There are only limited treatment options for metastatic
mutant melanoma patients with resistance to immune checkpoint inhibitors. Besides activation of the mitogen-activated protein (MAP) kinase ...pathway, they often have additional disturbances in cell cycle regulation. However, unlike
mutant melanoma, no targeted therapy has yet been approved for
mutant melanoma so far. Here we present a
mutant melanoma patient with response to combined binimetinib and ribociclib therapy following characterization of the molecular defects of the tumor by panel sequencing. Next generation sequencing (708 cancer genes) of a soft tissue metastasis revealed a homozygous deletion of
in addition to the previously known
mutation, as well as amplification of
and
Immunohistochemical staining of the altered cell cycle genes confirmed loss of p16, reduced expression of p21 and high expression of CDK6 and cyclin D1. As the patient had been progressive on combined immunotherapy, targeted therapy with combined MEK and CDK4/6 inhibition was initiated as recommended by the molecular tumor board. Response to treatment was monitored with PET/CT and liquid biopsy, serum LDH, and S100. In addition, a patient-derived xenograft (PDX) was used to prove the efficacy of the two drugs in combination. Furthermore, senescence-associated beta-galactosidase staining showed that more cells were senescent under the combination treatment of binimetinib and ribociclib. Our case demonstrates how an individualized, molecular-based therapeutic approach could be found based on next-generation sequencing results. Furthermore our report highlights the fruitful and efficient collaboration of dermatooncologists, human geneticists, molecular pathologists, biochemists, radiologists, and nuclear physicians. Further studies are urgently needed to expand the very limited therapeutic landscape of
mutated melanoma.
Summary
Background
Sentinel lymph node biopsy (SLNB) is useful for staging of patients with melanoma. Although SLNB is mostly performed under general anesthesia (GA), tumescence local anesthesia ...(TLA) can also be used. However, less data are available regarding feasibility of SLNB under TLA. Here we present a post‐operative follow‐up of 150 patients.
Patients and Methods
We prospectively analyzed data from 150 patients with primary cutaneous malignant melanoma. We assessed pain, post‐operative complications and patients’ satisfaction after SLNB under TLA.
Results
32 % of the patients reported post‐operative pain within the first 48 h after SLNB. Seroma was the most frequent complication, as 29 seromas after SLNB were observed. Wound infection was observed in 3.3 % of the patients. 98.7 % of the patients were satisfied with SLNB under TLA.
Conclusions
SLNB under TLA is a safe and feasible option and should be considered for patients with melanoma. Especially with multimorbid or elderly patients, the risks of GA can be avoided.
Zusammenfassung
Hintergrund
Für die Stadieneinteilung von Patienten mit malignem Melanom ist die Wächterlymphknotenbiopsie (WLKB) eine wichtige Methode. Meist erfolgt die WLKB in Vollnarkose (VN). ...Sie kann auch in Tumeszenz‐Lokalanästhesie (TLA) durchgeführt werden, jedoch liegen wenige Daten zur WLKB in TLA vor. In dieser Studie wurden die Daten von 150 Patienten mit WLKB in TLA ausgewertet.
Patienten und Methodik
Die Daten von 150 Patienten mit malignem Melanom der Haut wurden prospektiv analysiert. Schmerzen, Komplikationen und die Patientenzufriedenheit nach WLKB in TLA wurden ausgewertet.
Ergebnisse
32 % der Patienten berichteten über postoperative Schmerzen innerhalb der ersten 48 Stunden nach WLKB. Das Serom war die häufigste Komplikation. Es traten 29 Serome nach WLKB auf. Eine Wundinfektion wurde bei 3,3 % der Patienten beobachtet. 98,7 % der Patienten waren mit der WLKB in TLA zufrieden.
Schlussfolgerungen
WLKB in TLA ist eine sichere und praktikable Option und sollte bei Patienten mit Melanom in Betracht gezogen werden. Insbesondere bei multimorbiden oder älteren Patienten können die Risiken der VN vermieden werden.
Zusammenfassung Hintergrund Für die Stadieneinteilung von Patienten mit malignem Melanom ist die Wächterlymphknotenbiopsie (WLKB) eine wichtige Methode. Meist erfolgt die WLKB in Vollnarkose (VN). ...Sie kann auch in Tumeszenz‐Lokalanästhesie (TLA) durchgeführt werden, jedoch liegen wenige Daten zur WLKB in TLA vor. In dieser Studie wurden die Daten von 150 Patienten mit WLKB in TLA ausgewertet. Patienten und Methodik Die Daten von 150 Patienten mit malignem Melanom der Haut wurden prospektiv analysiert. Schmerzen, Komplikationen und die Patientenzufriedenheit nach WLKB in TLA wurden ausgewertet. Ergebnisse 32 % der Patienten berichteten über postoperative Schmerzen innerhalb der ersten 48 Stunden nach WLKB. Das Serom war die häufigste Komplikation. Es traten 29 Serome nach WLKB auf. Eine Wundinfektion wurde bei 3,3 % der Patienten beobachtet. 98,7 % der Patienten waren mit der WLKB in TLA zufrieden. Schlussfolgerungen WLKB in TLA ist eine sichere und praktikable Option und sollte bei Patienten mit Melanom in Betracht gezogen werden. Insbesondere bei multimorbiden oder älteren Patienten können die Risiken der VN vermieden werden.
Stress experience modulates behavior, metabolism, and energy expenditure of organisms. One molecular hallmark of an acute stress response is a rapid induction of immediate early genes (IEGs) such as ...c-Fos and Egr family members. IEG transcription in neurons is mediated by the neuronal activity-driven gene regulator serum response factor (SRF). We show a first role of SRF in immediate and long-lasting acute restraint stress (AS) responses. For this, we employed a standardized mouse phenotyping protocol at the German Mouse Clinic (GMC) including behavioral, metabolic, and cardiologic tests as well as gene expression profiling to analyze the consequences of forebrain-specific SRF deletion in mice exposed to AS. Adult mice with an SRF deletion in glutamatergic neurons (
Srf;
CaMKIIa-CreERT2
) showed hyperactivity, decreased anxiety, and impaired working memory. In response to restraint AS, instant stress reactivity including locomotor behavior and corticosterone induction was impaired in
Srf
mutant mice. Interestingly, even several weeks after previous AS exposure, SRF-deficient mice showed long-lasting AS-associated changes including altered locomotion, metabolism, energy expenditure, and cardiovascular changes. This suggests a requirement of SRF for mediating long-term stress coping mechanisms in wild-type mice. SRF ablation decreased AS-mediated IEG induction and activity of the actin severing protein cofilin. In summary, our data suggest an SRF function in immediate AS reactions and long-term post-stress-associated coping mechanisms.
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