Signaling lymphocytic activation molecule family receptors as potential immune therapeutic targets in solid tumors.

Recently, cancer immunotherapy has revolutionized cancer treatment. Various forms of immunotherapy have a manageable safety profile and result in prolongation of overall survival in patients with solid tumors, but only in a proportion of patients. Various factors in the tumor microenvironment play critical roles and may be responsible for this lack of therapeutic response. Signaling lymphocytic activation molecule family (SLAMF) members are increasingly being studied as factors impacting the tumor immune microenvironment. SLAMF members consist of nine receptors mainly expressed in immune cells. However, SLAMF receptors have also been detected in cancer cells, and they may be involved in a spectrum of anti-tumor immune responses. Here, we review the current knowledge of the expression of SLAMF receptors in solid tumors and tumor-infiltrating immune cells and their association with patient outcomes. Furthermore, we discuss the therapeutic potential of targeting SLAMF receptors to improve outcomes of cancer therapy in solid tumors. We believe the research on SLAMF receptor-targeted strategies may enhance anti-cancer immunity in patients with solid tumors and improve clinical outcomes.

Are nonfunctioning adrenal incidentalomas really nonfunctioning? A retrospective single-center study.

OBJECTIVE: In patients with adrenal incidentaloma (AI), cortisol levels <1.8 µg/dL after a dexamethasone suppression test (DST) are considered nonfunctioning in terms of autonomic cortisol hypersecretion (ACH). We aimed to investigate the frequency of hypertension (HT) in patients with nonfunctioning AI. PATIENTS AND METHODS: Individuals with AI who were admitted to the endocrinology clinic between September 2020 and May 2023 were included as the patient group, and age- and gender-matched individuals admitted with thyroid nodules between the same dates were included as the control group. RESULTS: The participants included 123 AI patients who fulfilled the study criteria and 114 age- and sex-matched patients with thyroid nodules (age: 53.0±10.9 years and 52.9±7.4 years, respectively, p=0.98; female/male distribution: 90/33 and 91/23, respectively, p=0.28). The frequency of HT was higher in the AI group than in the control group (50.4% and 31.6%, respectively, p=0.004). The frequency of HT was significantly lower in patients with a DST result <0.87 µg/dL compared to those with a DST result ≥0.87 µg/dL (42.6% and 66.1%, respectively, p=0.009). The factors affecting HT were analyzed using binary logistic regression analysis; it was found that age [ß=0.068, odds ratio (OR); 1.07 (95% confidence interval (CI); 1.02-1.12), p=0.004] and DST [ß=1.18, OR; 3.24 (95% CI); 1.02-10.34, p=0.047] were independent factors. CONCLUSIONS: The frequency of HT increases in patients with nonfunctioning AI. The reason for this increase may possibly be the presence of ACH, which is not detected by the cut-off values we currently use to exclude ACH.

Total testosterone cut-off value indicating androgen-secreting tumor in premenopausal women with hirsutism.

OBJECTIVE: There is insufficient data on which cut-off value must be used to measure the increase in total testosterone (TT) compared to the upper limit of normal (CULN) in the diagnosis of androgen-secreting tumor (ASTM) in female individuals with premenopausal hirsutism (FIPH). PATIENTS AND METHODS: A total of 413 FIPH over 18 years of age who were admitted to the endocrinology clinic between May 2013 and 30 April 2018 were eligible for the study. Hormone profiles of the participants in the follicular phase and other information were obtained from their files. The androgen suppression ratio (ASR) was analyzed after 48 hours of low-dose dexamethasone suppression test (LDDST) in those whose TT CULN (nmol/L) increased two-fold. RESULTS: Idiopathic hirsutism was found in 193 participants (46.73%) and polycystic ovary syndrome (PCOS) in 200 (48.43%) and other sources of hirsutism; non-classical congenital adrenal hyperplasia (NCCAH) in 10 patients (2.42%), hyperprolactinemia in 6 patients (1.45%), ASTM of ovarian origin in 2 patients (0.48%), Cushing's disease in 1 patient (0.24%), and adrenal ASTM in 1 patient (0.24%). A cut-off value of two-fold CULN increase for TT sensitivity of 100% and a specificity of 99.5% in indicating an ASTM source, and ASR above 49% in LDDST sensitivity of 80% and a specificity of 100% in excluding an ASTM source, was used. CONCLUSIONS: At the TT level, a two-fold increase CULN in FIPH indicates an ASTM source. In addition, ASR after LDDST is a useful parameter in the exclusion of ASTM sources in the same patient population.

Efficacy of switching from basal-bolus insulin therapy to twice-daily insulin degludec/insulin aspart co-formulation plus insulin aspart in patients with poorly controlled type 2 diabetes.

OBJECTIVE: The aim of this study was to evaluate the efficacy of twice-daily (BID) insulin degludec/insulin aspart (IDegAsp) co-formulation + once-daily (OD) bolus insulin aspart (IAsp) injection (IDegAsp BID-Plus) as simplified intensive insulin therapy in patients with poorly controlled type 2 diabetes mellitus (T2DM) with basal-bolus insulin therapy (BBIT). PATIENTS AND METHODS: The retrospective study included 155 patients who switched from BBIT to IDegAsp BID-Plus. After the initiation of the treatment, 73 patients continued regular follow-up and insulin doses, number of injections, hemoglobin A1c (HbA1c) levels, and other parameters were recorded from their files at baseline, 24, and 52 weeks. RESULTS: The mean age of the study population was 54.3±10.2 years, the duration of T2DM was 9.7±5.7 years, fasting plasma glucose (FPG) was 252.7±66.7 mg/dl, and HbA1c levels were 10.5±1.5%. Among the included patients, 15 patients received five injections, 51 patients received four injections, and 7 patients received three injections per day. There was a significant decrease in HbA1c (respectively; 10.46±1.54%, 7.97±1.24%, 7.98±1.23%, baseline and 6th-month p<0.001, baseline and 12th-month p<0.001), FPG (respectively; 251.6±66.5 mg/dl, 136.1±34.7 mg/dl, 125.4±67.0  mg/dl, baseline and 6th-month p<0.001, baseline and 12th-month p<0.001) and daily dose of insulin (respectively; 102.9±29.0 Unit, 73.2±18.2 U,  63.7±20.3 Unit, baseline and 6th-month p<0.001, baseline and 12th-month p<0.001) at the end of week 24 and 52. CONCLUSIONS: Based on real-world data, this study demonstrated that IDegAsp BID-Plus treatment provides rapid and sustainable blood glucose control with lower insulin doses and fewer injections than previous intensive insulin therapy.

Targeting macrophages for enhancing CD47 blockade-elicited lymphoma clearance and overcoming tumor-induced immunosuppression.

Tumor-associated macrophages (TAMs) are often the most abundant immune cells in the tumor microenvironment (TME). Strategies targeting TAMs to enable tumor cell killing through cellular phagocytosis have emerged as promising cancer immunotherapy. Although several phagocytosis checkpoints have been identified, the desired efficacy has not yet been achieved by blocking such checkpoints in preclinical models or clinical trials. Here, we showed that late-stage non-Hodgkin lymphoma (NHL) was resistant to therapy targeting phagocytosis checkpoint CD47 due to the compromised capacity of TAMs to phagocytose lymphoma cells. Via a high-throughput screening of the US Food and Drug Administration-approved anticancer small molecule compounds, we identified paclitaxel as a potentiator that promoted the clearance of lymphoma by directly evoking phagocytic capability of macrophages, independently of paclitaxel's chemotherapeutic cytotoxicity toward NHL cells. A combination with paclitaxel dramatically enhanced the anticancer efficacy of CD47-targeted therapy toward late-stage NHL. Analysis of TME by single-cell RNA sequencing identified paclitaxel-induced TAM populations with an upregulation of genes for tyrosine kinase signaling. The activation of Src family tyrosine kinases signaling in macrophages by paclitaxel promoted phagocytosis against NHL cells. In addition, we identified a role of paclitaxel in modifying the TME by preventing the accumulation of a TAM subpopulation that was only present in late-stage lymphoma resistant to CD47-targeted therapy. Our findings identify a novel and effective strategy for NHL treatment by remodeling TME to enable the tumoricidal roles of TAMs. Furthermore, we characterize TAM subgroups that determine the efficiency of lymphoma phagocytosis in the TME and can be potential therapeutic targets to unleash the antitumor activities of macrophages.

Effect of cabazitaxel on macrophages improves CD47-targeted immunotherapy for triple-negative breast cancer.

BACKGROUND: Limited therapeutic options are available for triple-negative breast cancer (TNBC), emphasizing an urgent need for more effective treatment approaches. The development of strategies by targeting tumor-associated macrophages (TAMs) to stimulate their ability of Programmed Cell Removal (PrCR) provides a promising new immunotherapy for TNBC treatment. METHODS: CD47 is a critical self-protective "don't eat me" signal on multiple human cancers against macrophage immunosurveillance. Using human and mouse TNBC preclinical models, we evaluated the efficacy of PrCR-based immunotherapy by blocking CD47. We performed high-throughput screens on FDA-approved anti-cancer small molecule compounds for agents potentiating PrCR and enhancing the efficacy of CD47-targeted therapy for TNBC treatment. RESULTS: We showed that CD47 was widely expressed on TNBC cells and TAMs represented the most abundant immune cell population in TNBC tumors. Blockade of CD47 enabled PrCR of TNBC cells, but the efficacy was not satisfactory. Our high-throughput screens identified cabazitaxel in enhancing PrCR-based immunotherapy. A combination of CD47 blockade and cabazitaxel treatment yielded a highly effective treatment strategy, promoting PrCR of TNBC cells and inhibiting tumor development and metastasis in preclinical models. We demonstrated that cabazitaxel potentiated PrCR by activating macrophages, independent of its cytotoxicity toward cancer cells. When treated with cabazitaxel, the molecular and phenotypic signatures of macrophages were polarized toward M1 state, and the NF-kB signaling pathway became activated. CONCLUSION: The combination of CD47 blockade and macrophage activation by cabazitaxel synergizes to vastly enhance the elimination of TNBC cells. Our results show that targeting macrophages is a promising and effective strategy for TNBC treatment.

Prospective randomized clinical trial of Jean Rives technique versus laparoscopic TEP repair for primary inguinal hernia: 10-year follow-up.

BACKGROUND: The purpose of the present randomized trial was to compare the Jean Rives (JR) technique and the laparoscopic totally extraperitoneal (TEP) repair for the treatment of primary inguinal hernias with respect to operating time, hospital stay, sick leave, chronic pain and recurrences after a follow-up of 10 years. METHODS: 110 patients with primary inguinal hernia were randomized to either a JR repair (53 patients) or to a laparoscopic (TEP) repair (57 patients). All the interventions were exclusively realized by two experienced surgeons. Follow-up examinations were performed after 1, 6 months, 1, 5 and 10 years. RESULTS: Both groups were identical concerning age and hernia type, which were type II and type IIIa according to Nyhus classification. No significant difference was found concerning hospital stay, chronic pain and recurrences. The operating time was significantly lower in JR group, whereas the sick leave was significantly in favor of TEP group. CONCLUSION: Jean Rives technique is a relatively easy technique to perform, requires shorter operating time when compared to laparoscopic TEP technique. JR technique should be taken into consideration while planning surgical treatment of inguinal hernia.

Diagnosis and treatment of pulmonary cystic hydatidosis.

OBJECTIVE: Hydatidosis is a parasitic infection that is still an important public health problem in Turkey. In the present study, it was planned to review the diagnostic and treatment options. METHODS: The study was conducted in pediatric pulmonary chest ward of Izmir Chest Diseases and Surgery Training Hospital, a referral tertiary hospital for pulmonary diseases in Western Turkey. Cases were evaluated in clinical presentations, radiological, histopathologic and serological features retrospectively. RESULTS: Consecutive 17 (11 male and 6 female; mean age 11.29 + 2.44) pediatric cases between 1996 and 2001 were evaluated. Liver involvement was found in 8 (47%) cases. Casoni skin test and IHA test were found positive in 7 (63.6%) and 8 (72.7%) out of 11 cases, respectively. Surgical treatment was performed only in 7 (41.1%) cases as well as surgical plus medical treatment was given in 3 (17.6%) cases. Seven (41.1%) cases were treated just medically. CONCLUSION: Hydatidosis should be considered in the existence of appropriate clinical and radiological findings as a probable diagnosis in all children in our region. Surgery should be the first choice for treatment but, medical therapy was considered as effective for treatment complicated and/or nonsurgical pediatric cases.

Soft drugs--XIV. Synthesis and anticholinergic activity of soft phenylsuccinic analogs of methatropine.

Three soft drug analogs and a metabolite of methatropine based on phenylsuccinic structural moiety were synthesized and tested for activity. In an in vivo assay, the soft drugs were found to be two orders of magnitude less potent than methatropine while the carboxylate metabolite was found to be one order of magnitude less potent than the soft drugs. A structural isomer of compound 4a was found to be less potent. All the soft drugs tested elicited shorter durations of mydriatic action in rabbit eyes compared to atropine. The untreated eye was dilated in the atropine treated animals while no dilation occurred in the soft drug treated animals indicating facile systemic metabolism of the soft drugs to inactive moieties, possibly the carboxylate metabolite. In in vitro stability studies, the soft drugs have been found to be more hydrolytically labile than atropine. The shorter duration of mydriatic action of compound 4a coupled with increased hydrolytic lability make this a candidate for further study.