Complete Remission of Metastatic Melanoma of the Scalp Following Treatment With Nivolumab Plus Relatlimab.

Melanoma is an aggressive malignancy accounting for approximately 1% of all skin cancers. The standard of care for distant melanoma of the skin is immunotherapy with PD-1 inhibitors (nivolumab) or CTLA-4 inhibitors. In March 2022, the FDA approved the combination of nivolumab with relatlimab, a lymphocyte-activation gene 3 antibody. There are few reports on the efficacy of treating widespread multivisceral metastatic melanoma with nivolumab plus relatlimab with a complete clinical response. We describe the diagnosis and management of a patient with metastatic nodular melanoma treated with palliative resection of the primary tumor followed by immunotherapy with nivolumab and relatlimab. Four months after his first treatment, he had no evidence of disease on PET scan. He continued to show no evidence of disease at recent follow-up. Treatment of metastatic melanoma of the skin with nivolumab and relatlimab is an effective approach showing greater benefit to patients than nivolumab alone.

CD133⁺ melanoma subpopulation acquired resistance to caffeic acid phenethyl ester-induced apoptosis is attributed to the elevated expression of ABCB5: significance for melanoma treatment.

According to the cancer stem-like cell (CSC) hypothesis, neoplastic clones are maintained by a small fraction of cells with stem cell properties. Also, melanoma resistance to chemo- and radiotherapy is thought to be attributed to melanoma stem-like cells (MSCs). Caffeic acid phenethyl ester (CAPE) is a bioactive molecule, whose antitumor activity is approved in different tumor types. CAPE induced both apoptosis and E2F1 expression in CD133(-), but not in CD133(+) melanoma subpopulations. The resistance of CD133(+) melanoma subpopulation is attributed to the enhanced drug efflux mediated by ATP-binding cassette sub-family B member 5 (ABCB5), since the knockdown of ABCB5 was found to sensitize CD133(+) cells to CAPE. CAPE-induced apoptosis is mediated by E2F1 as evidenced by the abrogation of apoptosis induced in response to the knockdown of E2F1. The functional analysis of E2F1 in CD133(+) melanoma subpopulation demonstrated the ability of E2F1 gene transfer to trigger apoptosis of CD133(+) cells and to enhance the activation of apoptosis signal-regulating kinase (ASK1), c-Jun N-terminal kinase and p38, and the DNA-binding activities of the transcription factors AP-1 and p53. Also, the induction of E2F1 expression was found to enhance the expression of the pro-apoptotic proteins Bax, Noxa and Puma, and to suppress the anti-apoptotic protein Mcl-1. Using specific pharmacological inhibitors we could demonstrate that E2F1 overcomes the chemo-resistance of MSCs/CD133(+) cells by a mechanism mediated by both mitochondrial dysregulation and ER-stress-dependent pathways. In conclusion, our data addresses the mechanisms of CAPE/E2F1-induced apoptosis of chemo-resistant CD133(+) melanoma subpopulation.

Comparative analysis of innate immune system function in metastatic breast, colorectal, and prostate cancer patients with circulating tumor cells.

In recent years, circulating tumor cells (CTCs) in metastatic cancer patients have been found to be a promising biomarker to predict overall survival and tumor progression in these patients. A relatively high number of CTCs has been correlated with disease progression and poorer prognosis. This study was designed to assess innate immune system function, known to be responsible for the immune defense against developing neoplasms, in metastatic cancer patients with CTCs. Our aim is to provide a link between indication of poorer prognosis, represented by the number of CTCs to the cytotoxic activity of natural killer cells, an important component of the innate immune system, and to represent a promising expanded approach to management of metastatic cancer patients with CTCs. Seventy-four patients, with metastatic breast, colorectal, or prostate cancer, were recruited for this study. Using a flow cytometric assay, we measured natural killer (NK) cell cytotoxicity against K562 target cells; and CTCs were enumerated using the CellSearch System. Toll-like receptors 2 and 4 expression was also determined by flow cytometry. We found that within each of our three metastatic cancer patient groups, NK cell cytotoxic activity was decreased in patients with a relatively high number of CTCs in peripheral blood compared to patients with a relatively low number of CTCs. In the breast and prostate cancer group, patients with CTCs greater than 5 had decreased NK cell cytotoxicity when compared to patients with less than 5 CTCs. In the colorectal cancer group, we found that 3 or more CTCs in the blood was the level at which NK cell cytotoxicity is diminished. Additionally, we found that the toll-like receptors 2 and 4 expression was decreased in intensity in all the metastatic cancer patients when compared to the healthy controls. Furthermore, within each cancer group, the expression of both toll-like receptors was decreased in the patients with relatively high number of CTCs, i.e. greater than 5 for the breast and prostate cancer group and greater than 3 for the colorectal cancer group, compared to the patients with relatively low number, i.e. less than 5 or 3, respectively. Treatment options to increase NK cell cytotoxic activity should be considered in patients with relatively high numbers of CTCs.

Isoform-specific effects of apolipoprotein E on secretion of inflammatory mediators in adult rat microglia.

Inflammation mediated by activated microglia cells has been shown to contribute to the pathogenesis of Alzheimer disease (AD) [1]. Microglia are the immune cells in the central nervous system, and when activated they secrete the lipid-derived mediator prostaglandin E2 (PGE2), the cytokine interleukin-1beta (IL-1beta), and other inflammatory mediators. Apolipoprotein E isoform 4 (apoE4), coded for by the gene APOE4 (epsilon4), has been shown to correlate with higher risk of onset of AD, as well as with increased severity of other diseases with a neuroinflammatory component. This study investigated isoform-specific effects of apoE on the regulation of PGE2, COX2, and IL-1beta expression. Two physiologically relevant preparations of apoE displayed an isoform-specific effect on inflammation in primary adult microglia cultured from adult rat brain cortex. Specifically, apoE4 alone, but not the more common isoform apoE3, stimulated secretion of PGE2 and IL-1beta. The increase in PGE2 release stimulated by apoE4 was not accompanied by the upregulation of the COX-2 enzyme in microglia.

Prognostic factors in breast cancer: the predictive value of the Nottingham Prognostic Index in patients with a long-term follow-up that were treated in a single institution.

The Nottingham Prognostic Index (NPI) is an index, derived from a retrospective multivariate study, that is able to predict survival in patients with breast cancer. The index is based on tumour size, lymph node stage and histological grade and allows the stratification of patients into three different prognostic groups. The aim of this study was to verify, according to our experience with a long-term follow-up, the effect of some prognostic variables on survival and to establish the independent influence of each of them by means of a survival regression analysis. Then we applied the NPI to the same group of patients in order to assess the predictive power and reproducibility of the index. 402 patients treated from January 1979 to December 1987 were evaluated. In multivariate analysis (Cox proportional hazard model), only size, lymph node involvement and histological grade remained independent prognostic factors. The survival curves obtained after applying the NPI are similar to those for the factors with independent prognostic significance derived from our multivariate analysis. Our improved survival rates may be attributed to the administration of adjuvant therapies to a larger number of patients. The NPI allow us to accurately predict prognosis and we advocate its more common use.

Sleep apnea in adults with traumatic brain injury: a preliminary investigation.

OBJECTIVE: To determine the occurrence and nature of sleep-related breathing disorders in adults with traumatic brain injury (TBI). DESIGN: Prospective, observational, consecutive sample enrollment of subjects admitted for rehabilitation after TBI. SETTING: Inpatient rehabilitation and subacute rehabilitation units of a tertiary care university medical system. PARTICIPANTS: Subjects (n = 28) included adults with TBI and a Rancho Los Amigos Scale level of 3 or greater who were less than 3 months postinjury and admitted for comprehensive inpatient rehabilitation. INTERVENTIONS: Overnight sleep study using portable 6-channel monitoring system. MAIN OUTCOME MEASURE: Respiratory disturbance index (RDI), which is the number of apneic and hypopneic episodes per hour of sleep. RESULTS: Evidence of sleep apnea was found in 10 of 28 (36%) subjects as measured by a RDI level of 5 or greater and in 3 of 28 (11%) subjects as measured by a RDI level of 10 or greater. This rate of sleep apnea is significantly (p =.002) higher than would be predicted based on population norms. No correlation was found between the occurrence of significant sleep apnea and measures of TBI severity or other demographic variables. Sleep-related breathing disorders were primarily central though obstructive apneas were also noted. CONCLUSION: In this preliminary investigation, sleep-related breathing disorders as defined by a respiratory disturbance index of 5 or greater appears to be common in adult subjects with TBI.

Initial experience with sentinel lymph node mapping and biopsy in breast cancer. Preliminary results on 80 consecutive patients.

Sentinel node biopsy, in breast cancer, is a promising surgical technique for predicting histological findings in the remaining axillary lymph nodes, especially in patients with clinically node-negative breast cancer. 80 patients with breast cancer were evaluated for enrollment in this study. For mapping procedure 32 patients underwent lymphoscintigraphy in combination with an injection of vital blue dye, while 48 utilized only vital dye. In all patients, after sentinel node (SLN) biopsy, a complete axillary dissection was performed. The mapping procedure was possible in 79 cases (98.7%). The SLNs were positive in 27 (34.1%), in 52 patients SLNs were negative and in 50 of these all axillary nodes were negative. There was concordance in 77/79 cases (97.4%). The false negative rate was 3.8% (2/52). The overall sensitivity of the SNL biopsy was 93.1% (27/29), with a negative predictive value of 96.1% (50/52). This study demonstrates that accurate SLN identification was obtained combining lymphoscintigraphy and blue dye. Moreover, each method requires a suitable learning curve. Further studies are needed to define an accurate patient selection and the most speedy and precise method for intraoperative histological examination of SLNs.

[Pica in psychotic patients: an unusual cause of acute abdomen]. / Il picacismo nei pazienti psicotici: una inconsueta causa di addome acuto.

Pica is a pathologic craving for substances not commonly regarded as foods. In this study the authors report their experience about five cases presented with an acute abdomen following foreign bodies ingestion by patients mentally handicapped. Therapeutic treatment was emergency laparatomy with postoperative morbidity of 40% and mortality of 40%. It is hoped that specific drug therapy with more aggressive surgical treatment will reduce the mortality significantly.

[Influence of thyroid states on PGE2 biosynthesis]. / Influenza degli stati tiroidei sulla biosintesi di PGE2.

Hyperthyroid and hypothyroid states were induced in the rat by daily injection of 3,3',5-triiodothyronine (T3; 33 microgram/100 g b. wt., ip for 6 days) or by thyroparathyroidectomy, respectively. Control animals underwent only a sham operation or received the T3 vehicle. In these experimental conditions the biosynthesis of PGE2-like substance was determined "in vitro" in the fraction obtained after centrifugation at 80,000xg for 60 min of pooled spleens (5). Assays of PGE2 activity were carried out on rat stomach strip preparations according to Vane (8). In a series of additional experiments the influence of thyroid states on the inhibitory activity exerted by Indomethacin, Oxametacine and Phenylbutazone on PGE2 biosynthesis was also evaluated. The results obtained indicate that the hyperthyroidism induces a significant increase of PGE2 production "in vitro" from added arachidonic acid (100% enhancement above the control values) while thyroparathyroidectomy is unable to interfere with such biosynthetic activity. In addition, the inhibitory effect of Indomethacin, Oxametacine and Phenylbutazone on PGE2 production is not affected by hyperthyroid state whereas hypothyroidism significantly limits the action of the mentioned non-steroid anti-inflammatory agents.

[Influence of propyl-gallate and 2-mercaptopropionylglycine on the development of acute inflammatory reactions and on biosynthesis of PGE2]. / Influenze del propil gallato e della 2-mercaptopropionilglicina sullo sviluppo di reazioni infiammatorie acute e sulla biosinte si di PGE2.

Anti-inflammatory activity of Propyl Gallate and 2.mercaptopropionylglycine, administered intraperitoneally to the rat, was evaluated against paw edema induced by Carrageenan, Bradykinin, Serotonin and Dextran. In addition, the influence of these chemicals on PGE2 formation from added arachidonic acid to spleen microsomal fraction incubated "in vitro" was assayed. Our results indicate Propyl Gallate and 2.mercaptopropionylglycine depress significantly the development of acute inflammatory reactions provoked by the above mentioned phlogogens and are able to limit the biosynthesis of PGE2. The last inhibitory activity appears to be less potent than that exerted by some non-steroidal anti-inflammatory agents, namely Indomethacin and Oxametacine, which act primarily by interfering with cyclo-oxigenase activity. In our opinion, the anti-inflammatory effect of Propyl Gallate and 2.mercaptopropionylglycine might be dependent on both the scavenger properties of the two compounds against some final products of lipid peroxides (aldehydes) originated at the inflammation site and the partial inhibition of the formation of PGE2 by acting on the cyclo-oxigenase system.

Effect of a new anti-inflammatory drug (oxametacine) on the prostaglandin biosynthesis.

The influence of oxametacine, 2-[1-(4-chlorobenzoyl)-5-methoxy-2-methyl-3-indoyl]acetohydroxamic acid, a new non-steroidal anti-inflammatory drug, on prostaglandin-synthetase was studied in vitro on rat spleen tissue. The drug exerts an inhibitory effect on prostaglandin biosynthesis which closely mimics that of indomethacin. On the other hand, oxametacine proves more active than other non-steroidal anti-inflammatory agents, namely ketoprofen, flufenamic acid, phenylbutazone and acetylsalicylic acid.