The gut microbiome has been shown to influence the response of tumors to anti-PD-1 (programmed cell death-1) immunotherapy in preclinical mouse models and observational patient cohorts. However, ...modulation of gut microbiota in cancer patients has not been investigated in clinical trials. In this study, we performed a phase 1 clinical trial to assess the safety and feasibility of fecal microbiota transplantation (FMT) and reinduction of anti-PD-1 immunotherapy in 10 patients with anti-PD-1-refractory metastatic melanoma. We observed clinical responses in three patients, including two partial responses and one complete response. Notably, treatment with FMT was associated with favorable changes in immune cell infiltrates and gene expression profiles in both the gut lamina propria and the tumor microenvironment. These early findings have implications for modulating the gut microbiota in cancer treatment.
Objective
To compare characteristics, disease course, and prognosis of spontaneous versus iatrogenic benign metastasizing leiomyoma (BML).
Methods
A retrospective cohort study comparing iatrogenic ...and spontaneous BML.
Results
Twenty cases were included, 12 (60%) spontaneous and 8 (40.0%) iatrogenic with a median follow up of 3.4 years. The rate of asymptomatic presentation did not differ between study groups (P = 0.157). When symptoms occurred, dyspnea was more common in the spontaneous group (66.6% vs 0%, P = 0.023) and self‐palpation was more common in the iatrogenic group (57.1% vs 0%, P = 0.023). Intravascular masses were more common in the spontaneous group (66.6% vs 0%, P = 0.029). Rate of BML located in abdominal/pelvic cavity was higher in the iatrogenic group (100.0% vs 41.6%, P = 0.014). Of the 12 women in the spontaneous group, 50% had recurrent disease following surgical resection or unresectable lesions surgical resection was successfully attempted in seven of the eight (87.5%) women in the iatrogenic group, with no residual/recurrent disease. None of the patients died of her disease.
Conclusion
Spontaneous and iatrogenic BML can probably be regarded as two separate etiologies of the same pathologic phenomenon, usually with favorable prognosis. However, spontaneous BML may have a less favorable course.
Benign metastasizing leiomyoma (BML) is a rare condition of extrauterine leiomyomas. Spontaneous BML may carry less favorable characteristics than iatrogenic BML.
Emerging mutations in the ESR1 gene that encodes for the estrogen receptor (ER) are associated with resistance to endocrine therapy. ESR1 mutations rarely exist in primary tumors (~ 1%) but are ...relatively common (10-50%) in metastatic, endocrine therapy-resistant cancers and are associated with a shorter progression-free survival. Little is known about the incidence and clinical implication of these mutations in early recurrence events, such as local recurrences or newly diagnosed metastatic disease.
We collected 130 archival tumor samples from 103 breast cancer patients treated with endocrine therapy prior to their local/metastatic recurrence. The cohort consisted of 41 patients having at least 1 sample from local/loco-regional recurrence and 62 patients with metastatic disease (of whom 41 newly diagnosed and 28 with advanced disease). The 5 most common ESR1 hotspot mutations (D538G, L536R, Y537S/N/C) were analyzed either by targeted sequencing or by droplet digital PCR. Progression-free survival (PFS), disease-free survival (DFS), and distant recurrence-free survival (DRFS) were statistically tested by Kaplan-Meier analysis.
The prevalence of ESR1 mutations was 5/41 (12%) in newly diagnosed metastatic patients and 5/28 (18%) for advanced metastases, detected at allele frequency > 1%. All mutations in advanced metastases were detected in patients previously treated with both tamoxifen (TAM) and aromatase inhibitors (AI). However, in newly diagnosed metastatic patients, 4/5 mutations occurred in patients treated with TAM alone. PFS on AI treatment in metastatic patients was significantly shorter for ESR1 mutation carriers (p = 0.017). In the local recurrence cohort, ESR1 mutations were identified in 15/41 (36%) patients but only 4/41 (10%) were detected at allele frequency > 1%. Again, most mutations (3/4) were detected under TAM monotherapy. Notably, 1 patient developed ESR1 mutation while on neoadjuvant endocrine therapy. DFS and DRFS were significantly shorter (p = 0.04 and p = 0.017, respectively) in patients that had ESR1 mutations (> 1%) in their loco-regional recurrence tumor.
Clinically relevant ESR1 mutations are prevalent in newly diagnosed metastatic and local recurrence of endocrine-treated breast cancer. Since local recurrences are amenable to curative therapy, these mutations may inform the selection of subsequent endocrine therapies.
After the publication of the original article 1, we were notified the upper panel of the Fig. 1, where the patients' codes are listed, was cropped by mistake so the patients 1-8 are repeated.
Omics analyses often result in dozens to hundreds of potential targets, requiring validation for their biological relevance. Current high-throughput functional investigation methods are frequently ...labor-intensive, expensive, and display low reproducibility. The Immune Co-Culture Cell Microarray (ICCM) is a formalin-fixed paraffin-embedded cell block microarray based on co-cultures of patient-derived tumor-infiltrating lymphocytes and their autologous melanoma cells. Each ICCM slide represents the same experiment and can be stained using standard immunohistochemistry and immunofluorescence techniques. Functional dynamics assessment of both proteins and microRNAs using ICCM stained slides demonstrated similar findings to flow cytometry assays and to previously published patient-derived biopsy reports.
Can ovarian reserve parameters predict the outcome of ovarian tissue cryopreservation (OTCP) in patients ≤18 years with non-iatrogenic premature ovarian insufficiency (POI)?
Retrospective cohort ...analysis carried out in a single tertiary hospital between August 2010 and January 2020. Thirty-seven patients ≤18 years with non-iatrogenic POI (27 with Turner syndrome, six with POI of unknown aetiology, three with galactosemia and one with blepharophimosis, ptosis, epicanthus inversus syndrome) were included. Three parameters were used to evaluate ovarian reserve: anti-Müllerian hormone (AMH), follicle-stimulating hormone (FSH) and transabdominal antral follicle count. Fertility preservation (most commonly OTCP) was offered if ovarian reserve was diminished and one or more parameters was positive. Follicles were counted in ovarian samples obtained at the time of OTCP.
Ovarian reserve was diminished in 34 patients and 19 of them had one or more positive parameter. Fourteen (11 aged ≥12 years and 3 aged <12) underwent OTCP, one (14 years old) underwent ovarian stimulation and oocyte cryopreservation and four declined fertility preservation. Follicles were detected in 11 of 14 patients who underwent OTCP with one or more positive parameters (79%), and in all those (100%) who had two or three positive parameters. The median number of follicles was 27 (range 5–64) and 48 (range 21–75) in patients ≥12 years and those <12 years, respectively.
This study shows that if OTCP is performed in patients with one or more positive parameters of ovarian activity, a 79% positive predictive value is achieved for the detection of follicles. The incorporation of this criterion for OTCP will minimize the risk of harvesting ovarian tissue with a low number of follicles.
Abstract
Background: The majority of metastatic melanoma patients treated with Programed cell Death (PD)-1 blockade fail to achieve durable response. The gut microbiota profoundly affects host ...immunity, and fecal microbiota transplantations (FMT), which transfers the entire gut microbiota from one host to another, has been shown to enhance anti-PD-1 effectiveness in murine models. We report initial safety and efficacy results from the first three patients treated on a Phase I study of FMT and re-induction anti-PD-1 therapy in anti-PD-1 refractory metastatic melanoma.
Methods: FMT donors were two metastatic melanoma patients who achieved a durable complete response. FMT Recipients were metastatic melanoma patients who failed at least one anti-PD-1 line of treatment. FMT was conducted by both colonoscopy and oral ingestion of stool capsules, followed by anti-PD-1 re-treatment (Nivolumab, BMS). Each recipient underwent pre- and post-treatment stool sampling, tissue biopsy of both gut and tumor, and total body imaging.
Results: Recipients #1 and #3 received fecal implants from Donor #1, while Recipient #2 receive implants from Donor #2. No FMT-related or immunotherapy-related adverse events were observed. To assess engraftment of the new microbiota, recipients were paired with their respective donors and stool 16S rDNA gene sequence analysis performed. Ideal engraftment from a single donor would result in identical microbiota composition between that donor and recipients. In the case of two donors, ideal engraftment would result in two distinctive recipient-donor compositions. Sequencing results demonstrated post-FMT compositional dissimilarity (Unweighted UniFrac, p=0.04, FDR q=0.22) between the two recipient-donor groups. Immunohistochemical stains of biopsies demonstrated an increased post-FMT infiltration of antigen presenting cells (CD68+) in the gut (paired T test, p=0.008) and in the tumor (p=0.076). Post-treatment intra-tumoral CD8+ T-cells infiltration was
also increased (p=0.096), especially in recipients #1, #3. Recipient #1 and Recipient #3 demonstrated clinical and radiological benefit from treatment.
Conclusion: FMT in metastatic melanoma patients seemed to be safe and may alter recipient gut microbiota to resemble that of a responder donor. This alteration may result in intra-tumoral T-cell activity, which was translated to a clinical and radiological benefit in two recipients.
Citation Format: Erez N. Baruch, Ilan Youngster, Rona Ortenberg, Guy Ben-Betzalel, Lior H. Katz, Adi Lahat, Iris Barshack, Daniela Dick-Necula, Ronac Mamtani, Naamah Bloch, Bella Ungar, Daniel Rotin, Camila Avivi, Liat Anafi, Yael Steinberg-Silman, Nethanel Asher, Ronnie Shapira-Frommer, Tal Brosh-Nissimov, Yael Eshet, Stephen Raskin, Hagit Harati, Jenny Melnichenko, Jacob Schachter, Omry Koren, Gal Markel, Ben Boursi. Fecal microbiota transplantation (FMT) and re-induction of anti-PD-1 therapy in refractory metastatic melanoma patients - preliminary results from a phase I clinical trial (NCT03353402) abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr CT042.
On Hoofs and Zebras - Struma Ovarii Schattner, Ami; Dubin, Ina; Uliel, Livnat ...
The American journal of medicine,
11/2023, Volume:
136, Issue:
11
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