Uterine endometrial cancer is one of the most common gynecological malignancies worldwide. With relatively few options for late-line therapies for advanced or relapsed endometrial cancer, the use of pretreated therapies may broaden the choice of treatments. Here, we report a case of recurrent microsatellite instability-high endometrial cancer that acquired resistance to pembrolizumab but favorably responded to the lenvatinib and pembrolizumab combination therapy. Lenvatinib combined with pembrolizumab may be effective against endometrial cancer resistant to pembrolizumab monotherapy, encouraging its use regardless of prior administration of immune checkpoint inhibitors. Further investigation on the lenvatinib and pembrolizumab combination therapy and the mechanism underlying its anticancer effect may provide new insights into cancer immunotherapy and tumor microenvironments.

The immune checkpoint blockade therapy has profoundly revolutionized the field of cancer immunotherapy. However, despite great promise for a variety of cancers, the efficacy of immune checkpoint inhibitors is still low in colorectal cancer (CRC). This is mainly due to the immunosuppressive feature of the tumor microenvironment (TME). Emerging evidence reveals that certain chemotherapeutic drugs induce immunogenic cell death (ICD), demonstrating great potential for remodeling the immunosuppressive TME. In this study, the potential of ginsenoside Rg3 (Rg3) as an ICD inducer against CRC cells was confirmed using in vitro and in vivo experimental approaches. The ICD efficacy of Rg3 could be significantly enhanced by quercetin (QTN) that elicited reactive oxygen species (ROS). To ameliorate in vivo delivery barriers associated with chemotherapeutic drugs, a folate (FA)-targeted polyethylene glycol (PEG)-modified amphiphilic cyclodextrin nanoparticle (NP) was developed for co-encapsulation of Rg3 and QTN. The resultant nanoformulation (CD-PEG-FA.Rg3.QTN) significantly prolonged blood circulation and enhanced tumor targeting in an orthotopic CRC mouse model, resulting in the conversion of immunosuppressive TME. Furthermore, the CD-PEG-FA.Rg3.QTN achieved significantly longer survival of animals in combination with Anti-PD-L1. The study provides a promising strategy for the treatment of CRC.

Novel treatment in multiple myeloma represented by proteasome inhibitors, immunomodulatory drugs and monoclonal antibodies have produced a deep response. However, relapses are possible, and all classes of drugs are refractory to patients. Next-generation sequencing has improved our understanding of the multiple myeloma genome related to drug resistance and has discovered many genomic variants. Therefore, this study was conducted to investigate new variants associated with drug resistance in MM patients who relapsed and refractory to bortezomib regimen and daratumumab treatment using next-generation sequencing for whole-exome sequencing. Peripheral blood samples were collected in EDTA tubes from six patients; four were in relapsed and refractory to bortezomib regimens and daratumumab; two patients responded to bortezomib regimens. Whole-exome sequencing was performed by the MGI-DNBSEQ-G400 instrument. We identified 21 variants in multiple myeloma patients. Seventeen variants were found in relapsed and refractory multiple myeloma in 11 genes (GNAQ, PMS1, CREB1, NSUNS2, PIK3CG, ROS1, PMS2, FIT4, KDM5A, STK11 and ZFHX3). And four variants were identified in two patients with response to bortezomib regimens in 4 genes (RAF1, CREB1, ZFHX3 and INSR). We have observed several genetic variants in many genes that may have been associated with the poor prognosis and poor response to treatment in these patients. These values should be further confirmed in large sample studies using the RNA-seq technique to identify genome expression.

Artificial intelligence (AI) is a general term that refers to the use of a machine to imitate intelligent behavior for performing complex tasks with minimal human intervention, such as machine learning; this technology is revolutionizing and reshaping medicine. AI has considerable potential to perfect health-care systems in areas such as diagnostics, risk analysis, health information administration, lifestyle supervision, and virtual health assistance. In terms of immunotherapy, AI has been applied to the prediction of immunotherapy responses based on immune signatures, medical imaging and histological analysis. These features could also be highly useful in the management of cancer immunotherapy given their ever-increasing performance in improving diagnostic accuracy, optimizing treatment planning, predicting outcomes of care and reducing human resource costs. In this review, we present the details of AI and the current progression and state of the art in employing AI for cancer immunotherapy. Furthermore, we discuss the challenges, opportunities and corresponding strategies in applying the technology for widespread clinical deployment. Finally, we summarize the impact of AI on cancer immunotherapy and provide our perspectives about underlying applications of AI in the future.

Genomic instability remains an enabling feature of cancer and promotes malignant transformation. Alterations of DNA damage response (DDR) pathways allow genomic instability, generate neoantigens, upregulate the expression of programmed death ligand 1 (PD-L1) and interact with signaling such as cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) signaling. Here, we review the basic knowledge of DDR pathways, mechanisms of genomic instability induced by DDR alterations, impacts of DDR alterations on immune system, and the potential applications of DDR alterations as biomarkers and therapeutic targets in cancer immunotherapy.

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Primary peritoneal malignant tumors are exceptional. Among them, clear cell carcinoma is extremely rare, being only thirteen cases previously reported in the literature since 1990. We report a case of a 48-year-old Caucasian woman who was treated at the University General Hospital of Alicante. She consulted because of progressive abdominal pain over the last seven months, with the initial diagnosis of renal-ureteral colic. Ultrasound and computed tomography of the abdomen and pelvis revealed a 25 × 15 cm, well-defined cystic lesion with papillary projections, centrally located in the abdomen. The radiology report suggested a primary ovarian tumor versus peritoneal implant as the first option. The patient underwent an exploratory laparotomy showing a large cystic mass located in the urinary bladder peritoneum, firmly attached to the mesentery. The entire abdominal tumor was completely excised, and total hysterectomy with bilateral salpingo-oophorectomy and infra-colical omentectomy were performed. The final histological study revealed a new case of primary peritoneal clear cell carcinoma located in the urinary bladder peritoneum, firmly attached to the mesentery. Grossly, it was well-circumscribed and multicystic with papillary growth involving part of the inner wall. Microscopically, it showed tubulocystic and papillary patterns with highly atypical tumor cells. After an extensive immunohistochemical analysis, the most relevant finding was an ARID1A loss that was corroborated by molecular analysis showing an ARID1A deletion. The patient received systemic chemotherapy with carboplatin and paclitaxel protocol (Å ~ 4 cycles). Patient follow-up after the eighth month showed peritoneal implants predominantly in the right diaphragmatic cupule that were histologically confirmed as recurrence. She has just received another six cycles of chemotherapy with carboplatin and paclitaxel. Recognition of primary peritoneal clear cell carcinoma in this uncommon location, and exclude metastasis from the ovary, represents a diagnostic challenge.

Recent studies have shown that cancers arise as a result of the positive selection of driver somatic events in tumor DNA, with negative selection playing only a minor role, if any. However, these investigations were concerned with alterations at nonrepetitive sequences and did not take into account mutations in repetitive sequences that have very high pathophysiological relevance in the tumors showing microsatellite instability (MSI) resulting from mismatch repair deficiency investigated in the present study.
We performed whole-exome sequencing of 47 MSI colorectal cancers (CRCs) and confirmed results in an independent cohort of 53 MSI CRCs. We used a probabilistic model of mutational events within microsatellites, while adapting pre-existing models to analyze nonrepetitive DNA sequences. Negatively selected coding alterations in MSI CRCs were investigated for their functional and clinical impact in CRC cell lines and in a third cohort of 164 MSI CRC patients.
Both positive and negative selection of somatic mutations in DNA repeats was observed, leading us to identify the expected true driver genes associated with the MSI-driven tumorigenic process. Several coding negatively selected MSI-related mutational events (n = 5) were shown to have deleterious effects on tumor cells. In the tumors in which deleterious MSI mutations were observed despite the negative selection, they were associated with worse survival in MSI CRC patients (hazard ratio, 3; 95% CI, 1.1-7.9; P = .03), suggesting their anticancer impact should be offset by other as yet unknown oncogenic processes that contribute to a poor prognosis.
The present results identify the positive and negative driver somatic mutations acting in MSI-driven tumorigenesis, suggesting that genomic instability in MSI CRC plays a dual role in achieving tumor cell transformation. Exome sequencing data have been deposited in the European genome-phenome archive (accession: EGAS00001002477).

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