Dynamics of neutrophils to lymphocyte ratio (NLR) predict outcomes of PD-1/PD-L1 blockade

Introduction. Baseline neutrophil-to-lymphocyte ratio (NLR) has been repeatedly reported as a significant prognostic factor in advanced cancer patients. We explored whether changes in NLR may predict outcome of advanced cancer patients enrolled into phase 1 trials and treated with PD-1/PD-L1 inhibitors. Patients and Methods. Advanced cancer patients enrolled into phase 1 trials between September 2013 and May 2016 and treated with anti-PD-1/PD-L1 agents were included in this retrospective study. NLR was calculated at baseline and after 2 cycles of treatment. Royal Marsden Hospital (RMH) prognostic score and Eastern Cooperative Group (ECOG) performance status (PS) were determined at baseline. Kaplan-Meier estimation and Cox regression analyses were used to assess the impact of NLR dynamics on PFS. Results. Among the 55 patients eligible, 26 (47%) were treated with anti-PD-L1 monotherapy, 22 (40%) received single agent anti-PD-1, and 7 (13%) were given a tyrosine kinase inhibitor (TKI) plus a PD-1 inhibitor. Neither ECOG PS nor RMH prognostic score was significantly associated with PFS in our cohort, whereas changes in NLR significantly impacted on PFS. Conclusion. Changes in the NLR may be a useful predicting factor in advanced cancer patients treated with anti-PD-1/PD-L1 agents. Further prospective trials are needed to verify these findings

Managing myelodysplastic symptoms in elderly patients

Most patients with myelodysplastic syndromes (MDS) are elderly (median age range 65 to 70 years); as a consequence, the incidence and prevalence of these diseases are rising as the population ages. Physicians are often uncertain about how to identify patients who may benefit from specific treatment strategies. The International Prognostic Scoring System is a widely used tool to assess the risk of transformation to leukemia and to guide treatment decisions, but it fails to take into account many aspects of treating elderly patients, including comorbid illnesses, secondary causes of MDS, prior therapy for MDS, and other age-related health, functional, cognitive, and social problems that affect the outcome and managing of myelodysplastic symptoms. Patients with low-risk disease traditionally have been given only best supportive care, but evidence is increasing that treatment with novel non-conventional drugs such as lenalidomide or methyltransferase inhibitors may influence the natural history of the disease and should be used in conjunction with supportive-care measures. Supportive care of these patients could also be improved in order to enhance their quality of life and functional performance. Elderly patients commonly have multiple medical problems and use medications to deal with these. In addition, they are more likely to have more than one health care provider. These factors all increase the risk of drug interactions and the consequent treatment of toxicities. Manifestations of common toxicities or illnesses may be more subtle in the elderly, owing to age-associated functional deficits in multiple organ systems. Particularly important to the elderly MDS patient is the age-related decline in normal bone marrow function, including the diminished capacity of response to stressors such as infection or myelosuppressive treatments. Through the integration of geriatric and oncological strategies, a personalized approach toward this unique population may be applied. As with many diseases in the elderly, reliance on family members or friends to maintain the prescribed treatments, including travel to and from appointments, may place additional stressors on the patient and his/her support network. Careful evaluation and knowledge of functional status, ability to tolerate treatments, effect of disease progression, and general overall health conditions can provide the best opportunity to support these patients. Immediate assessment of daily living activities may detect deficiencies or deficits that often require early interventions

Incorporation of cholesterol in sphingomyelin- phosphatidylcholine vesicles has profound effects on detergent-induced phase transitions

Abstract Vesicle ↔ micelle transitions are important phenomena during bile formation and intestinal lipid processing. The hepatocyte canalicular membrane outer leaflet contains appreciable amounts of phosphatidylcholine (PC) and sphingomyelin (SM), and both phospholipids are found in the human diet. Dietary SM enrichment inhibits intestinal cholesterol absorption. We therefore studied detergent-induced vesicle → micelle transitions in SM-PC vesicles. Phase transitions were evaluated by spectrophotometry and cryotransmission electron microscopy (cryo-TEM) after addition of taurocholate (3–7 mM) to SM-PC vesicles (4 mM phospholipid, SM/PC 40%/60%, without or with 1.6 mM cholesterol). After addition of excess (5–7 mM) taurocholate, SM-PC vesicles were more sensitive to micellization than PC vesicles. As shown by sequential cryo-TEM, addition of equimolar (4 mM) taurocholate to SM-PC vesicles induced formation of open vesicles, then (at the absorbance peak) fusion of bilayer fragments into large open structures (around 200 nm diameter) coexisting with some multilamellar or fused vesicles and thread-like micelles and, finally, transformation into an uniform picture with long thread-like micelles. Incorporation of cholesterol in the SM/PC bilayer changed initial vesicular shape from spherical into ellipsoid and profoundly increased detergent resistance. Disk-like micelles and multilamellar vesicles, and then extremely large vesicular structures, were observed by sequential cryo-TEM under these circumstances, with persistently increased absorbance values by spectrophotometry. These findings may be relevant for bile formation and intestinal lipid processing. Inhibition of intestinal cholesterol absorption by dietary SM enrichment may relate to high resistance against bile salt-induced micellization of intestinal lipids in presence of the sphingolipid

Role of unenhanced breast MRI for detecting and differentiating breast lesions

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Invasive apocrine carcinoma of the breast: Myth or fact?

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Impaired gallbladder motility and delayed orocecal transit contribute to pigment gallstone and biliary sludge formation in β-thalassemia major adults

Aim: Gallbladder and gastrointestinal motility defects exist in gallstones patients and to a lesser extent in pigment gallstone patients. To investigated the role of gallbladder and gastrointestinal motility disorders in pigment gallstone formation in β-thalassemia major. Methods: Twenty-three patients with β-thalassemia major (16 females; age range 18-37 years) and 70 controls (47 females, age range 18-40 years) were studied for gallbladder and gastric emptying (functional ultrasonography), orocecal transit (OCTT, H2-breath test), autonomic dysfunction (sweat-spot, cardiorespiratory reflex tests), bowel habits, gastrointestinal symptoms and quality of life (all with questionnaires). Gallbladder content (ultrasonography) was examined before and during 8-12 mo follow-up. Results: Gallstones and/or biliary sludge were found in 13 (56%) patients. β-thalassemia major patients had increased fasting (38.0±4.8 mL vs 20.3±0.7 mL, P = 0.0001) and residual (7.9±1.3 mL vs 5.1±0.3 mL, P = 0.002) volume and slightly slower emptying (24.9±1.7 min vs 20.1±0.7 min, P = 0.04) of the gallbladder, together with longer OCTT (132.2±7.8 min vs 99.7±2.3 min, P = 0.00003) than controls. No differences in gastric emptying and bowel habits were found. Also, patients had higher dyspepsia (score: 6.7±1.2 vs 4.9±0.2, P = 0.027), greater appetite (P = 0.000004) and lower health perception (P = 0.00002) than controls. Autonomic dysfunction was diagnosed in 52% of patients (positive tests: 76.2% and 66.7% for parasympathetic and sympathetic involvement, respectively). Patients developing sludge during follow-up (38%, 2 with prior stones) had increased fasting and residual gallbladder volume. Conclusion: Adult β-thalassemia major patients have gallbladder dysmotility associated with delayed small intestinal transit and autonomic dysfunction. These abnormalities apparently contribute together with haemolytic hyperbilirubinemia to the pathogenesis of pigment gallstones/ sludge in β-thalassemia major. Copyright © 2004 by The WJG Press

Induction therapy and stem cell mobilization in patients with newly diagnosed multiple myeloma

Autologous stem cell transplantation (ASCT) is considered the standard therapy for younger patients with newly diagnosed symptomatic multiple myeloma (MM). The introduction into clinical practice of novel agents, such as the proteasome inhibitor bortezomib and the immunomodulatory derivatives (IMiDs) thalidomide and lenalidomide, has significantly contributed to major advances in MM therapy and prognosis. These novel agents are incorporated into induction regimens to enhance the depth of response before ASCT and further improve post-ASCT outcomes. Between January 2000 and November 2011, 65 patients with MM were transplanted in the Department of Biomedical Science and Clinical Oncology at the University of Bari. According to Durie-Salmon, 60 patients had stage III of disease and 5 stage II. Only 7 patients were in stage B (renal failure). Induction regimens that were administered in two or more cycles were VAD (vincristine, adriamycin, and dexamethasone), Thal-Dex (thalidomide, dexamethasone), Len-Dex (lenalidomide, dexamethasone), Vel-Dex (bortezomib, dexamethasone), VTD (bortezomib, thalidomide, and dexamethasone), and PAD (bortezomib, pegylated liposomal doxorubicin, and dexamethasone). In mobilization procedure, the patients received cyclophosphamide and granulocyte colony-stimulating factor (G-CSF). The number of cells collected through two or more leukapheresess, response after induction, and toxicity were evaluated to define the more adequate up-front induction regimen in transplantation-eligible MM patients. © Copyright 2012 Roberto Ria et al

Adhesion of platelets to colon cancer cells is necessary to promote tumor development in xenograft, genetic and inflammation models

Platelets represent the linkage between tissue damage and inflammatory response with a putative role in tumorigenesis. Given the importance of the microenvironment in colon cancer development, we elucidated the eventual role of platelets‐cancer cells crosstalk in in vivo colon cancer models. To evaluate the involvement of platelets in intestinal tumorigenesis, we first analyzed if the ablation of β‐integrin P‐selectin that drives platelets‐cell adhesion, would contribute to platelets‐colon cancer cell interaction and drive cancer progression. In a xenograft tumor model, we observed that when tumors are inoculated with platelets, the ablation of P‐selectin significantly reduced tumor growth compared to control platelets. Furthermore, in genetic models, as well as in chronic colitis‐associated colorectal carcinogenesis, P‐selectin ablated mice displayed a significant reduction in tumor number and size compared to control mice. Taken together, our data highlights the importance of platelets in the tumor microenvironment for intestinal tumorigenesis. These results support the hypothesis that a strategy aimed to inhibit platelets adhesion to tumor cells are able to block tumor growth and could represent a novel therapeutic approach to colon cancer treatment

Pre-surgery supportive and goal-oriented strategies are associated with lower post-surgery perceived distress in women diagnosed with breast cancer

Background: Psycho-oncology literature pointed out that individual health outcomes may depend on patients’ propensity to adopt approach or, conversely, avoidant coping strategies. Nevertheless, coping factors associated with postoperative distress remain unclear, unfolding the lack of tailored procedures to help breast cancer patients manage the psychological burden of scheduled surgery. In view of this, the present study aimed at investigating: 1. pre-/post-surgery distress variations occurring among women diagnosed with breast cancer; 2. the predictivity of approach and avoidant coping strategies and factors in affecting post-surgery perceived distress. Methods: N = 150 patients (mean age = 59.37; SD = ± 13.23) scheduled for breast cancer surgery were administered a screening protocol consisting of the Distress Thermometer (DT) and the Brief-COPE. The DT was used to monitor patients’ distress levels before and after surgery (± 7 days), whereas the Brief-COPE was adopted only preoperatively to evaluate patients’ coping responses to the forthcoming surgical intervention. Non-parametric tests allowed for the detection of pre-/post-surgery variations in patients’ perceived distress. Factor analysis involved the extraction and rotation of principal components derived from the Brief-COPE strategies. The predictivity of such coping factors was investigated through multiple regression (Backward Elimination). Results: The Wilcoxon Signed-Rank Test yielded a significant variation in DT mean scores (TW = -5,68 < -zα/2 = -1,96; p <.001) indicative of lower perceived distress following surgery. The four coping factors extracted and Varimax-rotated were, respectively: 1. cognitive processing (i.e., planning + acceptance + active coping + positive reframing); 2. support provision (i.e., instrumental + emotional support); 3. emotion-oriented detachment (i.e., self-blame + behavioral disengagement + humor + denial); 4. goal-oriented detachment (i.e., self-distraction). Among these factors, support provision (B =.458; β = −.174; t = − 2.03; p =.045), encompassing two approach coping strategies, and goal-oriented detachment (B =.446; β = −.176; t = − 2.06; p =.042), consisting of one avoidant strategy, were strongly related to post-surgery distress reduction. Conclusion: The present investigation revealed that the pre-surgery adoption of supportive and goal-oriented strategies led to postoperative distress reduction among breast cancer patients. These findings highlight the importance of timely psychosocial screening and proactive interventions in order to improve patients’ recovery and prognosis