Pembrolizumab, a programmed death 1 ligand (PD‐1) checkpoint inhibitor, has elicited responses in mismatch repair (MMR)–deficient advanced solid tumors, leading to its agnostic approval by the US ...Food and Drug Administration in 2017 when no other therapeutic options are available. However, there are still insufficient data on the response to checkpoint inhibitors in advanced endometrial cancer related to Lynch syndrome (LS) and, specifically, in uterine serous carcinoma, which is uncommon in LS. Here we report a case of metastatic uterine serous carcinoma due to a germline MSH6 mutation (Lynch syndrome) that was discovered because of a patient's tumor MMR deficiency. The patient was started on first‐line pembrolizumab in 2018 and sustained a partial response. She remains asymptomatic and progression free for more than 2 years. Tumor sequencing showed a high mutational burden and an upstream somatic mutation in the same gene, p.F1088fs. Immunohistochemical staining was negative for PD‐L1 expression. We discuss clinical characteristics of the patient, molecular features of her tumor, and the mechanism of her tumor response. We also discuss the duration of immunotherapy in her case.
Our case demonstrated a partial response and a long‐term remission from the frontline single‐agent pembrolizumab in a woman with metastatic uterine serous carcinoma and Lynch syndrome due to a germline MSH6 gene mutation. Our experience suggests a potential significant clinical benefit of checkpoint inhibitors used as single agents early on in the treatment of MMR‐deficient/high microsatellite instability/hypermutated uterine cancers in women with Lynch syndrome.
Key Points
Even though checkpoint inhibitors are effective in mismatch repair‐deficient endometrial cancer, it is unknown whether the response to them differs between women with endometrial cancer due to germline mutations in a mismatch repair gene (Lynch syndrome) and women with sporadic endometrial cancer.
In our case, a patient with Lynch syndrome and recurrent mismatch repair‐deficient serous endometrial cancer achieved a durable remission on the first‐line therapy with the checkpoint inhibitor pembrolizumab and remains progression free after more than 2 years.
Based on our observation and the data, suggesting the stronger immune activation in women with Lynch syndrome–associated endometrial cancer, we propose to use checkpoint inhibitor monotherapy early in the course of their treatment and stratify patients for the presence of Lynch syndrome in clinical trials.
This case report describes a partial response and a long‐term remission from the front‐line single‐agent pembrolizumab in a patient with metastatic uterine serous carcinoma and Lynch syndrome due to a germline MSH6 gene mutation, suggesting a potential significant clinical benefit of checkpoint inhibitors used as single agents early on in the treatment of uterine cancers in women with Lynch syndrome.
Cracks in amalgam-filled teeth may be related to amalgam expansion. This study measured cuspal flexure and used finite element analysis to assess associated stress levels in amalgam-filled teeth.
...External surfaces of 18 extracted molars were scanned in three dimensions. Nine molars were restored with mesio-occluso-distal amalgam fillings; the other teeth were left intact as controls. All teeth were stored in saline and scanned after two, four, and eight weeks. Cuspal flexure and restoration expansion were determined by calculating the difference between scanned surfaces. Stresses in a flexed tooth were calculated using finite element analysis.
Cusps of amalgam-filled teeth flexed outward approximately 3 μm, and restoration surfaces expanded 4 to 8 μm during storage. Cuspal flexure was significantly higher in the amalgam group (multivariate tests, p<0.05), but storage time had no significant effect (repeated measures, p>0.05). Expansion caused stress concentrations at the cavity line angles. These stress concentrations increased stresses due to mastication 44% to 178%.
Amalgam expansion pushed cavity walls outward, which created stress concentrations at the cavity line angles. Expansion stresses can raise stresses in amalgam-filled teeth and contribute to incidentally observed cracks.
•We analyzed documented PDE5 inhibitor use in prostate cancer post radical prostatectomy•Documented PDE5 inhibitor use has a positive association with overall survival•Documented PDE5 inhibitor use ...has a positive association with biochemical relapse-free survival•Further studies investigating this association are needed for validation
To determine whether phosphodiesterase-5 inhibitor documentation is associated with biochemical relapse-free and overall survival of patients with prostate cancer treated with radical prostatectomy.
We undertook a retrospective cohort analysis of 3,100 patients with prostate cancer treated with radical prostatectomy between 2003 and 2015. The patients were categorized as a phosphodiesterase- 5- inhibitor user or non-user. The biochemical relapse-free and overall survival at 5-years and 10-years were determined.
Of the patients, 1,372 reported phosphodiesterase-5 inhibitor documentation, and 1,728 did not. The biochemical recurrence-free survival for non-users at 5- and 10-years follow-up was 87.6% and 85.3%, respectively, and the overall survival at these time intervals was 97.9% and 94.5%. The biochemical recurrence-free survival for phosphodiesterase-5 inhibitor users was 94.3% and 93.2% at 5- and 10-years follow-up, respectively, and overall survival was 99.2% and 95.8% at these intervals. The hazard ratio for biochemical recurrence-free survival was 0.44 (CI 0.34–0.56) and for overall survival was 0.65 (CI 0.45–0.94). On the multivariate analysis, phosphodiesterase-5 inhibitor documentation was associated with a lower risk of biochemical recurrence and death when corrected for the other variables. Age at surgery and Gleason scores >8 was associated with a higher risk of death. Higher pathological stage, higher Gleason score, presence of lymph node metastases, and nonwhite race were associated with a higher risk of recurrence.
This retrospective analysis revealed a significant association of postoperative phosphodiesterase-5 inhibitor documentation with biochemical recurrence-free- and overall survival in patients with localized prostate cancer treated with radical prostatectomy. Larger scale studies are warranted to investigate the clinical significance of this association.
We present new precision measurements of the elastic electron-proton scattering cross section for momentum transfer (Q^{2}) up to 15.75 (GeV/c)^{2}. Combined with existing data, these provide an ...improved extraction of the proton magnetic form factor at high Q^{2} and double the range over which a longitudinal or transverse separation of the cross section can be performed. The difference between our results and polarization data agrees with that observed at lower Q^{2} and attributed to hard two-photon exchange (TPE) effects, extending to 8 (GeV/c)^{2} the range of Q^{2} for which a discrepancy is established at >95% confidence. We use the discrepancy to quantify the size of TPE contributions needed to explain the cross section at high Q^{2}.
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