CDK4/6 and aromatase inhibitors as first-line treatment in metastatic high-grade neuroendocrine carcinoma of the breast: A case report.

Key Clinical Message: There is no consensus regarding the therapeutic approach of breast neuroendocrine carcinomas (NECs). As most NECs are hormone receptor positive and HER-2 negative, we suggest that endocrine-based strategies may play a leading role. Here, we report a new treatment strategy by incorporating CDK4/6 inhibitors in the therapeutic armamentarium. Abstract: Primary neuroendocrine neoplasms of the breast constitute a rare entity. They are characterized by predominant neuroendocrine differentiation and are further divided into well-differentiated neuroendocrine tumors and poorly differentiated (high-grade) neuroendocrine carcinomas (NECs). Regarding their therapeutic approach, there are no standardized guidelines. Herein, we present the first case ever reported, concerning a female patient with de novo metastatic breast NEC who received hormonal therapy, a combination of a CDK4/6 inhibitor palbociclib with letrozole and triptorelin, as first-line treatment with significant clinical and radiological response. As most NECs are estrogen receptor and/or progesterone receptor positive and HER-2 negative, we suggest that hormonal therapy may play a leading role even in the first-line setting. The present report provides a new treatment strategy by incorporating CDK4/6 inhibitors in the therapeutic armamentarium of breast NECs.

Laying the groundwork for the Biobank of Rare Malignant Neoplasms at the service of the Hellenic Network of Precision Medicine on Cancer.

Biobanks constitute an integral part of precision medicine. They provide a repository of biospecimens that may be used to elucidate the pathophysiology, support diagnoses, and guide the treatment of diseases. The pilot biobank of rare malignant neoplasms has been established in the context of the Hellenic Network of Precision Medicine on Cancer and aims to enhance future clinical and/or research studies in Greece by collecting, processing, and storing rare malignant neoplasm samples with associated data. The biobank currently comprises 553 samples; 384 samples of hematopoietic and lymphoid tissue malignancies, 72 samples of pediatric brain tumors and 97 samples of malignant skin neoplasms. In this article, sample collections and their individual significance in clinical research are described in detail along with computational methods developed specifically for this project. A concise review of the Greek biobanking landscape is also delineated, in addition to recommended technologies, methodologies and protocols that were integrated during the creation of the biobank. This project is expected to re­enforce current clinical and research studies, introduce advances in clinical and genetic research and potentially aid in future targeted drug discovery. It is our belief that the future of medical research is entwined with accessible, effective, and ethical biobanking and that our project will facilitate research planning in the '­omic' era by contributing high­quality samples along with their associated data.

Macrophage Involvement in Medication-Related Osteonecrosis of the Jaw (MRONJ): A Comprehensive, Short Review.

Antiresorptive agents such as bisphosphonates (BP) and denosumab are commonly prescribed for the management of primary bone malignancy, bone metastasis, osteoporosis, Paget disease, or other bone disorders. Medication-related osteonecrosis of the Jaws (MRONJ) is a rare but significant complication of antiresorptive medications. Duration, dose, and antiresorptive potency as well as concomitant diseases, additional medications, and local factors affect MRONJ incidence and severity. MRONJ pathophysiology is still poorly understood. Nevertheless, decreased bone resorption due to osteoclastic inhibition along with trauma, infection/inflammation, or blood supply inhibition are considered synergistic factors for disease development. In addition, previous data research examined the effects of antiresorptive medication on immune system components and introduced potential alterations on immune response as novel elements in MRONJ pathogenesis. Considering that macrophages are the first cells in the nonspecific immune response, it is not surprising that these multifaceted players attracted increased attention in MRONJ research recently. This current review attempted to elucidate the effects of antiresorptive medications on several aspects of macrophage activity in relation to the complex inflammatory microenvironment of MRONJ. Collectively, unravelling the mode of action and extent of macrophages' potential contribution in MRONJ occurrence will provide novel insight in disease pathogenesis and potentially identify intrinsic therapeutic targets.

MTOR/4EBP1 signaling and MMR status in colorectal cancer: New correlations and arising perspectives.

This is the first study aiming to investigate mTOR signaling and its relation to mismatch repair status (MMR status) in colorectal cancer (CRC). MMR status and the phosphorylated proteins, pmTOR and p4EBP1, have been immunohistochemically analyzed in 108 formalin-fixed, paraffin-embedded CRC specimens. The correlations between them and with clinicopathological data, MAPK pathway (KRAS, NRAS, BRAF) as well as their impact on patients' overall survival have been statistically analyzed. Our results indicated that positive pmTOR expression was significantly associated with KRAS mutations (p = 0.004). From multivariate survival analysis, only p4EBP1 expression emerged as independent adverse prognostic factor for overall survival (HR, 3.322; 95%CI, 1.110-9.945; p = 0.032). Furthermore, MMR deficient carcinomas tend to express low p4EBP1 protein levels (p = 0.002). A survival analysis stratified by MMR status and p4EBP1 expression, showed that MMR proficient tumours with high p4EBP1 expression had the worst overall survival compared with the other examined subgroups (p = 0.019). In conclusion, MAPK and PI3k/Akt pathways seem to be simultaneously overactivated in CRC. P4EBP1 could be used as a prognostic biomarker. By further analyzing the significant association between MMR status and p4EBP1 expression, we suggest that MMR deficient tumours could represent a subpopulation most likely to derive treatment benefit from mTOR inhibition.

Melanoma and Sarcoidosis in Patients Receiving or Not Antineoplastic Therapy.

Sarcoidosis and sarcoid-like reactions have been associated with many solid tumors including malignant melanoma. There are reports of melanoma patients who develop sarcoidosis without having received any antineoplastic treatment, but there are also melanoma patients who have received immunotherapy or targeted therapy and, therefore, develop drug-associated sarcoidosis. Herein, we describe 2 cases of thoracic sarcoidosis which occurred in asymptomatic patients with known malignant melanoma. The first patient had metastatic disease, and she was under melanoma treatment with BRAF/MEK inhibitors at the time of sarcoidosis diagnosis. The second case involves a patient with early stage melanoma who had received no antineoplastic treatment. In both cases, the thoracic lesions were suspicious for metastatic involvement, and it was the biopsy which gave the diagnosis of granulomatous disease. Sarcoidosis induced by immune checkpoint or BRAF/MEK inhibitors seems to be more frequent in real-world studies than in large phase 3 melanoma trials. Sarcoidosis can mimic metastasis, predominately in mediastinum, representing a diagnostic pitfall. Therefore, biopsies must always be performed to exclude the metastatic spread before initiation of any antineoplastic treatment.

Granulomatous colitis in a patient with metastatic melanoma under immunotherapy: a case report and literature review.

BACKGROUND: Immune checkpoint inhibitors (ICPIs) have changed the way advanced malignancies are currently confronted, improving cancer patients' outcomes but also generating distinct immune-related (ir) adverse events. ICPIs-induced colitis is a common complication showing different clinical and histological manifestations. In the literature review, 14 cases with ICPIs related colon granulomas have been reported in 5 studies with either limited or unavailable information regarding histology. Granulomatous reactions can be mistakenly perceived as disease recurrence or progression. Better understanding and identification of this infrequent histological display can help to avoid misdiagnosis and mismanagement. CASE PRESENTATION: A 63-year-old female patient with metastatic melanoma was admitted to the hospital with symptoms of nausea, persistent diarrhea and shivering fever under consecutive treatments with ICPIs, initially pembrolizumab and subsequently ipilimumab. Sigmoidoscopy was performed revealing mucosal edema, hyperemia and erosions of the rectum and sigmoid colon. Histological evaluation of sigmoid colon mucosa biopsies revealed an unusual colitis pattern characterized by multiple intracryptal granulomas attributed to ICPIs therapy. Steroids were administered and the patient recovered. ICPIs treatment was discontinued. The patient was subsequently treated with chemotherapy but follow up radiology showed disease progression. A re-challenge with another ICPI regimen was decided and the patient is currently under immunotherapy with stable disease regarding melanoma status and without any sign of colitis recurrence. CONCLUSIONS: The present report provides detailed histological description of a distinctive ICPIs-induced granulomatous colitis and highlights the need for awareness of the distinct adverse events and reaction patterns in the context of immunotherapy.