Safety and efficacy of salvage endoscopic submucosal dissection for Barrett's neoplasia recurrence after radiofrequency ablation.

BACKGROUND: This study evaluated the safety and efficacy of salvage endoscopic submucosal dissection (ESD) for Barrett's neoplasia recurrence after radiofrequency ablation (RFA). METHODS: Data from patients at 16 centers were collected for a multicenter retrospective study. Patients who underwent at least one RFA treatment for Barrett's esophagus and thereafter underwent further esophageal ESD for neoplasia recurrence were included. RESULTS: Data from 56 patients who underwent salvage ESD between April 2014 and November 2022 were collected. Immediate complications included one muscular tear (1.8%) treated with stent (Agree classification: grade IIIa). Two transmural perforations (3.6%; treated with clips) and five muscular tears (8.9%; two treated with clips) had no clinical impact and were not considered as adverse events. Seven patients (12.5%) developed strictures (grade IIIa), which were treated with balloon dilation. Histological analysis showed 36 adenocarcinoma, 17 high grade dysplasia, and 3 low grade dysplasia. En bloc and R0 resection rates were 89.3% and 66.1%, respectively. Resections were curative in 33 patients (58.9%), and noncurative in 22 patients (39.3%), including 11 "local risk" (19.6%) and 11 "high risk" (19.6%) resections. At the end of follow-up with a median time of 14 (0-75) months after salvage ESD, and with further endoscopic treatment if necessary (RFA, argon plasma coagulation, endoscopic mucosal resection, ESD), neoplasia remission ratio was 37/53 (69.8%) and the median remission time was 13 (1-75) months. CONCLUSION: In expert hands, salvage ESD was a safe and effective treatment for recurrence of Barrett's neoplasia after RFA treatment.

The Association Between Meningioma and Breast Cancer: A Systematic Review and Meta-analysis.

Importance: A potential relationship between meningioma and breast cancer was suggested 70 years ago. However, to date, no conclusive evidence is available on this topic. Objective: To provide a comprehensive review of the literature on the association of meningioma with breast cancer, supported by a meta-analysis. Data Sources: A systematic PubMed search was performed up to April 2023 to identify articles on the association of meningioma with breast cancer. The following key words were used strategically: meningioma, breast cancer, breast carcinoma, association, relation. Study Selection: All studies reporting women diagnosed with meningioma and breast cancer were identified. The search strategy was not limited by study design or publication date but only included articles in English. Additional articles were identified via citation searching. Studies reporting a complete population of meningiomas or breast cancer patients throughout a specific study period and a proportion of patients with a second pathology could be used for the meta-analysis. Data Extraction and Synthesis: Data extraction was performed by 2 authors in accordance with the Preferred Reporting Items for Systematic Reviews (PRISMA) statement. Meta-analyses regarding both populations were performed using a random-effects model. Risk of bias was assessed. Main Outcomes and Measures: The main measures were whether there was an increased prevalence of breast cancer in female patients with meningioma and whether there was an increased prevalence of meningioma in female patients with breast cancer. Results: A total of 51 retrospective studies (case reports, case series, and cancer registry reports) describing 2238 patients with both diseases were identified; 18 studies qualified for prevalence analyses and meta-analysis. The random-effects meta-analysis (13 studies) revealed a significantly greater prevalence of breast cancer in female patients with meningioma than in the overall population (odds ratio [OR], 9.87; 95% CI, 7.31-13.32). Meningioma incidence in patients with breast cancer (11 studies) was greater than that in the baseline population; however, the difference according to the random-effects model was not statistically significant (OR, 1.41; 95% CI, 0.99-2.02). Conclusions and Relevance: This large systematic review and the meta-analysis on the association between meningioma and breast cancer found nearly 10-fold higher odds of breast cancer in female patients with meningioma compared with the general female population. These findings suggest that female patients with meningioma should be screened more intensively for breast cancer. Further research is required to identify the factors causing this association.

RHOJ controls EMT-associated resistance to chemotherapy.

The resistance of cancer cells to therapy is responsible for the death of most patients with cancer1. Epithelial-to-mesenchymal transition (EMT) has been associated with resistance to therapy in different cancer cells2,3. However, the mechanisms by which EMT mediates resistance to therapy remain poorly understood. Here, using a mouse model of skin squamous cell carcinoma undergoing spontaneous EMT during tumorigenesis, we found that EMT tumour cells are highly resistant to a wide range of anti-cancer therapies both in vivo and in vitro. Using gain and loss of function studies in vitro and in vivo, we found that RHOJ-a small GTPase that is preferentially expressed in EMT cancer cells-controls resistance to therapy. Using genome-wide transcriptomic and proteomic profiling, we found that RHOJ regulates EMT-associated resistance to chemotherapy by enhancing the response to replicative stress and activating the DNA-damage response, enabling tumour cells to rapidly repair DNA lesions induced by chemotherapy. RHOJ interacts with proteins that regulate nuclear actin, and inhibition of actin polymerization sensitizes EMT tumour cells to chemotherapy-induced cell death in a RHOJ-dependent manner. Together, our study uncovers the role and the mechanisms through which RHOJ acts as a key regulator of EMT-associated resistance to chemotherapy.

Embolization before Gamma Knife radiosurgery for cerebral arteriovenous malformations does not negatively impact its obliteration rate: a series of 190 patients.

PURPOSE: Embolization of arteriovenous malformations (AVMs) before radiosurgery has been reported to negatively impact the obliteration rate. This study aims to assess treatment outcomes in a series of 190 patients treated by Gamma Knife radiosurgery (GKRS) for previously embolized AVMs. METHODS: The institutional database of AVMs was retrospectively reviewed between January 2004 and March 2018. The clinical and radiological data of patients treated with GKRS for previously embolized AVMs were analyzed. Predicting factors of obliteration and hemorrhage following GKRS were assessed with univariate and multivariate regression analyses. RESULTS: The mean AVM size was significantly reduced after embolization (p < 0.001). The obliteration rate was 78.4%. Multivariate analyses showed that a lower Spetzler-Martin grade (p = 0.035) and a higher marginal dose (p = 0.007) were associated with obliteration. Post-GKRS hemorrhages occurred in 14 patients (7.4%). A longer time between diagnosis and GKRS was the only factor associated with post-GKRS hemorrhages in multivariate analysis (p = 0.022). Complications related to the combined treatment were responsible for a new permanent neurological disability in 20 patients (10.5%), and a case of death (0.5%). CONCLUSIONS: This study shows that the embolization of AVMs does not have a negative impact on the obliteration rate after radiosurgery. Embolization reduces the AVM size to a treatable volume by GKRS. However, the combined treatment results in an increased complication rate related to the addition of the risks of each treatment modality.

Fibrin-coated collagen fleece versus absorbable dural sealant for sellar closure after transsphenoidal pituitary surgery: a comparative study.

Various surgical methods to prevent postoperative cerebrospinal fluid (CSF) leaks during transsphenoidal surgery have been reported. However, comparative studies are scarce. We aimed to compare the efficacy of a fibrin-coated collagen fleece (TachoSil) versus a dural sealant (DuraSeal) to prevent postoperative CSF leakage. We perform a retrospective study comparing two methods of sellar closure during endoscopic endonasal transsphenoidal surgery (EETS) for pituitary adenoma resection: TachoSil patching versus DuraSeal packing. Data concerning diagnosis, reconstruction technique, and surgical outcomes were analyzed. The primary endpoint was postoperative CSF leak rate. We reviewed 198 consecutive patients who underwent 219 EETS for pituitary adenoma from February 2007 and July 2018. Intraoperative CSF leak occurred in 47 cases (21.5%). A total of 33 postoperative CSF leaks were observed (15.1%). A reduction of postoperative CSF leaks in the TachoSil application group compared to the conventional technique using Duraseal was observed (7.7% and 18.2%, respectively; p = 0.062; Pearson exact test) although non-statistically significant. Two patients required lumbar drainage, and no revision repair was necessary to treat postoperative CSF rhinorrhea in Tachosil group. Fibrin-coated collagen fleece patching may be a valuable method to prevent postoperative cerebrospinal fluid (CSF) leaks during EETS for pituitary adenoma resection.

Effectiveness of benzyl benzoate treatment on clinical symptoms and Demodex density over time in patients with rosacea and demodicosis: a real life retrospective follow-up study comparing low- and high-dose regimens.

BACKGROUND: Patients with rosacea and demodicosis have high facial skin Demodex densities (Dds), which decrease with benzyl benzoate (BB) treatment. OBJECTIVES: To evaluate the impact of topical BB (+crotamiton) treatment on Dds and clinical symptoms during prolonged follow-up and to compare low (12% once daily) and high (12% twice daily or 20-24% once daily) BB dose regimens. METHODS: This retrospective study included 344 patients (103 rosacea, 241 demodicosis) observed for 7.1 ± 0.5 months. Dds were measured on two consecutive standardized skin surface biopsies and symptoms evaluated using investigator global assessment. Compliance was considered good if patients correctly followed treatment instructions. RESULTS: At final follow-up, in the 248 patients with good compliance, Dd had normalized in 217 (88%) and symptoms cleared in 204 (82%). The high dose was associated with better compliance and faster results than the low-dose. The higher the initial Dd, the longer it took to normalize. In the 96 poorly compliant patients, treatment was less effective and slower. CONCLUSIONS: These findings indirectly support a key role of the mite in rosacea and suggest that topical treatment with BB (+crotamiton), especially the higher dose, may be a useful alternative treatment for rosacea as well as for demodicosis.[Formula: see text].

Which factors influence Demodex proliferation? A retrospective pilot study highlighting a possible role of subtle immune variations and sebaceous gland status.

Demodex folliculorum and brevis are commensal mites that live in low densities in human pilosebaceous follicles as part of the normal adult microbiota, but that give rise to demodicosis and, possibly, rosacea, when they proliferate excessively. This proliferation is favored by various factors, including age, marked immunosuppression, sebaceous gland hyperplasia, and hypervascularization-related factors. To study possible factors influencing mite proliferation, we explored the effects of different variables on Demodex densities (Dd) in a retrospective study of two groups of subjects selected on the basis of their clinical diagnosis: Demodex+, consisting of subjects with demodicosis or with centro-facial papulopustules suggesting rosacea (n = 844, mean Dd 263.5 ± 8.9 D/cm2 ), and Demodex-, consisting of subjects with other facial dermatoses or healthy facial skin (n = 200, mean Dd 2.3 ± 0.4 D/cm2 ). Demodex densities were measured using two consecutive standardized skin surface biopsies (SSSB1 [superficial] and SSSB2 [deep]) taken from the same facial site on each subject. In the Demodex+ group: the SSSB1 decreased with age in women (p = 0.004), and the SSSB2 increased with age in men (p = 0.001) (the pattern was similar for SSSB1 + 2, but not statistically significant); Dds were lower in those who had received cortisone (either topically or systemically); 13 subjects (1.5%) had known immunosuppression, 62 (7.3%) had hypothyroidism, and in 20 (3.6% of the women) there was a reported link with pregnancy; 78 of the subjects (9.2%) were part of a pair from the same family or household; when associated bacterial infection was suspected, Staphylococcus epidermidis was often isolated. Our results suggest close interactions between the mite, sebaceous gland size and function, and subtle variations of immune status. Potential factors influencing Demodex proliferation should be further investigated, including hypothyroidism, pregnancy, corticosteroid administration, Staphylococcus epidermidis, contagiousity, and genetic background.

Prevalence of scratching during examination among patients with scabies and among patients with other pruritic dermatoses.

BACKGROUND: Scabies is a parasitic skin disease. Its clinical diagnosis may be challenging. METHODS: In a prospective observational study, we enrolled all consecutive patients ≥16 years of age with a presumptive diagnosis of scabies and all patients ≥16 years of age with a diffuse itchy dermatosis lasting for more than 1 week. We investigated whether patients with scabies were more prone to scratch themselves during the consultation than patients with other pruritic dermatoses. RESULTS: We observed that a significant proportion of patients (25/62, 40%) with scabies had to scratch while talking or being examined. This clinical sign was less frequently noticed in patients with pruritic dermatoses of other origins (26/196, 13%) (P < 0.001). CONCLUSIONS: The observation of a patient scratching himself during the consultation should prompt serious consideration of scabies. This easily observable clinical sign may be especially useful in low-resource settings, where scabies is known to be very prevalent.

Heterotypic cell-cell communication regulates glandular stem cell multipotency.

Glandular epithelia, including the mammary and prostate glands, are composed of basal cells (BCs) and luminal cells (LCs)1,2. Many glandular epithelia develop from multipotent basal stem cells (BSCs) that are replaced in adult life by distinct pools of unipotent stem cells1,3-8. However, adult unipotent BSCs can reactivate multipotency under regenerative conditions and upon oncogene expression3,9-13. This suggests that an active mechanism restricts BSC multipotency under normal physiological conditions, although the nature of this mechanism is unknown. Here we show that the ablation of LCs reactivates the multipotency of BSCs from multiple epithelia both in vivo in mice and in vitro in organoids. Bulk and single-cell RNA sequencing revealed that, after LC ablation, BSCs activate a hybrid basal and luminal cell differentiation program before giving rise to LCs-reminiscent of the genetic program that regulates multipotency during embryonic development7. By predicting ligand-receptor pairs from single-cell data14, we find that TNF-which is secreted by LCs-restricts BC multipotency under normal physiological conditions. By contrast, the Notch, Wnt and EGFR pathways were activated in BSCs and their progeny after LC ablation; blocking these pathways, or stimulating the TNF pathway, inhibited regeneration-induced BC multipotency. Our study demonstrates that heterotypic communication between LCs and BCs is essential to maintain lineage fidelity in glandular epithelial stem cells.

Did Osteoblastic Cell Therapy Improve the Prognosis of Pre-fracture Osteonecrosis of the Femoral Head? A Randomized, Controlled Trial.

BACKGROUND: In patients with nontraumatic osteonecrosis of the femoral head (ONFH), implantation of bone marrow aspirate concentrate (BMAC) could delay the progression of osteonecrosis and improve symptoms in pre-fracture ONFH. However, the BMAC content, especially in osteoblastic stem cells, could have an important individual variability. An autologous osteoblastic cell product could improve the effect of such cell-based therapy. QUESTIONS/PURPOSES: (1) Does autologous osteoblastic cell therapy decrease the likelihood of progression to subchondral fracture with or without early collapse corresponding to Association Research Circulation Osseous (ARCO) classification Stage III or higher, and provide a clinically important pain improvement compared with BMAC treatment alone? (2) Were patients treated with osteoblastic cell therapy less likely to undergo subsequent THA? (3) What proportion of patients in the treatment and control groups experienced adverse events after surgery? METHODS: Between 2004 and 2011, we treated 279 patients for Stage I to II hip osteonecrosis (ON) with surgery. During that time, our general indications for surgery in this setting included non-fracture ON lesions. To be eligible for this randomized, single-blind trial, patients needed to have an ONFH Stage I or II; we excluded those with traumatic ONFH, hemoglobinopathies and positive serology for hepatitis B, C or HIV. Of those treated surgically for this diagnosis during the study period, 24% (67) agreed to participate in this randomized trial. Hips with pre-fracture ONFH were randomly treated with a core decompression procedure associated with either implantation of a BMAC (BMAC group; n = 26) or osteoblastic cell (osteoblastic cell group; n = 30). The groups were not different in terms of clinical and imaging characteristics. The primary study outcome was treatment response, defined as the absence of progression to subchondral fracture stage (ARCO stage III or higher) plus a clinically important pain improvement defined as 1 cm on a 10-cm VAS. The secondary endpoint of interest was the frequency in each group of subsequent THA and the frequency of adverse events. The follow-up duration was 36 months. We used an as-treated analysis (rather than intention-to-treat) for our efficacy endpoint, and an intention-to-treat analysis for adverse events. Overall, 26 of 26 patients in the BMAC group and 27 of 30 in the osteoblastic cell group completed the trial. RESULTS: At 36 months, no clinically important differences were found in any study endpoint. There was no difference in the proportion of patients who had progressed to fracture (ARCO stage III or higher; 46% of the BMAC hips [12 of 26] versus 22% in the hips with osteoblastic cells [six of 27], hazard ratio, 0.47 [95% CI 0.17 to 1.31]; p = 0.15). There was no clinically important difference in VAS pain scores. No differences were found for either the WOMAC or the Lequesne indexes. With the numbers available, there was no difference in the proportion of patients in the groups who underwent THA at 36 months 15% (four of 27) with osteoblastic cells versus 35% (nine of 26) with BMAC; p = 0.09 With the numbers available, we found no differences between the treatment and control groups in terms of the frequencies of major adverse events. CONCLUSIONS: We found no benefit to osteoblastic cells over BMAC in patients with pre-collapse ONFH; side effects were uncommon and generally mild in both groups. This study could be used as pilot data to help determine sample sizes for larger (presumably multicenter) randomized controlled trials. However, this novel treatment cannot be recommended in routine practice until future, larger studies demonstrate efficacy. LEVEL OF EVIDENCE: Level II, therapeutic study.

Context Dependency of Epithelial-to-Mesenchymal Transition for Metastasis.

Epithelial-to-mesenchymal transition (EMT) has been proposed to be important for metastatic dissemination. However, recent studies have challenged the requirement of EMT for metastasis. Here, we assessed in different models of primary skin squamous cell carcinomas (SCCs) whether EMT is associated with metastasis. The incidence of metastasis was much higher in SCCs presenting EMT compared to SCCs without EMT, supporting the notion that a certain degree of EMT is required to initiate the metastatic cascade in primary skin SCCs. Most circulating tumor cells presented EMT, whereas most lung metastasis did not present EMT, showing that mesenchymal-to-epithelial transition is important for metastatic colonization. In contrast, immunodeficient mice transplanted with SCCs, whether displaying EMT or not, presented metastasis. Altogether, our data demonstrate that the association of EMT and metastasis is model dependent, and metastasis of primary skin SCCs is associated with EMT.

Letrozole-associated controlled ovarian hyperstimulation in breast cancer patients versus conventional controlled ovarian hyperstimulation in infertile patients: assessment of oocyte quality related biomarkers.

BACKGROUND: Fertility preservation (FP) protocols in case of breast cancer (BC) include mature oocyte cryopreservation following letrozole associated controlled ovarian hyperstimulation (Let-COH). To date, the impact of Let-COH on the follicular microenvironment has been poorly investigated, although a high androgen/estrogen ratio was previously associated with low oocyte quality. METHODS: In this prospective study, follicular fluid (FF) steroid levels (estradiol, testosterone, progesterone) and cumulus cell (CC) gene expression related to oocyte quality (HAS2, PTGS2, GREM1) were compared between 23 BC patients undergoing Let-COH for FP and 24 infertile patients undergoing conventional COH without letrozole. All patients underwent an antagonist COH cycle, and ovulation was triggered with hCG or GnRHa in both groups. RESULTS: FF estradiol levels were significantly lower while testosterone levels were significantly higher in the study group compared to controls irrespective of the trigger method. However, estradiol levels increased significantly with GnRHa triggering compared to hCG in the study group (median = 194.5 (95.4-438) vs 64.4 (43.8-152.4) ng/ml, respectively, p < 0.001), but not in the control group (median = 335.5 (177.5-466.7) vs 354 (179-511) ng/ml, respectively). After hCG trigger, Cumulus cell (CC) gene expression was lower in the study group compared to the control group, and difference was significant for PTGS2. Conversely, CC gene expression of PTGS2 and GREM1 was significantly higher in the study group compared to controls when ovulation was triggered with GnRHa. CONCLUSIONS: Let-COH triggered with hCG may negatively impact oocyte quality. However, ovulation triggering with GnRHa may improve the oocyte microenvironment and cumulus cell genes expression in Let-COH, suggesting a positive impact on oocyte quality in breast cancer patients. TRIAL REGISTRATION: Clinicaltrials.gov - NCT02661932 , registered 25 January 2016, retrospectively registered.

Rosacea and Demodicosis: Little-known Diagnostic Signs and Symptoms.

Papulopustular rosacea and demodicosis are characterized by non-specific symptoms, which can make clinical diagnosis difficult. This retrospective study of 844 patients assessed the diagnostic importance of clinical signs and symptoms that are poorly recognized as being associated with these conditions. In addition to well-known signs (vascular signs (present in 80% of patients), papules (39%), pustules (22%) and ocular involvement (21%)), other signs and symptoms (discreet follicular scales (93%), scalp symptoms (pruritus, dandruff or folliculitis; 38%) and pruritus (15%)) may also suggest a diagnosis not only of demodicosis, but also of papulopustular rosacea. Facial Demodex densities (measured by 2 consecutive standardized skin biopsies) were higher when ocular or scalp involvement was present, suggesting more advanced disease, but further investigations are needed to confirm this hypothesis. Recognition of these clinical signs and symptoms should encourage dermatologists to perform a Demodex density test, thus enabling appropriate diagnosis to be made.

Safety and tolerance of cidofovir as a 2% gel for local application in high-grade cervical intraepithelial neoplasia: A phase 1 investigation.

OBJECTIVES: The primary objective was to evaluate the safety and local tolerance of a topical 2% (w/w) cidofovir gel, applied directly to the cervices of women with high-grade cervical intraepithelial neoplasia (CIN 2+). The secondary objective was to evaluate the pharmacokinetics of cidofovir during the treatment. MATERIALS AND METHODS: Nine women with CIN 2+, were treated with a course of 3 g of cidofovir gel, applied locally once per week for 3 weeks in total (9 g). The treatment was administered in a cervical cap, applied to the cervix for 5 or 10 hours (n = 6 and 3 patients, respectively). Follow-up included a structured questionnaire, a gynecological examination, blood analysis for hematology, C-reactive protein (CRP), and renal function assessment plus pharmacokinetic analyses of cidofovir after each treatment and at the end of the full course. RESULTS: No clinically significant hematological/biochemical abnormalities or serious adverse events (SAE) were reported, although 6 mild to moderate adverse events (AE) occurred in relation to the study drug: 1 flu-like syndrome and 5 local AEs. Plasma concentrations of cidofovir were very low (mean Cmax of 103.0 and 99.2 ng/mL after 5 and 10 hours of exposure, respectively). CONCLUSION: Cidofovir, directly applied on CIN 2+, is reasonably well tolerated and the systemic exposure following topical application is much lower than that seen with intravenous administration, at the approved dose.
.

Inefficacy of autologous bone marrow concentrate in stage three osteonecrosis: a randomized controlled double-blind trial.

PURPOSE: The fracture stage of non-traumatic osteonecrosis (ON stage 3) of the femoral head (ONFH) has an unfavourable prognosis frequently requiring total hip replacement (THR). The percentage could be lowered after core decompression. In earlier non-fracture ON stages, implantation of autologous bone marrow aspirate concentrate (BMAC) improved the effect of core decompression. The purpose was to evaluate the effect of BMAC in addition to core decompression in stage 3 ONFH. METHODS: A double blind RCT was conducted comparing two groups: core decompression plus saline injection or core decompression plus BMAC implantation. Both patients and assessors were blinded to the treatment assignments. Evaluations were done at baseline, three, six, 12, and 24 months, including pain (VAS), WOMAC, side-effects, radiological evolution including ARCO subclassifications, together with possible THR requirement. The primary endpoint was the need for THR. The second endpoints included the clinical symptoms such as pain and functional ability and the progression of the ON lesions as well as the appearance of osteoarthritis features (ARCO stage 4). Both groups included 23 hips (19 patients). RESULTS: No differences were found between the groups for THR requirements, clinical tests, and radiological evolution. In both groups, 15/23 hips needed THR. The radiological evolution of the ONFH lesions in term of location, extension, surface collapse, and dome depression was moderate in both groups and was not correlated with the need of THR. CONCLUSIONS: Implantation of BMAC after core decompression did not produce any improvement of the evolution of ONFH stage 3. Level of evidence I.

Two Consecutive Standardized Skin Surface Biopsies: An Improved Sampling Method to Evaluate Demodex Density as a Diagnostic Tool for Rosacea and Demodicosis.

Diagnosing papulopustular rosacea is not always straightforward; no specific diagnostic test is currently available. A high density of Demodex mites is consistently observed in this condition. This retrospective study assesses an improved method for evaluating Demodex density among 1,044 patients presenting to our dermatology practice. The skin was cleaned with ether and Demodex densities were measured in 2 consecutive standardized skin surface biopsies taken from the same site. Mean densities in patients with rosacea and demodicosis were much higher than those in healthy controls and patients with other facial dermatoses. The optimal cut-off values for the 2 biopsies were combined and the resultant criterion (presence of a first biopsy density < 5 Demodex/cm2 or a second biopsy density < 10 Demodex/cm2) enabled confirmation of a diagnosis of rosacea or demodicosis with a sensitivity of 98.7% and specificity of 95.5%, making this a valuable diagnostic tool for dermatologists in routine clinical practice.

No Evidence for the Benefit of Gonadotropin-Releasing Hormone Agonist in Preserving Ovarian Function and Fertility in Lymphoma Survivors Treated With Chemotherapy: Final Long-Term Report of a Prospective Randomized Trial.

PURPOSE: We have reported previously that after 1-year follow up, gonadotropin-releasing hormone agonist (GnRHa) did not prevent chemotherapy-induced premature ovarian failure (POF) in patients with lymphoma, but may provide protection of the ovarian reserve. Here, we report the final analysis of the cohort after 5 years of follow up. PATIENTS AND METHODS: A total of 129 patients with lymphoma were randomly assigned to receive either triptorelin plus norethisterone (GnRHa group) or norethisterone alone (control group) during chemotherapy. Ovarian function and fertility were reported after 2, 3, 4, and 5 to 7 years of follow up. The primary end point was POF, defined as at least one follicle-stimulating hormone value of > 40 IU/L after 2 years of follow up. RESULTS: Sixty-seven patients 26.21 ± 0.64 years of age had available data after a median follow-up time of 5.33 years in the GnRHa group and 5.58 years in the control group (P = .452). Multivariate logistic regression analysis showed a significantly increased risk of POF in patients according to age (P = .047), the conditioning regimen for hematopoietic stem cell transplant (P = .002), and the cumulative dose of cyclophosphamide > 5 g/m(2) (P = .019), but not to the coadministration of GnRHa during chemotherapy (odds ratio, 0.702; P = .651). The ovarian reserve, evaluated using anti-Müllerian hormone and follicle-stimulating hormone levels, was similar in both groups. Fifty-three percent and 43% achieved pregnancy in the GnRHa and control groups, respectively (P = .467). CONCLUSION: To the best of our knowledge, this is the first long-term analysis confirming that GnRHa is not efficient in preventing chemotherapy-induced POF in young patients with lymphoma and did not influence future pregnancy rate. These results reopen the debate about the drug's benefit in that it should not be recommended as standard for fertility preservation in patients with lymphoma.

Methylprednisolone-Induced Lymphocytosis in Patients with Immune-Mediated Inflammatory Disorders.

BACKGROUND: Transient acute reversible lymphopenia occurring within hours after glucocorticoid administration is a well-known phenomenon. The objective of this study was to establish the impact of chronic methylprednisolone (mPDN) administration on lymphocyte counts in patients with immune-mediated inflammatory disorders. METHODS: The charts of 44 women and 17 men (median age, 59 years) with several immune-mediated inflammatory disorders receiving oral mPDN for at least 4 months were reviewed. Morning lymphocyte counts measured during treatment (LP) were compared with pretreatment values (LA). In addition, the acute effect of mPDN on lymphocyte counts was evaluated in 43 of these patients by quantifying lymphocyte subpopulations before and 8 hours after mPDN administration. Values are expressed as median with 25%-75% interquartile range. RESULTS: The initial daily oral mPDN dose was 28 mg (12-32 mg). An increase in morning lymphocyte counts was detected 13 days (8.5-16 days) after initiation of mPDN treatment (LP: 2130/µL vs LA: 1650/µL; P = .0121) and persisted over time. Morning lymphocytosis (LP ≥4000/µL) was observed in 15 patients, including 7 with hyperlymphocytosis (LP ≥5000/µL). The increase in morning lymphocyte counts during treatment was most marked for CD4 T cells. In the subset of patients who agreed to a second blood test after mPDN absorption, a 49% decrease in the lymphocyte count (P <.0001) was transiently observed at the 8-hour time point. CONCLUSIONS: A significant increase of the morning lymphocyte count is frequently observed in patients with immune-mediated inflammatory disorders chronically treated with oral mPDN. Heightened awareness that the timing of blood sampling in corticosteroid-treated patients affects lymphocyte counts, with possible hyperlymphocytosis before absorption, should help avoid unnecessary investigations and worry.