Leptomeningeal carcinomatosis in gastric cancer: a case report of a rare yet aggressive entity.

Leptomeningeal carcinomatosis (LMC) is exceedingly rare in gastric cancer. It is most commonly seen in breast, lung cancer and melanoma, and is associated with an extremely poor prognosis. If untreated, median overall survival is four to six weeks. No standard treatment for LMC exists and published data are scarce. We present two cases of gastric carcinoma diagnosed with LMC that exemplify how aggressive this condition is and how short the time lapse is to perform any targeted therapy. This report aims to raise awareness of this rare metastatic possibility in gastric cancer and its diagnostic and therapeutic challenges.

Association of Weight Change, Inflammation Markers and Disease Staging with Survival of Patients Undergoing Chemotherapy for Pancreatic Adenocarcinoma.

INTRODUCTION: Cancer-associated-cachexia represents a systemic syndrome of unintended weight-loss (WL) and systemic inflammation, affecting >80% patients with pancreatic adenocarcinoma (PA). We aimed to evaluate the association of weight change (WC) with survival of patients treated with chemotherapy (ChT) for PA and the influence of disease staging. We also studied the prognostic and predictive value of inflammation-based scores. METHODS: Observational, retrospective cohort study. Individuals were divided into two cohorts, according to WC (WL ≥5% vs. non-WL <5%) after ChT. Main endpoints were weight change and survival time. Statistical analysis was performed using Stata software. RESULTS: Sixty-five patients were included (median age 69; 48% female), 60% with advanced disease. At 3 months after ChT start, 54% experienced WL. Advanced disease independently predicted WL (OR 2.10; 95% CI, 1.11-19.6; p = 0.041). With median follow-up of 14.8 mo, median survival time of patients with WL was 18.5 mo, vs. 33.2 vs. for non-WL (HR 2.28; 95% CI, 1.15-4.52; p = 0.019). In patients with early-stage disease, WL was associated with decreased survival time (21.9 vs. 67.6 mo; HR 23.68; 95% CI 2.39-234.75; p = 0.007), while the association of WL on survival time in advanced disease was not significant (HR 0.74; 95% CI, 0.34-1.60; p = 0.449). The multivariate survival model showed that WL (HR 1.11, 95% CI 1.03-1.20, p = 0.005) and cachexia (HR 3.76, 95% CI 1.07-13-18), p = 0.041) were associated with survival time, as well as location in body or tail (HR 3.05; 95% CI, 1.75-5.31; p < 0.001) and high Neutrophil-to-lymphocyte ratio (NLR) at 3 months (HR 6.20; 95% CI, 2.59-14.87; p < 0.001). CONCLUSION: WL was an independent prognostic factor for survival. Particularly in early stage disease, interventions targeting this modifiable factor may translate into better outcomes for PA patients. NLR may be a surrogate marker of systemic inflammatory status in this setting.

From Theory to Practice: Bone Health in Women with Early Breast Cancer Treated with Aromatase Inhibitors.

Aromatase inhibitors (AI) are extensively used as adjuvant endocrine therapy in post-menopausal women with hormone receptor-positive early breast cancer (HR+ EBC), but their impact on bone health is not negligible. This work aimed to assess bone loss, fracture incidence, and risk factors associated with these events, as well as the prognostic influence of fractures. We have conducted a retrospective cohort study of women with HR+ EBC under adjuvant therapy with AI, during a 3-year period. Four-hundred-and-fifty-one eligible women were reviewed (median age 68 years). Median time under AI was 40 months. A fracture event occurred in 8.4%, mostly in the radium and femoral neck and in older women (mean 74 vs. 68 years, p = 0.006). Age (OR 1.01, 95% CI 1.01-1.07, p = 0.024) and time under AI (OR 1.02, 95% CI 1.00-1.04, p = 0.037) were independent predictors of fracture, with a fair discrimination (AUC 0.71). Analysis of disease-free survival according to fracture event varied between groups, disfavoring the fracture cohort (at 73 months, survival 78.6%, 95% CI, 47.6-92.4 vs. 95.6%, 95% CI, 91.2-97.8, p = 0.027). The multivariate model confirmed the prognostic impact of fracture occurrence (adjusted HR of 3.17, 95% CI 1.10-9.11; p = 0.032). Bone health is often forgotten, despite its great impact in survivorship. Our results validate the pathophysiologic link between EBC and bone metabolism, which translates into EBC recurrence. Further research in this area may help refine these findings. Moreover, early identification of women at higher risk for fractures is warranted.

Challenges and Considerations on Risk-Reducing Surgery in BRCA1/2 Patients with Advanced Breast Cancer.

Cancer survivors harboring inherited pathogenic variants in the breast cancer (BC) susceptibility genes BRCA1 or BRCA2 are at increased risk of ovarian cancer (OC) and also of contralateral BC. For these women, risk-reducing surgery (RRS) may contribute to risk management. However, women with locally advanced or metastatic breast cancer (ABC) were excluded from clinical trials evaluating the benefit of these procedures in the BRCA1/2 carriers, and thus, current guidelines do not recommend RRS in this specific setting. Although ABC remains an incurable disease, recent advances in treatment have led to increased survival, which, together with improvement in RRS techniques, raise questions about the potential role of RRS in the management of BRCA1/2 ABC patients. When should RRS be discussed as an option for BRCA1/2 patients diagnosed with ABC? To address this issue, we report two clinical cases that reflect new challenges in routine oncology practice. Team experience and patient motivations may shape multidisciplinary decisions in the absence of evidence-based data. A wise rationale may be the analysis of the competing risks of death by a previous ABC against risk of death by a secondary BC or OC, tailored to patient preferences.

Endocrine therapy for the treatment of leptomeningeal carcinomatosis in luminal breast cancer: a comprehensive review.

Leptomeningeal disease (LMD) represents a devastating complication of advanced breast cancer (ABC), with survival of <5 months with multimodal treatment. The role of endocrine therapy (ET), due to its favorable toxicity profile and first-line indication in luminal ABC, appears promising in the setting of LMD, where symptom stabilization and quality-of-life preservation are the main goals; however, evidenced-based data are lacking. We conducted a thorough review of published evidence, aiming to investigate the role of ET in LMD treatment in luminal ABC. Twenty-one of 342 articles, evaluating 1302 patients, met inclusion criteria. ET use was rarely reported. New targeted agents show CNS activity. Research is lacking on the role of ET and targeted agents in BC-LMD treatment.

Daily exposure to phthalates and alkylphenols alters miR biogenesis and expression in mice ovaries.

Reproductive hormone imbalance in infertile women is correlated to high levels of phthalates and alkylphenols, which are among endocrine-disrupting chemicals (EDCs). Previous studies have shown that they interfere with gene expression by deregulating levels of microRNAs (miRs), small non-coding RNAs targeting mRNAs encoding enzymes in the hormone biosynthesis pathway. However, this effect depends on the target organ, dose and whether or not they are alone or in mixtures. Our goal was to study whether the biosynthesis, and a specific group of miRs targeting mRNAs encoding enzymes in steroid hormone biosynthesis, are deregulated in the ovaries of female mice chronically exposed to a mixture of three phthalates (DEHP+DBP+BBP) and two alkylphenols (NP+OP) at a human environmentally relevant dose. We performed qPCR and Western blot assays along with a bioinformatics approach and found that this mixture modified the biogenesis machinery of miRs, inducing an increase in the mRNA levels of Drosha and Dicer1 and DROSHA protein levels. In addition, we found changes in the precursor and mature forms of miR-96-5p, miR-200b-3p, miR-365-3p, miR-378a-3p and miR-503-5p which target steroidogenic pathway enzymes. Finally, using primary granulosa cell culture, we confirmed that miR-200b-3p targets Cyp19a1, transcript encoding CYP19A1, the enzyme that produces estradiol (E2). These results indicate that chronic exposure to phthalates and alkylphenols mixture alters the biogenesis of ovary miRs and increases the expression of miRs implicated in the control of steroidal hormone synthesis in female mice, thus contributing to reproductive pathologies.

Pretreatment hemoglobin level as a prognostic factor in patients with locally advanced head and neck squamous cell carcinoma.

AIM: Evaluate pretreatment hemoglobin values as a prognostic factor in patients with locally advanced head and neck squamous cell carcinoma treated with concurrent chemoradiotherapy. BACKGROUND: Anemia is one of the most prevalent laboratory abnormalities in oncological disease. It leads to a decrease in cellular oxygen supply, altering radiosensitivity of tumor cells and compromising therapeutic outcomes. MATERIALS AND METHODS: Retrospective evaluation of patients with HNSCC treated with cCRT. Primary and secondary endpoint was to evaluate the correlation of Hb levels (≥12.5 g/dL or <12.5 g/dL) at the beginning of cCRT with overall survival (OS) and progression-free survival (PFS), respectively. RESULTS: A total of 108 patients were identified. With a median follow-up of 16.10 months median OS was 59.70 months for Hb ≥12.5 g/dL vs. 14.13 months for Hb <12.5 g/dL (p = 0.004). PFS was 12.29 months for Hb ≥12.5 g/dL and 1.68 months for Hb <12.5 g/dL (p = 0.016). CONCLUSIONS: In this analysis, Hb ≥12.5 g/dL correlated with significantly better OS and PFS. Further studies are needed to validate these findings.

Sweet's Syndrome Induced by Aromatase Inhibitor in the Treatment of Early Breast Cancer.

BACKGROUND: Breast cancer is the most commonly diagnosed cancer in women, mainly at an early stage, allowing treatment with curative intent. Aromatase inhibitors are widely used in the adjuvant treatment of oestrogen receptor-positive breast cancer, mainly in postmenopausal women. The most frequent adverse events associated with these therapies are musculoskeletal symptoms and an increased risk of bone fractures. Cutaneous adverse events have been rarely described. Sweet's syndrome can present as an idiopathic disorder in addition to being malignancy-associated or drug-induced. CASE PRESENTATION: We report the case of a 69-year old woman, diagnosed with early stage breast cancer, who underwent breast-conserving surgery, followed by adjuvant radio and endocrine treatment with letrozole 2.5 mg daily, for a foreseeable duration of 5 years. Three months after starting letrozole, she presented with sudden fever and exuberant and painful erythematous skin papules and plaques on her upper body. After a full work-up and exclusion of other potential causes, a skin biopsy confirmed the presence of dermal oedema and a diffuse neutrophilic infiltrate, suggesting Sweet's syndrome. After discontinuation of letrozole and treatment with corticosteroids, the patient fully recovered. She resumed adjuvant treatment with tamoxifen, without symptom recurrence. CONCLUSIONS: Sweet's syndrome is a rare condition and an association with aromatase inhibitors has not been previously reported. Although its occurrence has already been observed in the onset of malignancies such as breast cancer, aromatase inhibitors must be added to the list of potential causes of drug-induced Sweet's syndrome. LEARNING POINTS: Aromatase inhibitors are widely used in the treatment of breast cancer and, though infrequent, it is important to recognize possible cutaneous adverse events.Sweet's syndrome is a rare but troublesome condition. Prompt recognition and management are crucial to alleviate symptoms.Drug-induced Sweet's syndrome associated with aromatase inhibitors has not been previously reported and should be considered when evaluating treatment toxicities.

Metastatic extramammary paget disease, a remarkable clinical case and a brief review of a rare disease.

Extramammary Paget Disease (EMPD) is an often-misdiagnosed rare disorder, whose cause remains unknown. Diagnosis is confirmed by skin biopsy. Primary treatment for EMPD is surgery. Recurrence is common in the first two years and prognosis is good if the disease is localized and there is no underlying associated cancer. Patients with invasive and metastatic EMPD are uncommon and exhibit a poor prognosis, even when there is good response to a first chemotherapy line. Multiple chemotherapeutic regimens, with varying levels of success, have been attempted, but standard of care is not established. The central nervous system seems to be a common metastatic site with better survival than visceral metastasis.We report a case of metastatic EMPD that addresses the difficulties associated with the treatment of this rare disease, that has no current guidelines.

Reproductive Alterations in Chronically Exposed Female Mice to Environmentally Relevant Doses of a Mixture of Phthalates and Alkylphenols.

Endocrine-disrupting chemicals (EDCs) are exogenous compounds that modify hormone biosynthesis, causing adverse effects to human health. Among them, phthalates and alkylphenols are important due to their wide use in plastics, detergents, personal care products, cosmetics, and food packaging. However, their conjoint effects over reproductive female health have not been addressed. The aim of this work was to test the effect of chronically exposed female mice to a mixture of three phthalates [bis (2-ethylhexyl), dibutyl, and benzyl butyl] and two alkylphenols (4-nonylphenol and 4-tert-octylphenol) from conception to adulthood at environmentally relevant doses. These EDCs were administered in two doses: one below the minimal risk dose to cause adverse effects on human development and reproduction [1 mg/kg body weight (BW)/d of the total mixture] and the other one based on the reference value close to occupational exposure in humans (10 mg/kg BW/d of the total mixture). Our results show that both doses had similar effects regarding the uterus and ovary relative weight, estrous cyclicity, serum levels of progesterone and 17ß-estradiol, and expression of key elements in the steroidogenesis pathway (acute steroidogenic regulatory protein and CYP19A1). However, only the 1-mg/kg BW/d dose delayed the onset of puberty and the transition from preantral to antral follicles, whereas the 10-mg/kg BW/d dose decreased the number of antral follicles and gonadotropin receptor expression. In addition, we observed changes in several fertility parameters in exposed females and in their progeny (F2 generation). In conclusion, our results indicate that chronic exposure to a complex EDC mixture, at environmentally relevant doses, modifies reproductive parameters in female mice.

Editor's Highlight: Differential Effects of Exposure to Single Versus a Mixture of Endocrine-Disrupting Chemicals on Steroidogenesis Pathway in Mouse Testes.

Endocrine-disrupting chemicals (EDCs) generate reproductive dysfunctions affecting the biosynthesis of steroid hormones and genes of the steroidogenic pathway. EDCs effects are mainly reported as a result of exposure to single compounds. However, humans are environmentally exposed to a mixture of EDCs. Herein, we assess chronic exposure to single alkylphenols and phthalates versus a mixture in mouse testes histology and steroidogenesis. Pregnant mice were exposed through drinking water to: 0.3 mg/kg-body weight (BW)/d of each phthalate (bis (2-ethylhexyl) phthalate, dibutyl phthalate, benzyl butyl phthalate), 0.05 mg/kg-BW/d of each alkylphenol (4-nonylphenol, 4-tert-octylphenol), or their mixture, covering from 0.5 postcoital day to weaning, continuing in the male offspring each exposure until adulthood (60-days old). Body and relative testis weight were increased in mixture-exposed mice along with histological alterations. Intratesticular testosterone (T) changed only in mice exposed to DBP, whereas estradiol (E2) levels were altered in all groups (except benzyl butyl phthalate). mRNA levels of genes encoding hormones of the steroid pathway (Cyp11a1, Hsd3b1, Cyp17a1, and Cyp19a1), cholesterol transporters (Star), and transcriptional factors (Sp1) showed that mice exposed to single or mixed compounds had alterations in at least 2 transcripts. However, none of the different types of exposure induced changes in all transcripts. In addition, changes at the mRNA or protein levels with single compounds were not always the same as those with a mixture. In conclusion, the effects of a chronic exposure to a mixture of EDCs on the expression of genes and proteins of the steroidogenic pathway and hormonal status were different from those exposed to single EDC.

Chondrosarcoma of the hyoid bone: an atypical site of a sarcoma of the head and the neck.

We describe a case of a 73-year-old man with a chondrosarcoma of the hyoid bone. The patient presented with a painless palpable lump in the upper anterior cervical region that had been growing for over 10 months. Fine-needle aspiration cytology suggested pleomorphic adenoma but further imaging investigation with CT revealed an exophytic tumour originating from the body of the hyoid bone with prominent chondroid-like calcifications typical of a chondrosarcoma. Histopathology of the surgical specimen confirmed the diagnosis of a moderately differentiated chondrosarcoma. Chondrosarcomas account for 11% of all bone cancers, of which up to 12% are in the head and neck. Primary sites of the head and the neck include the skull base, the nasal cavity, the maxilla, the mandible and the larynx. Chondrosarcomas of the hyoid bone are exceptionally rare, with only 20 such cases previously reported in the English literature.

Ca2+ signals generated by CatSper and Ca2+ stores regulate different behaviors in human sperm.

[Ca(2+)]i signaling regulates sperm motility, enabling switching between functionally different behaviors that the sperm must employ as it ascends the female tract and fertilizes the oocyte. We report that different behaviors in human sperm are recruited according to the Ca(2+) signaling pathway used. Activation of CatSper (by raising pHi or stimulating with progesterone) caused sustained [Ca(2+)]i elevation but did not induce hyperactivation, the whiplash-like behavior required for progression along the oviduct and penetration of the zona pellucida. In contrast, penetration into methylcellulose (mimicking penetration into cervical mucus or cumulus matrix) was enhanced by activation of CatSper. NNC55-0396, which abolishes CatSper currents in human sperm, inhibited this effect. Treatment with 5 µm thimerosal to mobilize stored Ca(2+) caused sustained [Ca(2+)]i elevation and induced strong, sustained hyperactivation that was completely insensitive to NNC55-0396. Thimerosal had no effect on penetration into methylcellulose. 4-Aminopyridine, a powerful modulator of sperm motility, both raised pHi and mobilized Ca(2+) stored in sperm (and from microsomal membrane preparations). 4-Aminopyridine-induced hyperactivation even in cells suspended in Ca(2+)-depleted medium and also potentiated penetration into methylcellulose. The latter effect was sensitive to NNC55-039, but induction of hyperactivation was not. We conclude that these two components of the [Ca(2+)]i signaling apparatus have strikingly different effects on sperm motility. Furthermore, since stored Ca(2+) at the sperm neck can be mobilized by Ca(2+)-induced Ca(2+) release, we propose that CatSper activation can elicit functionally different behaviors according to the sensitivity of the Ca(2+) store, which may be regulated by capacitation and NO from the cumulus.

Importance and effects of altered workplace ergonomics in modern radiology suites.

The transition from a film-based to a filmless soft-copy picture archiving and communication system (PACS)-based environment has resulted in improved work flow as well as increased productivity, diagnostic accuracy, and job satisfaction. Adapting to this filmless environment in an efficient manner requires seamless integration of various components such as PACS workstations, the Internet and hospital intranet, speech recognition software, paperless electronic hospital medical records, e-mail, office software, and telecommunications. However, the importance of optimizing workplace ergonomics has received little attention. Factors such as the position of the work chair, workstation table, keyboard, mouse, and monitors, along with monitor refresh rates and ambient room lighting, have become secondary considerations. Paying close attention to the basics of workplace ergonomics can go a long way in increasing productivity and reducing fatigue, thus allowing full realization of the potential benefits of a PACS. Optimization of workplace ergonomics should be considered in the basic design of any modern radiology suite.