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Background: Immunotherapy has revolutionized the approach to metastatic triple-negative breast cancers. Atezolizumab was approved for patients with metastatic triple-negative breast cancers whose tumors express PD-L1, determined by SP 142 assay. To assess the availability and practice of SP142 test we administered a survey to all the 15 pathology departments of the Lazio Region during a six-month period.Methods: The survey comprised 12 questions regarding the availability of SP142 in the pathology departments, the percentage of positive tests, the difficulties of pathologists in cases close to cut-off value and the tested samples.Results: The SP142 assay was available in only eight centers. In case of positive result, most centers (5/8, 62.5%) reported values of PD-L1 expression ranging from > 1 to ⩽ 5%, with values close to the cut-off point (⩾ 1% or < 1%) being the greatest challenge. Most of the centers (6/8, 75%) tested material from both their own and other hospitals. In most centers, the evaluations were performed either on primary tumors or metastasis, in particular lymph nodes (5/8, 62.5%), followed by lung (3/8, 37.5%) and liver (1/8, 12.5%) metastasis.Conclusion: Our results raise some important issues concerning the evaluation of PD-L1 in the “real-life” setting, providing strategies for its implementation.

Ghrelin is an octanoylated peptide acting by the activation of the growth hormone secretagogue receptor, namely, GHS-R1a. The involvement of ghrelin in several physiological processes, including stimulation of food intake, gastric emptying, body energy balance, glucose homeostasis, reduction of insulin secretion, and lipogenesis validates the considerable interest in GHS-R1a as a promising target for the treatment of numerous disorders. Over the years, several GHS-R1a ligands have been identified and some of them have been extensively studied in clinical trials. The recently resolved structures of GHS-R1a bound to ghrelin or potent ligands have provided useful information for the design of new GHS-R1a drugs. This perspective is focused on the development of recent nonpeptide small molecules acting as GHS-R1a agonists, antagonists, and inverse agonists, bearing classical or new molecular scaffolds, as well as on radiolabeled GHS-R1a ligands developed for imaging. Moreover, the pharmacological effects of the most studied ligands have been discussed.

IMPORTANCE: Geriatric (aged ≥80 years) patients are historically underrepresented in cancer clinical trials. Little is known about the efficacy of immune checkpoint inhibitors (ICIs) in geriatric patients. These agents are associated with immune-related adverse events (irAEs), which may be particularly associated with morbidity in this population. OBJECTIVE: To provide insight into the clinical outcomes and safety of ICIs among geriatric patients (aged ≥80 years) with cancer. DESIGN, SETTING, AND PARTICIPANTS: A Multicenter, international retrospective study of 928 geriatric patients with different tumors treated with single-agent ICIs between 2010 to 2019 from 18 academic centers in the US and Europe. Analyses were conducted from January 2021 to April 2021. MAIN OUTCOMES AND MEASURES: Clinical outcomes and irAE patterns in geriatric patients treated with single-agent ICIs. RESULTS: Median (range) age of the 928 patients at ICI initiation was 83.0 (75.8-97.0) years. Most patients (806 [86.9%]) were treated with anti–programmed cell death 1 therapy. Among the full cohort, the 3 most common tumors were non–small cell lung cancer (NSCLC, 345 [37.2%]), melanoma (329 [35.5%]), and genitourinary (GU) tumors (153 [16.5%]). Objective response rates for patients with NSCLC, melanoma, and GU tumors were 32.2%, 39.3%, and 26.2%, respectively. Median PFS and OS, respectively, were 6.7 and 10.9 months (NSCLC), 11.1 and 30.0 months (melanoma), and 6.0 and 15.0 months (GU). Within histologically specific subgroups (NSCLC, melanoma, and GU), clinical outcomes were similar across age subgroups (aged &lt;85 vs ≥85 years). Among all 928 patients, 383 (41.3%) experienced ≥1 irAE(s), including 113 (12.2%) that were reported to be grade (G) 3 to 4 based on Common Terminology Criteria for Adverse Events (version 5.0). The median time to irAE onset was 9.8 weeks; 219 (57%) occurred within the first 3 months after ICI initiation. Discontinuation of treatment with ICIs owing to irAEs occurred in 137 (16.1%) patients. There was no significant difference in the rate of irAEs among patients aged younger than 85, 85 to 89, and 90 years or older. Despite the similar rate of G3 or higher irAEs, ICIs were discontinued due to irAEs more than twice as often among patients aged 90 years or older compared with patients younger than 90 years (30.9% vs 15.1%, P = .008). CONCLUSIONS AND RELEVANCE: The findings of this international cohort study suggest that treatment with ICIs may be effective and generally well tolerated among older patients with cancer, though ICI discontinuation owing to irAEs was more frequent with increasing age.

Epithelial ovarian neoplasms can be divided into three distinct clinicopathological groups: benign, malignant and borderline tumours. Borderline tumours are less aggressive than epithelial carcinomas, with an indolent clinical course and delayed recurrence. However, a subset of these cases can progress to malignancy and relapse, and death from recurrent disease can occasionally occur. Telomerase activation is a critical element in cellular immortalisation and cancer. The enzyme telomerase comprises a catalytic subunit (TERT) expressed in various types of cancers and regulated by promoter methylation mainly in epithelial tumours.

Supplemental Digital Content is available in the text.The role of induction chemotherapy in the multidisciplinary treatment of locally advanced, nonlaryngeal high-risk human papilloma virus (HPV)-negative head and neck squamous cells carcinoma (HNSCC) is uncertain in terms of overall survival (OS). The primary objective of this study was to identify possible predictive factors of survival and outcome in patients with HNSCC who were treated with induction chemotherapy. Fifty-nine patients with stage IVa/b HPV-negative non-laryngeal HNSCC (mostly originating from the oral cavity) who underwent induction chemotherapy at Policlinico Umberto I were reviewed. Treatment outcomes in term of objective response rate (ORR), progression-free survival (PFS), OS and toxicities were analyzed. A significant association between nodal status, ORR, ongoing smoking use, toxicities and OS was demonstrated. ORR (obtained in 61% of patients) was associated with a reduction in mortality of 80% (P< 0.0001). Early discontinuation after just one cycle of induction chemotherapy was associated to a significantly shorter OS. In oral cavity radical surgery with negative margins was obtained in 15/16 patients. In 42% of patients G3-G4 toxicity occurred. Toxicity requiring hospitalization occurred in 42% and 21% of patients with oropharyngeal and oral cavity carcinoma, respectively. Five patients died of treatment-related causes. No treatment-related mortality occurred in oral cavity patients. G5 toxicities were different according to the sub-sites of disease (P= 0.05). Induction chemotherapy in non-laryngeal high-risk HNSCC is an active strategy, most importantly in oral cavity cancer, even though burdened with a high (G ≥ 3) toxicity and early discontinuation rate. These data will however need to be confirmed in further and larger studies.

Aim: To examine the association of cleft severity at infancy and velopharyngeal competence in preschool children with unilateral cleft lip and palate operated with early or delayed hard palate repair.Design: Subgroup analysis within a multicenter randomized controlled trial of primary surgery (Scandcleft).Setting: Tertiary health care. One surgical center.Patients and Methods: One hundred twenty-five infants received cheilo-rhinoplasty and soft palate repair at age 3 to 4 months and were randomized to hard palate closure at age 12 or 36 months. Cleft size and cleft morphology were measured 3 dimensionally on digital models, obtained by laser surface scanning of preoperative plaster models (mean age: 1.8 months).Main outcome measurements: Velopharyngeal competence (VPC) and hypernasality assessed from a naming test (VPC-Sum) and connected speech (VPC-Rate). In both scales, higher scores indicated a more severe velopharyngeal insufficiency.Results: No difference between surgical groups was shown. A low positive correlation was found between posterior cleft width and VPC-Rate (Spearman = .23; P= .025). The role of the covariate “cleft size at tuberosity level” was confirmed in an ordinal logistic regression model (odds ratio [OR] = 1.17; 95% confidence interval [CI]:1.01-1.35). A low negative correlation was shown between anteroposterior palatal length and VPC-Sum (Spearman = −.27; P= .004) and confirmed by the pooled scores VPC-Pooled (OR = 0.82; 95% CI: 0.69-0.98) and VPC-Dichotomic (OR = 0.82; 95% CI: 0.68-0.99).Conclusions: Posterior cleft dimensions can be a modest indicator for the prognosis of velopharyngeal function at age 5 years, when the soft palate is closed first, independently on the timing of hard palate repair. Antero-posterior palatal length seems to protect from velopharyngeal insufficiency and hypernasality. However, the association found was significant but low.

Aim: To investigate whether infant cleft dimensions, in a surgical protocol with early or delayed hard palate closure, influence occlusion before orthodontics.Design: Subgroup analysis within a randomized trial of primary surgery (Scandcleft).Setting: Tertiary health care. One surgical centre.Patients and Methods: A total of 122 unilateral cleft lip and palate infants received primary cheilo-rhinoplasty and soft palate closure at age 4 months and were randomized for hard palate closure at age 12 versus 36 months. A novel 3D analysis of cleft size and morphology was performed on digitized presurgical models. Occlusion was scored on 8-year models using the modified Huddarth–Bodenham (MHB) Index and the Goslon Yardstick.Main Outcome Measurements: Differences in MHB and Goslon scores among the 2 surgical groups adjusted for cleft size.Results: The crude analysis showed no difference between the 2 surgical groups in Goslon scores but a better MHB (P= .006) for the group who received delayed hard palate closure. When adjusting for the ratio between cleft surface and palatal surface (3D Infant Cleft Severity Ratio) and for posterior cleft dimensions at tuberosity level, the delayed hard palate closure group received 3.65 points better for MHB (confidence interval: 1.81; 5.48; P< .001) and showed a trend for reduced risk of receiving a Goslon of 4 or 5 (P= .052). For posterior clefts larger than 9 mm, the Goslon score was better in the delayed hard palate closure group (P= .033).Conclusions: Seen from an orthodontic perspective, when the soft palate is closed first, and the cleft is large, the timing of hard palate closure should be planned in relation to posterior cleft size.

Background: Because of a lack of large-scale prospective studies there is no clear indication about the management of patients with small bowel adenocarcinoma (SBA). This study evaluated clinical outcome of patients diagnosed with SBA at our institution.Methods: Clinicopathologic features, treatments, and clinical outcome of patients diagnosed with SBA between 2006 and 2017 were retrospectively analyzed. Median time of survival was calculated and compared using the log-rank test. Multivariate Cox regression was used to test independence of significant factors in univariate analysis.Results: Forty patients were included in the study; the majority (82.5%) had a tumor in the duodenum (including ampulla of Vater) and an early stage disease at the diagnosis. Median overall survival (OS) in the whole study population was 26.5 months. Patients with a tumor of the lower part of the small intestine (jejunum, ileum, and appendix) showed a better OS compared with that of patients with upper SBA (40 months vs 26 months, respectively; P=0.09). Primary tumor site and stage were independent predictors of OS.Conclusions: Our results suggest a prognostic role for the primary tumor site. This finding deserves to be further investigated to ensure better classification as well as more effective management strategies for SBA.

Background: To evaluate the effect of two different implant macro-designs on the sequential osseointegration at bicortically installed implants in the rabbit tibia. A further aim is to compare the osseointegration at different topographic zones. Material and Methods: 27 New Zealand rabbits were implemented. Two implants, one for each macro-design (Ticare Inhex® or Ticare Quattro®, Mozo-Grau, Valladolid, Spain), were randomly implanted in the diaphysis or metaphysis of each tibia. The flaps were sutured to allow a submerged healing. The animals were sacrificed after 2, 4 or 8 weeks. Ground sections were prepared and analyzed. Results: No statistically significant differences were found between the two groups for newly formed bone in contact with the implant surface, being about 16%, 19% and 33% in both groups, after 2, 4, and 8 weeks of healing. Bone apposition was slightly higher in the diaphysis, reaching values of 36.4% in the diaphysis, and 29.3% in the metaphysis at 8 weeks of healing. It was observed that the implant position showed a statistical significance regarding BIC values at 4 and 8 weeks (p<0.05). Multivariate analysis fails to detect statistical significant differences for the interaction between implant designs and topographic site. Ticare Quattro® design had a slight better BIC values at diaphysis sites across healing stages, but without reaching a statistical significance. Conclusions: The both implant macro-designs provided similar degrees of osseointegration. Bone morphometry and density may affect bone apposition onto the implant surface. The apposition rates were slightly better in diaphysis compared to metaphysis. [ABSTRACT FROM AUTHOR]

ABSTRACTWe carried out a retrospective observational study of 264 HER2-positive advanced breast cancer (ABC) patients to explore the efficacy of first-line treatment with pertuzumab/trastuzumab/taxane in real-world setting. Survival data were analyzed by Kaplan Meier curves and log rank test.Median follow-up, length of pertuzumab/trastuzumab/taxane treatment and of pertuzumab, trastuzumab maintenance were 21, 4 and 15 months, respectively. The response rate was 77.3%, and the clinical benefit rate 93.6%. Median progression-free survival (mPFS) was 21 months, and median overall survival (mOS) was not reached.When comparing patients by trastuzumab-pretreatment, similar PFS were observed, although a longer OS was reached in trastuzumab-naïve patients (p = 0.02). Brain metastases at baseline and their development in course of therapy were associated with significantly shorter PFS (p = 0.0006) and shorter OS, although at a not fully statistically relevant extent (p = 0.06).The addition of maintenance endocrine therapy (ET) to pertuzumab/trastuzumab maintenance was associated with longer PFS (p = 0.0001), although no significant differences were detected in OS (p = 0.31). Results were confirmed by propensity score analysis (p = 0.003 and p = 0.46, respectively).In multivariate models, longer PFS was related to lower Performance Status (PS) (p = 0.07), metastatic stage at diagnosis (p = 0.006) and single metastatic site (p < 0.0001). An OS advantage was observed with lower PS (p < 0.0001), single metastatic site (p = 0.004), no prior exposure to trastuzumab (p = 0.004) and response to pertuzumab-based treatment (p = 0.003). Our results confirm that trastuzumab/pertuzumab/taxane is the standard of care as first-line treatment of patients with HER2-positive ABC even in the real-world setting. Moreover, the double-maintenance therapy (HER2 block and ET) is strongly recommended when feasible.

Aim of the study was to evaluate the reliability of 6 mm long implants compared to normal length implants placed in vertical augmented atrophic posterior mandible, supporting cemented single crowns. Thirty-six patients with bilateral posterior edentulous mandible and presented a bone availability height less than 9 mm from the mandibular canal were enrolled for the participation to this study. Patient hemi-arches were randomized to receive both 6 mm-long and normal length implants (10 mm). The technique used for the vertical bone augmentation was the "sandwich" technique, using a bone substitute block as graft. The data outcomes at 1 year post-loading follow-up were the loss of implants and the complications. Eighty-six 6 mm long implants and eighty-four normal implants were inserted. Five short implants and thirteen normal implants were lost. In 28 patients complications occurred, and in 21 cases the complication was present on the side of the ridge vertical augmentation. From the statistical analysis the association between the side of the ridge augmentation and the side of occurrence of the complication was statistically significant (p <0.05). The results from this trial suggest short implants can be the preferred choice to vertical bone augmentation for the placement of longer implants in the rehabilitation of edentulous posterior mandibles. These initial results must be confirmed by larger and longer follow-ups of 5 years or more.

Objective: To present a 3-D standardized analysis of cleft dimensions.Materials: Thirty-one plaster casts of unilateral cleft lip and palate (UCLP) infants were laser scanned. Landmarks and coordinate system were defined. Linear distances and surfaces were measured, and the ratio between cleft and palatal area was calculated (3-D infant cleft severity ratio [3D ICSR]). The digitally measured areas were compared with silicone membranes, adapted to the plaster casts, and analyzed by optic microscopy.Main Outcome Measures: Repeatability, reproducibility, and validity.Results: Bland-Altman plots showed minor bias for anterior cleft width (0.16 mm), arch length (0.23 mm), and palatal surface (−9.18 mm2). The random error was maximum 0.78 mm for linear measurements and 12.1 mm2for area measurements, reliability of 3D ICSR was 0.99 (intraclass correlation coefficient), differences between measurements on digital and plaster models were less than 2%.Conclusions: The method offers valid and reproducible 3-D assessment of cleft size and morphology. 3-D infant cleft severity ratio can be used as baseline value for surgical planning and may have a role in predicting dentofacial development.

Drug overdose is now the leading cause of injury death in the United States. Most overdose fatalities involve opioids, which include prescription medication, heroin, and illicit fentanyl. Current data reveal that the overdose crisis affects all demographic groups and that overdose rates are now rising most rapidly among African Americans. We provide a public health perspective that can be used to mobilize a comprehensive local, state, and national response to the opioid crisis. We argue that framing the crisis from a public health perspective requires considering the interaction of multiple determinants, including structural factors (eg, poverty and racism), the inadequate management of pain, and poor access to addiction treatment and harm-reduction services (eg, syringe services). We propose a novel ecological framework for harmful opioid use that provides multiple recommendations to improve public health and clinical practice, including improved data collection to guide resource allocation, steps to increase safer prescribing, stigma-reduction campaigns, increased spending on harm reduction and treatment, criminal justice policy reform, and regulatory changes related to controlled substances. Focusing on these opportunities provides the greatest chance of making a measured and sustained impact on overdose and related harms.

ABSTRACTThe evidence emerged from the TOURANDOT trial encourages evaluating the role of anthropometric determinants on treatment outcomes in HER2-negative metastatic breast cancer patients treated with bevacizumab-including regimens. We thus analyzed data from a subgroup of these patients from a larger cohort previously assessed for treatment outcomes. Patients were included in the present analysis if body mass index values had been recorded at baseline. Clinical benefit rates, progression free survival and overall survival were assessed for the overall study population and subgroups defined upon molecular subtype. One hundred ninety six patients were included (N:196). Body mass index showed no impact on clinical benefit rates in the overall study sample and in the luminal cancer subset (p = 0.12 and p = 0.79, respectively), but did so in the triple negative subgroup, with higher rates in patients with body mass index ≥25 (p = 0.03). In the overall study sample, body mass index did no impact progression free or overall survival (p = 0.33 and p = 0.67, respectively). Conversely, in triple negative patients, progression free survival was significantly longer with body mass index ≥25 (6 vs14 months, p = 0.04). In this subset, overall survival was more favorable (25 vs19 months, p = 0.02). The impact of the molecular subtype was confirmed in multivariate models including the length of progression free survival, and number of metastatic sites (p < 0.0001). Further studies are warranted to confirm our findings in more adequately sized, ad hoc, prospective studies.

Implantology research framed the implant surface as a key element for a good and sustainable osseointegration of an implant fixture. The aim of this study was to analyze the antibacterial properties of anatase-coated titanium healing screws through microbiological and scanning electron microscopy. The comparison of the bacterial colonies growth between the anatase-coated titanium healing screws and non-coated titanium healing screws showed comparable antibacterial properties, without significant statistical differences. The scanning electron microscopy observations confirmed the microbiological study. These data, also considering previous reports on the positive effects on osteoblasts genetic expressions, might suggest a use of the anatase-coated titanium healing screws to preserve the tissues surrounding implants from microbial attacks.

The aim of the present split-mouth (split-plot) study was to describe the sequential healing in the interface between autologous bone grafts and recipient parent bone, fixed using an n-butyl-2-cyanoacrylate adhesive with or without an additional titanium fixation screw. Bone grafts were collected from the calvaria and fixed to the lateral aspect of the mandible in 24 rabbits. The cortical layers of the recipient sites were perforated, and the grafts were randomly fixed using an n-butyl-2-cyanocrylate adhesive, either alone or in conjunction with a 1.5 mm × 6.0 mm titanium fixation screw. The animals were sacrificed after 3, 7, 20, and 40 days, and histomorphometric evaluations of the interface between graft and parent bone were performed. Only 2 of 6 grafts in each group were partially incorporated to the parent bone after 40 days of healing. The remaining grafts were separated from the parent bone by adhesive and connective tissue. It was concluded that the use of n-butyl-2-cyanoacrylate as fixation of an autologous bone graft to the lateral aspect of the mandible was able to maintain the fixation over time but did not incorporate the graft to the recipient sites. Use of fixation screws did not improve the healing.

Fluoropyrimidines combined with other agents are commonly used for gastrointestinal cancer treatment. Considering that severe toxicities occur in 30% of patients, we aimed to structure a nomogram to predict toxicity, based on metabolic parameter and patients’ characteristics. We retrospectively enrolled patients affected by gastrointestinal tract cancers. Pretreatment 5-fluorouracil (5-FU) degradation rate and DPYD, TSER, MTHFRA1298T, and C677T gene polymorphisms were characterized. Data on toxicities were collected according to CTCAE v3.0. Multivariate logistic regression analysis was used to structure a nomogram. 642 patients were enrolled (384 men; 258 female; median age: 67 years, range: 27–87): 449 (69.9%) patients were affected by colorectal cancer; 118 (18.4%) by gastroesophageal cancer; 66 (10.3%) by pancreatic cancer; and nine (1.4%) by other cancers. Grade 3–4 toxicities were observed in 118 (18.4%) patients and were most frequently observed in patients with altered 5-FU degradation rate (43.5 and 26.7% of the patients in the poor metabolizer and in the ultrarapid metabolizer group respectively, vs. 17% in the normal metabolizer group) and in DPYDheterozygous mutated patients (83.3% of the patients). Age, DPYDstatus, the number of drugs administered, and 5-FU degradation rate value were associated to severe toxicities. On the basis of these findings, we structured a nomogram to assess a score to predict the risk of developing severe toxicity. Compared with the available pharmacogenetic tests, this approach can be applied to the whole population, predicting the risk for severe toxicity, with an easy, low-cost, and not invasive technique.

This paper reviews genetic variations mainly related to the onset of adverse events during aromatase inhibitors in early breast cancer. Genetic variability could occur at different steps. The analysis included studies that involved breast cancer patients, treated with an aromatase inhibitor, genotyped for CYP19A1and/or CYP17A1and/or CYP27B1and/or TCLA1, and/or RANK/RANKL/OPGand/or ESR1/ESR2, and assessed for toxicity profile. Twenty-two articles were included for the analysis. Three studies evaluated outcomes and adverse events; 19 studies assessed only side effects. Functional variations may be useful in predicting the onset of toxicities. The identification of polymorphisms at increased risk of toxicity may enable patient management. However, more data are needed to be applied in the individualization of treatment in daily practice.

5-Fluorouracil is commonly used for gastrointestinal cancer treatment in an adjuvant setting; however, the toxicity can lead to a reduction, delay, or discontinuation of treatment. We retrospectively investigated the association between the 5-fluorouracil degradation rate (5-FUDR) and genetic polymorphisms of TSER, DPYD, and MHTFRwith toxicity in colorectal cancer patients treated with adjuvant FOLFOX. Pretreatment 5-FUDR and MTHFRA1298T or C677T, TSER, and DPYDgene polymorphisms were characterized in stages II–III colorectal cancer patients. Patients were classified into three metabolic classes according to the 5-FUDR value. Association with toxicities was evaluated retrospectively using logistic regression analysis. Overall, 126 patients were selected (35 women, 91 men). Seven patients were poor metabolizers, 116 patients were normal metabolizers and three patients were ultra-rapid metabolizers. The median 5-FUDR was 1.53 ng/ml/106cells/min (range: 0.42–2.57 ng/ml/106cells/min). Severe, rate-limiting toxicities (grades 3–4) were encountered in 22.2% of patients. No associations between MTHFRor TSERpolymorphisms and toxicity were detected, whereas 5-FUDR showed a statistically significant association with toxicity (P=0.0047). The DPYDheterozygous mutation was detected in only one patient, who showed grade 4 hematological toxicity and a lower 5-FUDR value. The 5-FUDR value seems not to be affected by MTHFRand TSERpolymorphisms. Compared with the available pharmacogenomics tests, the pretreatment evaluation of 5-FUDR increases the proportion of identified colorectal patients at high risk for severe toxicity. Thus, it appears to be a suitable pretreatment toxicity biomarker in a subgroup of patients in whom dose-intensity maintenance is the key factor.

Low doses of drugs delivered at close, regular intervals are increasingly being used to manage patients with different neoplasms. Despite the good tolerability, treatment-related adverse events still occur following metronomic protocols. The aim of this study was to retrospectively investigate whether polymorphisms of different genes involved in fluoropyrimidine metabolism and 5-fluorouracil (5-FU) degradation rate were associated with the outcome of a low-dose capecitabine schedule. Genotyping of DPYDIVS14+1 G>A, MTHFRC677T, and A1298C single-nucleotide polymorphisms was performed by pyrosequencing technology. A PCR technique was used for genotyping TYMS-TSER. Using peripheral blood mononuclear cells, we also evaluated the 5-FU degradation rate, which determines the net result of all the enzymatic transformation of 5-FU, in terms of the amount of drug consumed by the cells in a time unit. The association of these variables with clinical outcome was evaluated using multivariate logistic regression analysis. Eighty-four patients with metastatic gastrointestinal cancer, who had been treated with a low-dose fluoropyrimidine schedule, as a rescue therapy were included in the study. The TSER2R/2R genotype was significantly associated with both hematologic (odds ratio=7.90, P=0.002) and gastrointestinal toxicity (odds ratio=3.24, P=0.009). Because DPYDIVS14 G>A single-nucleotide polymorphism was not observed in the cohort, it was excluded from the statistical analysis. No significant association was detected between clinical outcome and both MTHFRpolymorphisms and the 5-FU degradation rate. In the advanced setting of cancer care, high attention should be paid toward avoiding toxicity and worsening of quality of life. Although metronomic chemotherapy is generally well tolerated, treatment toxicity nonetheless does occur. Our data suggest a possible role of the TSER2R/2R polymorphism as a predictive marker of toxicity in patients treated with low-dose capecitabine.

Background:The aim of this study is to investigate peri‐implant and intraconnection microflora of healthy implants restored with cemented and screwed superstructures. Methods:Patients with two to three implants restored with cemented or screwed restorations and 5 years of follow‐up were recruited. Samples were taken from peri‐implant sulci, adjacent teeth, and the inner portion of connections. Prevalence of positive sites and bacterial loads for 10 microorganisms were obtained with quantitative real‐time polymerase chain reaction. Implant connection permeability to the studied microorganisms was estimated using a standardized bacterial contamination index. Statistical analysis was performed using a generalized estimating equations model, Wald χ2test, and the least significant difference test. Results:The final sample consisted of 18 patients (55 implants) in the cemented group and 22 patients (46 implants) in the screw‐retained group. Regarding prevalence of positive sites, significant differences between groups were only found for Tannerella forsythia, which was 8.7 times more frequent at peri‐implant sulci of cemented than screw‐retained prostheses. Bacterial loads of Porphyromonas gingivalis, T. forsythia, Parvimonas micra, and total bacterial load were significantly higher at peri‐implant sulci for the cemented group; at the inner portion of connections, values were significantly higher for P. micraand Fusobacterium nucleatumfor the screw‐retained group. Contamination index values demonstrated higher permeability to most microbes in the cemented group. Conclusions:Internal implant surfaces were microbiologically contaminated for both cemented and screw‐retained superstructures. Differences were found between the two methods of prosthetic retention: the cemented group presented significantly higher bacterial loads in the peri‐implant sulcus but significantly lower bacterial loads at the inner portion of the implant connection.

5-Fluorouracil is among the most widely used anticancer drug, but a fraction of treated patients develop severe toxicity, with potentially lethal injuries. The predictive power of the available pretreatment assays, used to identify patients at risk of severe toxicity, needs improvements. This study aimed to correlate a phenotypic marker of 5-fluorouracil metabolism (the individual degradation rate of 5-fluorouracil—5-FUDR) with 15 functional polymorphisms in the dihydropyrimidine dehydrogenase gene (DPYD). Single SNP (single-nucleotide polymorphism) analysis revealed that the SNPs rs1801160, rs1801265, rs2297595 and rs3918290 (splice site variant IVS14+1G>A) were significantly associated with a decreased value of 5-FUDR, and the rs3918290 causing the larger decrease. Multi-SNP analysis showed that a three-SNP haplotype (Hap7) involving rs1801160, rs1801265 and rs2297595 causes a marked decrease in 5-FUDR, comparable to that caused by the splice site variant rs3918290, which is the main pharmacogenetic marker associated with severe fluorouracil toxicity. The similar effect played by Hap7 and by the splice site variant rs3918290 upon individual 5-FUDR suggests that Hap7 could also represent a similar determinant of fluorouracil toxicity. Haplotype assessment could improve the predictive value of DPYDgenetic markers aimed at the pre-emptive identification of patients at risk of severe 5-fluorouracil toxicity.

I respond to Darwin’s and Knoblauch’s discussions of my paper, coming around to the question of the value of theory in its application to “real-world” problems.

In an effort to make sense of several psychoanalytic and other accounts of war trauma in which homosexual themes appear, I work out in step-by-step fashion a series of psychic linkages by which trauma following on violence inflicted or undergone in war may recruit (homo)sexuality for its expression, in intergenerational or other transfers. I offer the conceit of a homosexual imaginary, a formation in cultural and psychic life, which may mediate such transfers. Invoking Jean Laplanche’s notion of the enigmatic message, his conception of sexuality as a traumatically violent implantation into the child on the part of the adult, I pose the question: Could we think of the intergenerational transmission of trauma as a kind of enigmatic message?