A Familial Case of Multiple Endocrine Neoplasia 2A: From Morphology to Genetic Alterations Penetration in Three Generations of a Family.

This paper illustrates a rare syndrome of multiple endocrine neoplasia type 2A (MEN2A) in a family of three generations. In our case, the father, son and one daughter developed phaeochromocytoma (PHEO) and medullary thyroid carcinoma (MTC) over a period of 35 years. Because of the metachronous onset of the disease and lack of digital medical records in the past, the syndrome was not found until a recent fine needle aspiration of an MTC-metastasized lymph node from the son. All resected tumors from the family members were then reviewed and supplemented with immunohistochemical studies, previously wrong diagnoses were then corrected. Further molecular study of targeted sequencing also revealed a RET germline mutation (C634G) in the family tree including the three members with onset of the disease and one granddaughter who had no disease at the time of testing. Despite the syndrome being well-known, it may still be misdiagnosed because of its rarity and long disease onset. A few lessons can be learned from this unique case. Successful diagnosis requires high suspicion and surveillance and a tri-level methodology including a careful review of family history, pathology and genetic counselling.

The Effect of immunotherapy on oligometastatic non-small cell lung cancer patients by sites of metastasis.

Introduction: The efficacy of immunotherapy for treatment of patients with oligometastatic non-small cell lung cancer (NSCLC) at different metastatic sites remains controversial. We investigated the effect of different metastatic sites on immunotherapy for oligometastatic NSCLC following local treatment (LT). Methods: We retrospectively analyzed patients with oligometastatic NSCLC from the latest 2018 registry on the SEER Stat software (8.3.9. Version) and a Chinese single-center cohort. The effects of immunotherapy on OS (overall survival) and CSS (cancer specific survival) were estimated for patients with different metastatic sites. Results: A total of 483 patients in the SEER-18 database and 344 patients in the single-center cohort were included. Immunotherapy was significantly correlated with improved OS (SEER: Hazard ratio 0.754, 95% CI 0.609-0.932; P=0.044; China: Hazard ratio 0.697, 95% CI 0.542-0.896; P=0.005) and CSS (SEER: Hazard ratio 0.743, 95% CI 0.596-0.928; P=0.009; China: Hazard ratio 0.725, 95% CI 0.556-0.945; P=0.018). Subgroup analysis showed that OS was improved after immunotherapy in the BRM (SEER: Hazard ratio 0.565, 95% CI 0.385-0.829; P=0.004; China: Hazard ratio 0.536, 95% CI 0.312-0.920; P=0.024) and MOM (SEER: Hazard ratio 0.524, 95% CI 0.290-0.947; P=0.032; China: Hazard ratio 0.469, 95% CI 0.235-0.937; P=0.032) subgroups, but not in the BOM (SEER: P=0.334; China: P=0.441), LIM (SEER: P=0.301; China: P=0.357), or OTM (SEER: P=0.868; China: P=0.489) subgroups. Conclusions: This study showed that immunotherapy conferred survival benefits on patients with oligometastatic NSCLC. Our subgroup analysis suggested that patients with oligometastatic NSCLC in the brain or multiple organs may particularly benefit from aggressive front-line therapies.

[Clinical results of arthroscopic anterior cruciate ligament reconstruction with short femoral tunnel].

OBJECTIVE: To evaluate the clinical outcome of arthroscopic reconstruction of anterior cruciate ligament (ACL) with short femoral tunnel. METHODS: From May 2013 to June 2017, 128 patients with anterior cruciate ligament reconstruction were performed with Transportal technique. Among them, 32 cases had short femoral tunnel were included, including 13 males and 19 females, aged 25.8 (17 to 43) years old, with a mean history of (4.5±1.1) months. The tibial tunnels were drilled in the middle of the footprint of the ACL, and femoral tunnels were drilled by transportal technique. Grafts were fixed with Endobutton at the femoral side and with interference screw at the tibial side. The changes of symptoms and signs were observed and the anterior tibial displacement was measured. The function of knee joint was evaluated by Lysholm score and Tegner score. RESULTS: All patients were followed up for over 2 years. At the latest follow-up, 30 patients were negative and 2 patients were positive in knee shift test; 28 patients were negative in Lachman sign, 4 patients were positive in degree I; 30 patients were negative in anterior drawer test, 1 patient was positive in degree I and 1 patient was positive in degree II. The anterior displacement of the tibia increased by (2.6±1.8) mm compared with the healthy side, which was significantly different from that before operation (t=19.77, P<0.05). Lysholm score of 82.2±6.1 was significantly higher than that before operation (t=17.33, P=0.001). According to Lysholm score evaluation, 15 cases got an excellent result, 10 were good, 7 were fair, and no bad results, with a significant difference compared with that before operation (z=-7.151, P<0.05). Tegner motor function score of (7.4±0.6) was significantly different from that before operation (t=9.11, P=0.000 5). After operation, the knee joint movement ability of the patients improved significantly. Twelve patients could participate in antagonistic sports and 15 patients could participate in non-antagonistic sports. Fifteen patients were very satisfied with the curative effect, 13 patients were satisfied with the curative effect. CONCLUSIONS: The incidence of short femoral tunnel in anterior cruciate ligament reconstruction with transportal technique is 25%. At present, the clinical effect of patients with short tunnel is acceptable. However, due to the lack of comparative study, the effect of short tunnel on the curative effect is still unclear.

[Acupuncture treatment of oligoasthenozoospermia].

Studies show that acupuncture can significantly elevate the level of serum testosterone (T), reduce the concentrations of follicle-stimulating hormone (FSH), luteinizing hormone (LH) and estradiol (E2), initiate spermatogenesis, enhance testicular blood flow, maintain a relative low temperature in the testis, increase the concentration, motility and antioxidative injury capability of spermatozoa by raising the levels of seminal α-glucosidase, fructose and super oxide dismutase, and eventually improve semen quality and the rate of conception in the treatment of oligoasthenozoospermia. Currently, the quality of the clinical studies of acupuncture treatment of oligoasthenozoospermia is relatively poor, the existing evidence remains at a low level, its clinical application is limited, and its therapeutic effect has to be further verified. The present paper summarizes the literature from domestic and international databases about acupuncture treatment of oligoasthenozoospermia, and offers an overview of the effects of acupuncture on the reproductive endocrine system, testicular blood flow, semen quality, and rate of conception in the treatment of the patient.

Concurrent involved-field radiotherapy and XELOX in gastric cancer patients with postoperative oligometastatic recurrence.

PURPOSE: The aim of this study was to retrospectively observe gastric adenocarcinoma patients with postoperative oligometastatic recurrence and investigated the effects of concurrent involved-field radiotherapy (RT) and XELOX on progression-free survival (PFS). PATIENTS AND METHODS: From 2008 to 2011, 246 patients underwent curative resection of gastric carcinoma was enrolled. A retrospective review was performed on 34 patients with distant recurrence. Among them, 19 patients were oligometastases patients, where 13 patients received involved-field RT with a dose of 40-60 Gy by an intensity-modulated RT technique and concurrent XELOX chemotherapy, four patients were treated with XELOX chemotherapy alone (oxaliplatin 130 mg/m2, capecitabine 1000 mg/m2, twice daily, 3 week each cycle), and two patients with only brain metastasis were not included in the analysis. RESULTS: The median PFS was 11 months in the 13 oligometastatic patients who received concurrent involved-field RT and XELOX. The oligometastatic patients receiving concurrent radiochemotherapy trended toward a better median PFS when compared with those receiving chemotherapy alone. CONCLUSIONS: For patients with postoperative oligometastatic recurrence, concurrent involved-field RT and XELOX showed better responses and was a choice for first-line treatment.

Nonpolar and short side chain groups at C-11beta of estradiol result in antiestrogens.

We have previously found that esters of 11beta-estradiol carboxylates are transformed from an estrogen into an antiestrogen when the 11beta-side chain is increased in length from four to five non-hydrogen atoms (n > or = 5). To understand the structural requirements for this transformation and obtain metabolically stable analogues that are not susceptible to esterase cleavage, we have synthesized other compounds having an 11beta-side chain composed of other functional groups: ketones, amides, ethers, and thiono esters. With the exception of amides, which bind poorly to the estrogen receptor (ER), all of these compounds exhibit antiestrogenic action when the side chain length is n > or = 5. Ethers (n > or = 5), studied in more detail, inhibit the action of estradiol with either ERalpha or ERbeta. In rat uteri they are estrogen antagonists/weak agonists and decrease the concentration of cholesterol in blood (an hepatic estrogenic action). Thus, these short chain and nonpolar 11beta-analogues of estradiol have tissue specific antiestrogenic/estrogenic actions, characteristics of selective estrogen receptor modulators.

Estrogen to antiestrogen with a single methylene group resulting in an unusual steroidal selective estrogen receptor modulator.

Selective estrogen receptor (ER) modulators (SERMs) are important therapeutic agents for breast cancer prevention and treatment. We have synthesized two analogs, E11-2,1 [methyl-(3,17beta-dihydroxyestra-1,3,5(10)-triene-11beta-yl)acetate] and E11-2,2 [ethyl-(3,17beta-dihydroxyestra-1,3,5(10)-triene-11beta-yl)acetate], the methyl and ethyl esters of an estradiol analog, substituted in the B ring at C-11beta with a carboxymethyl group. The shorter methyl ester, E11-2,1, has high ER affinity and high estrogenic potency in the Ishikawa estrogen cell bioassay, whereas the longer ethyl ester, E11-2,2, has even higher ER affinity, but little or no estrogenic activity. We found that this minor change of one methylene group transforms a potent estrogenic agonist into an antagonist in vitro with either ER alpha or beta. In the rat, E11-2,2 acts as a SERM in the uterus, where it inhibits estradiol-induced proliferation, and as an estrogen agonist in the liver and skeleton, where it decreases plasma cholesterol and increases bone growth. The characteristic feature of antiestrogens, including SERMs, is a long and polar side-chain that prevents agonist-induced conformation of helix 12 of ER. E11-2,2 with its short, nonpolar side-chain, lacks this critical structure, presenting the possibility that it might act through a unique mechanism.

Synthesis and evaluation of B-, C-, and D-ring-substituted estradiol carboxylic acid esters as locally active estrogens.

We have synthesized derivatives of estradiol that are structurally modified to serve as "soft" estrogens and act within a geographically limited area of the body; estrogens without systemic action. We have previously shown with 16alpha-substituted analogues of estradiol that carboxylates proximal to the steroid ring neither bind to the estrogen receptor nor activate estrogen-responsive genes. However, when the carboxylic acid is masked as an ester, they bind to the receptor and stimulate estrogenic responses. Enzymatic hydrolysis through nonspecific esterases can inactivate these estrogens and thereby limit their area of action. Here, we describe our continued studies to design "soft" estrogens by synthesizing carboxylic acid esters of estradiol at the 7alpha-, 11beta-, and 15alpha-positions in the steroid nucleus at which bulky substituents are accommodated by the estrogen receptor. These compounds were tested for estrogen receptor binding (estrogen receptors alpha and beta), stimulation of an estrogen sensitive gene in Ishikawa cells in culture, and as substrates for enzymatic hydrolysis. Likely candidates were tested in in vivo assays for systemic and local estrogenic action. The biological studies showed that regardless of the point of attachment, all of the short-chain carboxylic acids, C-1 to C-3, were devoid of hormonal action, while many of the esters were estrogenic. The site on the steroid nucleus had great influence on hormonal activity and esterase hydrolysis. Formate esters at 7alpha and 15alpha were good estrogens, but lengthening the chain to acetate dramatically decreased hormonal activity. However, the 7alpha-formate esters were not enzymatically hydrolyzed. At 11beta, the acetate (methyl ester) was an effective estrogen, but increasing the chain length to propionate dramatically reduced hormonal activity. In general, the length of the alcohol from methyl to butyl had only a small effect on receptor binding, and as the size of the alcohol increased, so did esterase hydrolysis. One exception was the 11beta-acetate esters where increasing the alcohol moiety from methyl to ethyl eliminated estrogenic activity (Ishikawa cells) without affecting estrogen receptor binding. Several of the esters were tested in vivo, and two, the methyl and ethyl esters of estradiol-15alpha-formate, appeared to have the requisite properties (high local and low systemic activity) of superior "soft" estrogens.