Phase II study of capecitabine-based concomitant chemoradiation followed by durvalumab as a neoadjuvant strategy in locally advanced rectal cancer: the PANDORA trial.

BACKGROUND: This study investigated the efficacy of chemoradiotherapy (CRT) followed by durvalumab as neoadjuvant therapy of locally advanced rectal cancer. PATIENTS AND METHODS: The PANDORA trial is a prospective, phase II, open-label, single-arm, multicenter study aimed at evaluating the efficacy and safety of preoperative treatment with durvalumab (1500 mg every 4 weeks for three administrations) following long-course radiotherapy (RT) plus concomitant capecitabine (5040 cGy RT in 25-28 fractions over 5 weeks and capecitabine administered at 825 mg/m2 twice daily). The primary endpoint was the pathological complete response (pCR) rate; secondary endpoints were the proportion of clinical complete remissions and safety. The sample size was estimated assuming a null pCR proportion of 0.15 and an alternative pCR proportion of 0.30 (α = 0.05, power = 0.80). The proposed treatment could be considered promising if ≥13 pCRs were observed in 55 patients (EudraCT: 2018-004758-39; NCT04083365). RESULTS: Between November 2019 and August 2021, 60 patients were accrued, of which 55 were assessable for the study's objectives. Two patients experienced disease progression during treatment. Nineteen out of 55 eligible patients achieved a pCR (34.5%, 95% confidence interval 22.2% to 48.6%). Regarding toxicity related to durvalumab, grade 3 adverse events (AEs) occurred in four patients (7.3%) (diarrhea, skin toxicity, transaminase increase, lipase increase, and pancolitis). Grade 4 toxicity was not observed. In 20 patients (36.4%), grade 1-2 AEs related to durvalumab were observed. The most common were endocrine toxicity (hyper/hypothyroidism), dermatologic toxicity (skin rash), and gastrointestinal toxicity (transaminase increase, nausea, diarrhea, constipation). CONCLUSION: This study met its primary endpoint showing that CRT followed by durvalumab could increase pCR with a safe toxicity profile. This combination is a promising, feasible strategy worthy of further investigation.

Sexual function after vaginal erbium laser: the results of a large, multicentric, prospective study.

The aim of this multicentric, prospective study was to evaluate the effects of vaginal erbium laser (VEL-SMOOTH®) on sexual function in postmenopausal women suffering from the genitourinary syndrome of menopause (GSM). This study was performed on an outpatient basis without anesthesia or drug use before or after the intervention, using an erbium laser (XS Fotona Smooth®, Fotona, Ljubljana, Slovenia) in 1081 postmenopausal women (age 54.3 ± 3.9 years) treated with up to three laser applications every 30 days. Patients were assessed using the Female Sexual Function Index (FSFI) and the Female Sexual Distress Scale-Revised (FSDS-R). No adverse events were recorded during the study. The FSDS-R scores (n = 554), from basal values of 25.5 ± 3.5, were 11.5 ± 3.0, 10.5 ± 3.5 and 11.5 ± 3.5 at the 4-, 12- and 24-week follow-ups, respectively (p < 0.01 vs. corresponding basal values). Individual FSFI domain scores (n = 569) significantly (p < 0.001) increased after VEL-SMOOTH® treatment and remained significantly higher up to the 24th week after the end of treatment. The total scores, from basal values of 15.5 ± 1.5, were 27.5 ± 2.5, 27.6 ± 2.7and 27.0 ± 3.5 at the 4-, 12- and 24-week follow-ups, respectively (p < 0.01 vs. corresponding basal values). Albeit not randomized, this large, prospective study shows that VEL-SMOOTH® treatment may improve sexual function in postmenopausal women suffering from GSM.

Rationale and design for the Vaginal Erbium Laser Academy Study (VELAS): an international multicenter observational study on genitourinary syndrome of menopause and stress urinary incontinence.

The genitourinary syndrome of menopause (GSM) and stress urinary incontinence (SUI) are common clinical challenges for women's health and quality of life. The laser treatment and particularly the vaginal erbium laser (VEL) may provide a new non-invasive treatment for both GSM and SUI. However, the estimation of the ultimate results of different laser treatments may be altered by different issues, such as patient selection, concomitant treatments, and long-term effect of vaginal laser thermotherapy. In the present paper, we present the protocol for a large multicenter study on the evaluation of the efficacy and safety of VEL for the treatment of GSM and SUI, the Vaginal Erbium Laser Academy Study (VELAS). This study will evaluate the effects of three laser applications in 1500 postmenopausal women. Subjective and objective symptoms will be evaluated prior to the first laser treatment with follow-up visits after 4 weeks from the last laser application, and subsequently after every 3 months for 1 year. Findings from the VELAS have the potential to affect clinical care practice and health decisions for millions of women world-wide for a non-hormonal treatment for GSM and a non-invasive treatment of SUI.

Lack of association of CYP1 B1*3 polymorphism and ovarian cancer in a Caucasian population.

CYP1B1 is the enzyme with the highest efficiency of conversion of estradiol to 4-hydroxyestradiol in humans. This metabolite has a well-known carcinogenic effect interacting with genomic DNA and has been hypothesized to be partly responsible for the role played by estrogens in ovarian cancer development. A polymorphism has been described for this enzyme causing a Leu to Val substitution in position 432 (CYP1B1*3). The Val432 allele has a higher efficiency of conversion of estradiol to 4-hydroxyestradiol and has been reported to increase the risk of ovarian cancer. A previous study reported a higher, significant prevalence of CYP1B1*3 polymorphism in ovarian cancer patients of mixed ethnicity. The aim of this study was to investigate the role of CYP1B1*3 polymorphism as a risk factor for ovarian cancer in a Caucasian population. The polymorphism frequency was determined in 223 cases of ovarian cancer and compared with that of 280 healthy female blood donors. Genetic analysis was performed on genomic DNA from PBMC and RFLP methods were used for mutation detection. No significant difference between cases and controls was found. These results do not support a favoring role of CYP1B1*3 in ovarian cancer development in our population.

Small intestine protection from radiation by means of a removable adapted prosthesis.

BACKGROUND: A prosthesis has been designed to protect intestinal loops from radiation when postsurgical radiotherapy is necessary in cancer treatment. It is a silicone balloon that allows the small bowel to be pushed back away from the radiation field, and it is easily removed at the conclusion of radiotherapy. METHODS: The device was used in 22 patients: 5 retroperitoneal tumors and 17 pelvic cancers. After surgical resection of the tumor, the device is placed either in the retroperitoneal area or in the pelvic cavity. A polyglactine 910 mesh is placed between the spacer and the bowel to prevent incarceration of the loops. The prosthesis can be filled or emptied between each radiation course and finally removed by means of a short incision under local or locoregional anesthesia. RESULTS: The tolerance of the small intestine to radiation therapy has been satisfactory in each case, with a mean follow-up of 24.5 months (range 10 to 73). No modification of biological parameters was observed during the pelvic radiation therapy at 30, 45, and 65 Gy. CONCLUSION: This device should appears to efficient for prevention of bowel injury during postsurgical radiation in successful treatment of abdominal, pelvic, or retroperitoneal tumors when indicated.

Local excision of rectal cancer for cure: should we always regard rigid pathologic criteria?

BACKGROUND/AIMS: The purposes of this study were to assess the relationship between the incidence of recurrence and the pathologic criteria usually applied to the selection of patients for curative local excision of rectal carcinoma and to determine whether failure to fulfill one of these criterias is always an indication for secondary abdominoperineal resection (APR). METHODOLOGY: From 1982 to 1992, 30 patients with rectal carcinoma (mean age: 69 +/- 10 years) were treated by local excision (LE). Univariate analysis of the cancer recurrence rate according to pathologic criteria was performed. RESULTS: The mean follow-up was 57 +/- 40 months (range: 6-145). Five patients (17%) had recurrent disease (local in 3, distant in 1, and local and distant in 1). Two of the three local cases were successfully treated. At the end of follow-up, 90% of the patients had no evidence of recurrence, and the rectal cancer-specific death rate was 10%. Although not significant, tumor penetration beyond the submucosa and vessel or nerve invasion were associated with an increased incidence of cancer recurrence. Tumor size and differentiation, and the presence of a mucinous component were not associated with a significant increase in recurrence. According to the usual pathologic criteria proposed for curative LE, 20 patients should, theoretically, have undergone secondary APR. However, 16 of them (80%) were treated by LE only, and at the end of follow-up, 17 (85%) were alive without recurrence. CONCLUSIONS: The rigid rule of systematically performing secondary APR after LE for rectal carcinoma when one or more pathologic selection criteria are not met should perhaps be reconsidered, especially for tumors exceeding 3 cm in diameter, moderately differentiated tumors, and in incidences when a mucinous component is present. However, in cases of vessel, nerve or muscular invasion, secondary APR is probably the best choice for cure.

[Therapeutic strategy in 46 cases of radiation injury of the intestine]. / Stratégie thérapeutique dans 46 cas d'intestin radique.

Our expérience in the treatment of 46 cases with radiation enteritis (RE) permitted to summarize 5 key points in the Surgical Strategy: laparotomy incision, enterolysis technique, small bowel and colon preservation, anastomosis technic and parenteral nutritional support. Surgery is imposed most of the time in digestive and nutritional Insufficiencies due to radiation enteritis. 46 patients aged to 33-81 years (mean age = 59) were included for possible surgery. The first clinical digestive symptoms were occlusion (n = 39) and/or digestive fistula (n = 7) and/or perforation (n = 3). These abnormalities were often associated with severe malnutrition (weight loss > or = 20% of usual weight) inducing surgery preparation with pre-operative parenteral nutrition (8 to 350 days). 3 patients were not operated because of general problems and lived 1 to 7 months after the beginning of parenteral nutrition. For operated patients (n = 43), 12 underwent 2 operations (resection and/or enteral liberation) and one patient underwent 4 surgical interventions because of digestive fistula. In 35 cases, small bowel resection was performed leaving 135.4 +/- 62.6 cm of intestine (0 to 225 cm of jejunum and/or ileum) and in 13 cases, complete enterolysis was achieved. All the patients received a post-operative parenteral nutrition during 1 to 23 months (median = 6.2 +/- 5.3 months). 31 patients received home parenteral nutrition during the pre and/or post-operative phase for a median duration of 6.3 +/- 3.2 months (range: 1-23 months). 4 patients died during the immediate post-operative phase and among them, 3 died after the second surgery. 12 deaths were observed due to the primary cancer and 6 due to the evolution of radiation lesions. Median survival of patients without cancer evolution reach 180 months with a 5-year survival rate of 94% (Kaplan-Meier method). In patients with radiation enteritis, the pre and post-operative nutritional support associated with radical surgery allows to obtain prolonged survival in non cancer patients.

[Therapeutic strategy for large cervical, mediastinal metastatic mature teratomas and large retro- and intraperitoneal lesions]. / Stratégie thérapeutique devant de volumineuses métastases tératomateuses matures cervicales, médiastinales et d'énormes lésions rétro et intra-péritonéales.

A 27 years old man was treated after surgery and classic chemotherapy for a right testicular teratoma (stage IV). Two months after the end of chemotherapy the patient developed "a Growing Teratoma Syndrome" with left subclavian and mediastinal nodes enlargement and bulky abdominal cystic masses with vena cava compression, collateral circulation and oedema of inferior members. Four debulking surgical approaches: cervical, thoracic and abdominal were performed and permitted complete functional recovery.

Regulation of aldosterone receptors in hypertension.

Mean mineralocorticoid receptor number in mononuclear leukocytes of patients with increased plasma aldosterone (Conn's syndrome, nephrovascular hypertension, preeclampsia) is lower than in controls and this reduction could be the consequence of a down-regulation of the receptor. A similar pattern is evident also in situations of excess of other mineralocorticoids (Cushing's syndrome, chronic licorice ingestion). In essential hypertension 20% of cases have reduced number of mineralocorticoid receptors in mononuclear leukocytes without increase of aldosterone and normal serum potassium. We postulate that in some cases with essential hypertension the reduction of mineralocorticoid receptors is an index of mineralocorticoid excess due to mineralocorticoids other than aldosterone.

Mineralocorticoid effector mechanism in preeclampsia.

Mineralocorticoid effector mechanisms were evaluated in 29 patients with preeclampsia and in 25 uncomplicated pregnancies by measurement of plasma aldosterone, levels of mineralocorticoid receptor (MR) in mononuclear leucocytes, and subtraction potential difference (SPD; rectal minus oral values). Mean values for plasma aldosterone were not different between the two groups, but significant differences were observed for MR (preeclampsia, 81 +/- 44 receptors/cell; controls, 306 +/- 168) and SPD (preeclampsia, 65 +/- 7 mV; controls, 12 +/- 5 mV). In six cases we determined MR, plasma aldosterone, and SPD in patients with preeclampsia before and 3 months after delivery. MR were reduced before delivery (96 +/- 27 receptors/cell), and SPD increased (64 +/- 8 mV), with both parameters normalizing after delivery (MR, 242 +/- 79; SPD, 14.0 +/- 4 mV). Aldosterone levels returned to normal nonpregnant values after delivery. These data suggest an important role for abnormalities in mineralocorticoid effector mechanisms in the etiology of preeclampsia and could be an useful marker for diagnosis.