Immunotherapy has improved the prognosis of metastatic melanoma patients, although most patients do not achieve a complete response. While specific gut microbiome and dietary habits might influence ...treatment success, there is a lack of concordance between the studies, potentially due to dichotomizing patients only into responders and non-responders. The aim of this study was to elucidate whether metastatic melanoma patients with complete and sustained response to immunotherapy exhibit differences in gut microbiome composition among themselves, and whether those differences were associated with specific dietary habits. Shotgun metagenomic sequencing revealed that patients who exhibited a complete response after more than 9 months of treatment (late responders) exhibited a significantly higher beta-diversity (
= 0.02), with a higher abundance of
(LDA 3.548,
= 0.010),
(LDA 3.392,
= 0.024), and lower abundance of
(
= 0.04) compared to early responders. Furthermore, late responders exhibited a different diet profile, with a significantly lower intake of proteins and sweets and a higher intake of flavones (
< 0.05). The research showed that metastatic melanoma patients with a complete and sustained response to immunotherapy were a heterogeneous group. Patients with a late complete response exhibited microbiome and dietary habits which were previously associated with an improved response to immunotherapy.
Although most patients with thyroid cancer have a favorable clinical course, some patients develop a more aggressive type of cancer and exhibit more rapid disease progression with worse prognosis. ...Those patients usually exhibit mutations of proteins such as tyrosine kinase enzymes that play a significant role in regulation of tumor proliferation and spreading. Development of targeted therapies is based on the inhibition of mutated kinases which are involved in the MAPK signaling pathway. The aim of this study was to present the initial results of clinical experience with kinase inhibitors in patients with metastatic differentiated thyroid cancer (DTC), poorly differentiated thyroid cancer (PDTC), and medullary thyroid cancer (MTC) who exhibited rapid disease progression. A total of 17 adult patients (11 women, mean age 53.3 years) managed for progressive, metastatic disease were included in the study. Twelve patients with DTC and PDTC were previously tested for BRAF mutations, of whom nine that had tumor tissue negative for the BRAF V600E mutation received sorafenib, while three patients with tumors harboring the BRAF V600E mutation were treated with vemurafenib. Patients with MTC were treated with sunitinib, vandetanib, and sorafenib. Two patients with tumors harboring the BRAF mutation treated with vemurafenib showed restoration of radioiodine uptake. Most of patients showed significant improvement in disease status but of limited duration until disease progression. Although there was an improvement in progression-free survival, future research has to achieve a greater and longer-lasting response, probably by utilizing combined targeted therapy.
Primary leptomeningeal melanoma is an extremely rare disease of the central nervous system. There are no standard treatment protocols with a poor prognosis in very few reported cases. Immunotherapy ...in primary brain melanoma has not been successfully applied so far.
We describe a female patient 72-year-old diagnosed in the Neurosurgery Department which presented with generalized seizures.
Histological examination confirmed atypical melanocytes immunohistochemically positive for melan A, HMB45 and S-100 protein in the meninges, BRAF V600E negative. Dermatological, ophthalmological examinations, and 18-FDG PET/CT were negative.
The patient was successfully treated with pembrolizumab 2 mg/kg every 3 weeks for 2 years.
The disease was stable for 2 years and the patient had no significant toxicity.
Our report describes durable intracranial tumor response suggesting the efficacy of PD-1 inhibitor pembrolizumab for central nervous system primary leptomeningeal melanoma.
Cancer cachexia is a syndrome characterized by weight and muscle loss and functional impairment, strongly influencing survival in cancer patients. In this study, we aimed to establish the role of ...saliva cytokine measurement in cancer cachexia investigation and define two potential independent salivary biomarkers of the condition. Methods: serum and saliva specimens were obtained from 78 patients. Forty-six patients were non-cachectic, and 32 patients were cachectic (per SCRINIO group criteria), all with metastatic solid tumors. Commercial ELISA kits were used to determine the salivary and serum concentrations of interleukin 13 (IL-13) and transforming growth factor beta (TGF-β) in two patient groups and healthy controls. Laboratory values were obtained from the hospital information system, and weight and height were measured at the time of sampling. Results: A statistically significant difference was observed between the groups in saliva IL-13 concentrations but no difference in serum concentrations. Statistically significant differences were also observed between the groups in saliva and serum concentrations of TGF-β. Logistic regression analysis has identified salivary IL-13 and TGF-β as independent factors for cancer cachexia. Conclusions: We demonstrated saliva as a valuable specimen for cachexia investigation and established IL-13 and TGF-β as potential cancer cachexia biomarkers. Further research is needed to evaluate these findings.
Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest cancers due to its aggressiveness and resistance to anti-cancer medications. Recent data suggest that solid tumors such as PDAC are ...infected with microbial agents, which can induce aggressive phenotype and metabolize chemotherapeutical agents. However, it was shown that gut microbiota can migrate to the pancreas and that fecal microbial transplantation (FMT) from long-term PDAC survivors can alter both gut and tumor microbiome, the immune response, and the growth of PDAC in a murine model.
Although the effect of FMT on enhancing the immune response was exhibited in melanoma patients, there is no robust data to support the use of immunotherapy in the majority of PDAC patients, as chemotherapy remains the mainstay of treatment. Along with its direct cytotoxic effect, chemotherapy can also reduce ineffective cytokine sinks via lymphodepletion and increase translocation of the gut microbiota leading to stimulation of the immune response. However, chemotherapy requires a functional microbiota to exert those effects.
We hypothesize that altering the microbiome with the FMT from the long-term PDAC survivors, combined with systemic treatment, can potentially enhance the relationship between chemotherapy, the immune system, and the microbiome. Albeit there is a lack of knowledge regarding the exact composition of the ideal donor microbiome and the optimal patient selection, due to the dismal prognosis of PDAC patients, such a trial could offer a low-risk, high-reward situation.
Soft-tissue sarcomas (STSs) are a heterogeneous group of rare malignancies. Treatment for advanced STS usually starts with anthracycline-based therapies, with no clear sequence for further treatment. ...A preferred option is trabectedin, especially for liposarcoma and leiomyosarcoma (L-sarcoma). However, due to severe side effects and few clinical trials, further research of the parameters affecting survival is necessary for the optimal selection of patients. We retrospectively analyzed 73 consecutive patients with STS treated with trabectedin at the University Hospital Centers at Zagreb and Osijek from 2014 to 2021. Our primary goals were evaluating factors affecting progression-free survival (PFS) and overall survival (OS). The median PFS and OS for trabectedin were 3.6 months and 13.7 months, respectively. Patients with L-sarcoma exhibited longer PFS and a trend towards longer OS compared to those with non-L-sarcoma. However, these effects were primarily a result of the myxoid liposarcoma subtype, which exhibited a median PFS of 21.1 months and a median OS of 33.3 months, both significantly longer compared to non-myxoid L-sarcoma. Additionally, patients with three or more sites of metastases exhibited shorter median PFS (3.1 months vs. 3.6 months) and OS (5.7 months vs. 23.8 months) compared to only one metastatic site. There was no correlation between the PFS values of trabectedin and pazopanib and no difference in survival, regardless of the treatment sequence. Trabectedin treatment yields the greatest survival benefit in patients with myxoid liposarcoma and low metastatic burden, whereas the additional use of pazopanib provides further clinical benefit, regardless of treatment sequence.
There is a lack of quality biomarkers of survival for patients with metastatic melanoma treated with immunotherapy. Although the baseline level of S100 has prognostic value, its role during/after ...therapy in survival is unclear.
We evaluated patients with metastatic melanoma treated with pembrolizumab with the goal of analysing the relationship between a relative change in S100 level at 12 weeks of immunotherapy and survival.
Patients with a relative change in S100 level >145% at 12 weeks of immunotherapy had significantly shorter progression-free (5.1 vs. 18.5 months, p≤0.0001) and overall survival (5.7 vs. 26.3 months, p<0.0001), further confirmed on multivariate analysis with hazard ratio of 32.25 (95% confidence interval=4.78-217.6, p=0.0004) for overall survival.
A relative change in S100 level might be useful as a more precise biomarker of survival for patients with metastatic melanoma treated with pembrolizumab.
Higher levels of urokinase-type plasminogen activator (uPA) and its inhibitor (PAI-1) are linked to the poor prognosis in a variety of malignances. uPA and PAI-1 were expressed in most thyroid ...carcinomas, as had been measured immunohistochemically. However, no relationship between their expression and clinicopathological parameters were found. Aim of the present study was to investigate the expression and clinical relevance of uPA and PAI-1 in thyroid cancer.
uPA and PAI-1 in paired cytosol samples of thyroid tumor and normal tissue were determined in 23 patients using enzyme-linked immunosorbent assay and correlated to the known prognostic features.
Both uPA and PAI-1 concentrations were significantly higher in malignant thyroid tumors (uPA=1.342 +/- 2.944 and PAI-1=17.615 +/- 31.933 ng/mg protein) than in normal tissue (uPA=0.002 +/- 0.009, P=0.011 and PAI-1=2.333 +/- 0.338 ng/mg protein, P=0.001) with positive correlation of the two proteins in the tumors. There were no differences in proteins' levels between benign tumors and normal tissue. Both proteins' concentrations were significantly different among various histological grades (uPA P=0.024 and PAI-1 P=0.017), showing higher values in higher tumor grades (grade I uPA=0.116 +/- 0.247 and PAI-1=4.802 +/- 4.151 ng/mg protein; grade III uPA=8.45 +/- 2.192 and PAI-1=94.65 +/- 59.468 ng/mg protein). The uPA and PAI-1 levels showed significant differences among different histological types of thyroid cancer (uPA P=0.049 and PAI-1=0.017). The lowest values were in adenomas (uPA=0.013 +/- 0.025 and PAI-1=2.785 +/- 1.069 ng/mg protein) and the highest in anaplastic carcinomas (uPA=8.45 +/- 2.192 and PAI-1=94.65 +/- 59.468 ng/mg protein). uPA and PAI-1 were significantly higher in anaplastic vs. well-differentiated cancers (uPA P=0.014 and PAI-1 P=0.026), if extrathyroidal invasion (uPA P=0.019 and PAI-1 P=0.009) or distant metastases (uPA P=0.006 and PAI-1 P=0.003) had been present, and in tumors whose size exceeded 1 cm in diameter (uPA P=0.009 and PAI-1 P=0.035). Only PAI-1, but not uPA was significantly higher in multicentric vs. solitary tumors (P=0.012) and lymph node positive compared to lymph node negative patients (P=0.042). The differences of uPA and PAI-1 did not reach the significant level when patients with well-differentiated tumors below and above 40 years of age had been compared. Survival analysis revealed the significant impact of both uPA and PAI-1 on the Progression-Free Survival (PFS) (38.84 vs. 3.67 months for patients with low and high uPA, respectively, P<0.001; 38.2 vs. 12 months for patients with low and high PAI-1, respectively, P=0.016).
The correlation of high uPA and PAI-1 with the known prognostic factors of poorer outcome and with lower PFS rate in patients with thyroid cancers proved that these proteins could be an additional prognostic parameter.
Not all cancer patients respond to immunotherapy, and the variation in response may be attributed to an individual’s microbiome, which is profoundly influenced by dietary habits. Understanding and ...manipulating the microbiome through dietary interventions offers a potential avenue for enhancing immunotherapy outcomes in cancer patients and may consequently serve as a complementary therapeutic strategy. Bearing in mind the latter, as well as our previous research on the importance of the gut microbiome as a co-denominator for immunotherapy response, we aimed to construct this study protocol on a personalized dietary intervention based on the Mediterranean diet as a complementary strategy to modify the gut microbiome, quality of life and outcomes in patients with metastatic melanoma treated with immunotherapy. The present protocol hypothesis is that remote intervention with the MD will be achievable and will positively affect all the aforementioned parameters. The potential gains of this study protocol and upcoming research extend to enhancing quality-of-life outcomes and the survival rates of patients with metastatic melanoma since it could also result in the reinforcement of the recommendation of nutritional intervention as a crucial component of cancer treatment.
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