in SOC. Nausea of any grade occurred in 35.0% receiving elacestrant and 18.8% receiving SOC (grade 3/4, 2.5% and 0.9%, respectively). CONCLUSION: Elacestrant is the first oral selective ER degrader demonstrating a significant PFS improvement versus SOC both in the overall population and in patients with ESR1 mutations with manageable safety in a phase III trial for patients with ER-positive/HER2-negative advanced breast cancer.

Activated CD4+ T cells dramatically enhance chemotherapeutic tumor responses in vitro and in vivo.

Chemoimmunotherapy has been widely studied in melanoma, with various degrees of success. One of the most common approaches is the so-called biochemotherapy, which is associated with increased toxicities, but without overall survival benefit. Another conventional strategy is the use of chemotherapy as an immunomodulator to enhance the effect of cancer vaccines or adoptive cell transfer therapy. Based on this approach, recent studies using chemotherapy to prepare the host before the infusion of ex vivo-activated, melanoma Ag-specific tumor-infiltrating lymphocytes and high dose IL-2 resulted in an impressive response rate. However, the development of immunotherapy for the treatment of a broad range of cancer type is still lacking. In this study, we report the development of a simple yet universal approach termed "chemocentric chemoimmunotherapy" that has potential application in the treatment of all cancer types. This technique uses nonspecifically activated CD4(+) T cells as a chemosensitizer before the administration of chemotherapy. Dramatic enhancement of the cytotoxic effect of chemotherapeutic drugs, either active or nonactive as single agents, was observed both in in vitro and in vivo human tumor xenograft models. Soluble factors secreted from activated CD4(+) T cells, likely acting on the tumor and its microenvironment, were responsible for the observed effect. Although IFN-gamma played a major role in the therapeutic outcome, it was consistently found to be inferior to the use of activated CD4(+) T cells in tumor chemosensitization. Our model may provide a plausible mechanism to facilitate further understanding, design and development of improved chemoimmunotherapy in the treatment of cancer.

Thrombotic Microangiopathy: A Rare Breast Cancer-associated Complication Treated Successfully With Doxorubicin and Cyclophosphamide.

BACKGROUND: Thrombotic microangiopathy (TMA) is a clinical syndrome consisting of hemolytic anemia, thrombocytopenia, and presence of schistocytes on peripheral blood smear secondary to disorders of systemic microvascular thrombosis. Malignancy-associated TMA is a rare entity and shares clinical features with that of HUS and TTP usually seen in patients with metastatic cancer, tumor cell infiltration of the bone marrow and/or response to cancer-directed therapy. CASE REPORT: We present a rare case of TMA secondary to breast cancer without evidence of bone marrow infiltration responsive to doxorubicin and cyclophosphamide treatment, after failed plasmapheresis with prednisone and later, eculizumab. CONCLUSION: Despite being a rare manifestation of metastatic carcinoma, early identification and treatment are essential to improving survival.

A Phase I Trial of Talimogene Laherparepvec in Combination with Neoadjuvant Chemotherapy for the Treatment of Nonmetastatic Triple-Negative Breast Cancer.

PURPOSE: Talimogene laherparepvec (TVEC) is an oncolytic herpes simplex 1 virus approved for treatment of melanoma. We hypothesized intratumoral TVEC may enhance response to neoadjuvant chemotherapy (NAC). This article reports the results of a trial combining NAC with TVEC for triple-negative breast cancer (TNBC). PATIENTS AND METHODS: Patients with stage II-III TNBC enrolled in a 3+3 phase I trial (NCT02779855) of two TVEC dose levels [DL; DL 1 = 106 plaque-forming units (PFU) × 5 doses; DL 2 = 106 PFUs first dose, then 108 PFUs × 4 doses] on weeks 1, 4, 6, 8, and 10 plus weekly paclitaxel (80 mg/m2) for 12 weeks, followed by doxorubicin/cyclophosphamide (60/600 mg/m2) every 2 weeks for 8 weeks. Postoperative response assessment using residual cancer burden (RCB) was performed. Primary endpoints were safety and MTD. Secondary endpoints were RCB0 rate and immune correlates. Dose-limiting toxicity (DLT) rule was grade 3-5 adverse events due to TVEC during first 5 weeks. RESULTS: Nine patients [DL 1 (n = 3); DL 2 (n = 6)] were enrolled. Six had stage II disease, and 3 had stage III (6 clinically N+). No DLTs occurred, and MTD was DL 2. Most common toxicities with TVEC were fever (n = 8), chills (n = 3), hematomas (n = 3), and injection site pain (n = 3). Thromboembolic events (n = 2) and bradycardia (n = 1) occurred during or after NAC. Five patients (55%) achieved RCB0, 2 had RCB1 (22%), and 2 had RCB2 (22%). CONCLUSIONS: The addition of TVEC to NAC was feasible at the approved dose, with manageable toxicity. The complete response rate was 55%.

Real-world benefit of combination palbociclib and endocrine therapy for metastatic breast cancer and correlation with neutropenia.

BACKGROUND: Combination CDK4/6 inhibitor and endocrine therapy has been shown to significantly improve progression-free survival (PFS) in patients with hormone receptor (HR)-positive, HER2-negative metastatic breast cancer (mBC). The aim of this retrospective study was to evaluate the real-world benefit of first-line combination therapy in this cohort and to correlate treatment efficacy with neutropenia, a common toxicity of CDK4/6 inhibitors. METHODS: This study included HR-positive, HER2-negative advanced or mBC patients who were treated with palbociclib plus endocrine therapy, mainly letrozole, between 1 January 2015 and 1 March 2018. Progression-free survival (PFS) was determined using Kaplan-Meier analysis. The predictive value of absolute neutrophil count (ANC) and neutrophil-to-lymphocyte ratio (NLR) for PFS were explored using Cox regression models. Both ANC and NLR were used as a time-dependent variable. RESULTS: In total, 165 patients were included with median PFS of 24.19 months (95% CI 18.93-NR). Median PFS for patients with bone-only metastases (n = 54) was not reached (95% CI 18.21-NR). Among patients with all other metastases (n = 111), median PFS was 24.19 months (95% CI 16.33-33.82). Lower ANC was correlated with decreased risk of progression (HR 0.84, 95% CI 0.71-0.97, p = 0.008). There was no significant association between NLR and the risk of disease progression (HR 1.07, 95% CI 0.97-1.18, p = 0.203). CONCLUSION: The effectiveness of palbociclib and endocrine therapy in the treatment of HR-positive, HER2-negative mBC in the real-world setting is similar to the efficacy reported in the PALOMA-2 trial. Patients with lower neutrophil count may have a lower risk of early disease progression.

Nivolumab and Stereotactic Radiosurgery for Patients With Breast Cancer Brain Metastases: A Nonrandomized, Open-Label Phase 1b Study.

PURPOSE: We hypothesize treatment with nivolumab and stereotactic radiosurgery (SRS) will be feasible and well tolerated, and may improve intracranial tumor control rates compared with SRS alone. METHODS AND MATERIALS: The study was designed as a prospective, single-arm, nonrandomized, open-label, phase 1b trial of nivolumab and SRS among patients with metastatic breast cancer brain metastases. Key eligibility criteria included patients with breast cancer brain metastases of all subtypes, age ≥18, Eastern Cooperative Oncology Group Performance Status ≤2 with ≤10 brain metastases. Treatment was initiated with a dose of nivolumab (480 mg intravenously) that was repeated every 4 weeks. The initial dose of nivolumab was followed 1 week later by SRS. This study is closed to accrual and is registered with ClinicalTrials.gov, NCT03807765. RESULTS: Between February 2019 and July 2020, a total of 12 patients were treated to 17 lesions. No dose limiting toxicities were noted in our patient population. The most common neurologic adverse events included grade 1 to 2 headaches and dizziness occurring in 5 (42%) of patients. Median intracranial control was 6.2 months (95% confidence interval, 3-14 months) with 6- and 12-month control rates of 55% and 22%, respectively. A total of 4 patients had systemic progression during the study. Median time to systemic progression free survival has not been reached with 6- and-12 month rates of 63% and 51%, respectively. CONCLUSIONS: Nivolumab and SRS is a safe and feasible treatment option in breast cancer brain metastases. Preliminary data reveals activity in certain breast cancer patients to study therapy.

Mitf-Mdel, a novel melanocyte/melanoma-specific isoform of microphthalmia-associated transcription factor-M, as a candidate biomarker for melanoma.

BACKGROUND: Melanoma incidence is on the rise and advanced melanoma carries an extremely poor prognosis. Treatment options, including chemotherapy and immunotherapy, are limited and offer low response rates and transient efficacy. Thus, identification of new melanocyte/melanoma antigens that serve as potential novel candidate biomarkers in melanoma is an important area for investigation. METHODS: Full length MITF-M and its splice variant cDNA were cloned from human melanoma cell line 624 mel by reverse transcription polymerase chain reaction (RT-PCR). Expression was investigated using regular and quantitative RT-PCR in three normal melanocytes (NHEM), 31 melanoma cell lines, 21 frozen melanoma tissue samples, 18 blood samples (peripheral blood mononuclear cell; PBMC) from healthy donors and 12 non-melanoma cancer cell lines, including three breast, five glioma, one sarcoma, two kidney and one ovarian cancer cell lines. RESULTS: A novel splice variant of MITF-M, which we named MITF-Mdel, was identified. The predicted MITF-Mdel protein contains two in frame deletions, 56- and 6- amino acid deletions in exon 2 (from V32 to E87) and exon 6 (from A187 to T192), respectively. MITF-Mdel was widely expressed in melanocytes, melanoma cell lines and tissues, but almost undetectable in non-melanoma cell lines or PBMC from healthy donors. Both isoforms were expressed significantly higher in melanoma tissues than in cell lines. Two of 31 melanoma cell lines expressed only one isoform or the other. CONCLUSION: MITF-Mdel, a novel melanocyte/melanoma-specific isoform of MITF-M, may serve as a potential candidate biomarker for diagnostic and follow-up purposes in melanoma.

Activated CD4+ T cells enhance radiation effect through the cooperation of interferon-gamma and TNF-alpha.

BACKGROUND: Approaches that enhance radiation effect may lead to improved clinical outcome and decrease toxicity. Here we investigated whether activated CD4+ T cells (aCD4) can serve as an effective radiosensitizer. METHODS: CD4+ T cells were activated with anti-CD3 and anti-CD28 mAbs. Hela cells were presensitized with aCD4 or conditioned supernatant (aCD4S) or recombinant cytokines for 2 days, followed gamma-irradiation. The treated cells were cultured for an additional 2 to 5 days for cell proliferation, cell cycle, and western blot assays. For confirmation, other cancer cell lines were also used. RESULTS: Presensitization of tumor cells with aCD4 greatly increased tumor cell growth inhibition. Soluble factors secreted from activated CD4+ T cells were primarily responsible for the observed effect. IFN-gamma seemed to play a major role. TNF-alpha, though inactive by itself, significantly augmented the radiosensitizing activity of IFN-gamma. aCD4S, but not IFN-gamma or IFN-gamma/TNF-alpha combination, was found to enhance the gamma-irradiation-induced G2/M phase arrest. Bax expression was highly upregulated in Hela cells presensitized with aCD4S followed by gamma-irradiation. The radio-sensitizing activity of aCD4 is not uniquely observed with Hela cell line, but also seen with other cancer cell lines of various histology. CONCLUSIONS: Our findings suggest possible molecular and cellular mechanisms that may help explain the radio-sensitization effect of activated lymphocytes, and may provide an improved strategy in the treatment of cancer with radiotherapy.

Recurrence risk of early-stage melanoma of the external ear: an investigation of surgical approach and sentinel lymph node status.

Surgical management of external ear melanoma presents unique technical challenges based on the unique anatomy and reconstruction concerns. Surgical technique, including preservation of cartilage, is variable and impact on recurrence is unclear. Our goal was to investigate surgical approach, including extent of surgical resection and sentinel lymph node biopsy (SLNB), and the impact on recurrence. In this retrospective review of primary clinical stage 1/2 external ear melanoma, demographics, tumor characteristics, surgical resection technique (including cartilage-sparing vs. cartilage removal), and SLNB results were evaluated for recurrence risk. One hundred and fifty-six patients total had an average follow-up of 5.6 years. Twenty-nine (18.6%) patients underwent cartilage-sparing surgery and 99 (63.5%) patients underwent SLNB, 14.1% of whom had micrometastatic disease. Ten (6.4%) patients recurred loco-regionally. Recurrence was associated with Breslow depth, initial stage at diagnosis, and SLNB status. Cartilage-sparing surgery was not associated with increased recurrence. Sentinel lymph node identification rate was 100% based on clinical detection with use of lymphoscintigraphy. In addition to confirming established risk factors for melanoma recurrence, we confirm the feasibility of SLNB in stratifying recurrence risk. Although we did not see an increased recurrence risk with surgical technique and cartilage-sparing approaches, these findings are limited by small sample size.

The Immune Checkpoint Kick Start: Optimization of Neoadjuvant Combination Therapy Using Game Theory.

PURPOSE: In an upcoming clinical trial at the Moffitt Cancer Center for women with stage 2/3 estrogen receptor-positive breast cancer, treatment with an aromatase inhibitor and a PD-L1 checkpoint inhibitor combination will be investigated to lower a preoperative endocrine prognostic index (PEPI) that correlates with relapse-free survival. PEPI is fundamentally a static index, measured at the end of neoadjuvant therapy before surgery. We have developed a mathematical model of the essential components of the PEPI score to identify successful combination therapy regimens that minimize tumor burden and metastatic potential, on the basis of time-dependent trade-offs in the system. METHODS: We considered two molecular traits, CCR7 and PD-L1, which correlate with treatment response and increased metastatic risk. We used a matrix game model with the four phenotypic strategies to examine the frequency-dependent interactions of cancer cells. This game was embedded in an ecological model of tumor population-growth dynamics. The resulting model predicts evolutionary and ecological dynamics that track with changes in the PEPI score. RESULTS: We considered various treatment regimens on the basis of combinations of the two therapies with drug holidays. By considering the trade off between tumor burden and metastatic potential, the optimal therapy plan was a 1-month kick start of the immune checkpoint inhibitor followed by 5 months of continuous combination therapy. Relative to a protocol giving both therapeutics together from the start, this delayed regimen resulted in transient suboptimal tumor regression while maintaining a phenotypic constitution that is more amenable to fast tumor regression for the final 5 months of therapy. CONCLUSION: The mathematical model provides a useful abstraction of clinical intuition, enabling hypothesis generation and testing of clinical assumptions.

Neutrophil-to-lymphocyte Ratio (NLR) as a predictor for recurrence in patients with stage III melanoma.

Neutrophil-to-lymphocyte ratio is a strong predictor for overall survival and disease free survival in many cancers. Our study is the first investigation aiming to determine the predictive value of neutrophil-to-lymphocyte ratio on prognosis of patients with stage III melanoma. This retrospective study utilized a cohort of 107 patients with stage III melanoma treated at Huntsman Cancer Institute, University of Utah, from May 2002 to March 2016. The optimal cutoff of neutrophil-to-lymphocyte ratio was determined by the significance of log-rank tests. A total of 97 log-rank tests were conducted to find the optimal cutoff. Disease free survival was assessed using the Kaplan-Meier method, and univariable and multivariable Cox models were applied to evaluate the predictive value of neutrophil-to-lymphocyte ratio. 2.5 was identified as the optimal cutoff. Kaplan-Meier curve showed that the disease free survival rate of the low value group was significantly higher compared to that of high value group. After adjusting for confounders and other prognostic factors, the neutrophil-to-lymphocyte ratio ≥ 2.5 remained a strong predictor for disease recurrence in patients with stage III melanoma.