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The Italian Register of Actionable Mutations (RATIONAL) is a multicentric, observational study collecting next-generation sequencing (NGS)-based tumour profiling data of patients with advanced solid tumours. The study enrols patients who had available an NGS-based tumour profiling (Pathway-A) or undergo comprehensive genomic profiling (CGP) with FoundationOne CDx assays within the trial (Pathway-B). The primary endpoint was the rate of actionable mutations identified. Sequencing data were available for 738 patients in Pathway-A (218) and -B (520). In Pathway-A, 154/218 (70.6%) tests were performed using NGS panels ≤52 genes, and genomic alterations (GAs) were found in 164/218 (75.2%) patients. In Pathway-B, CGP revealed GAs in 512/520 (98.5%) patients. Levels I/II/III actionable GAs according to the European Society of Medical Oncology Scale for Clinical Actionability of molecular Targets (ESCAT) were identified in 254/554 (45.8%) patients with non-small-cell lung cancer, cholangiocarcinoma, colorectal, gastric, pancreatic and breast cancer. The rate of patients with level I GAs was similar in Pathways A and B (69 versus 102). CGP in Pathway-B revealed a higher number of patients with level II/III GAs (99 versus 20) and potentially germline pathogenic/likely pathogenic variants (58 versus 15) as compared with standard testing in Pathway-A. In patients with cancer of unknown primary, CGP detected OncoKB levels 3B/4 GAs in 31/58 (53.4%) cases. Overall, 67/573 (11.7%) of patients received targeted therapy based on genomic testing. The Italian Register of Actionable Mutations represents the first overview of genomic profiling in Italian current clinical practice and highlights the utility of CGP for identifying therapeutic targets in selected cancer patients. • Comprehensive genomic profiling (CGP) is limited to selected cases in Italy. • European Society of Medical Oncology Scale for Clinical Actionability of molecular Targets level I alterations are equally identified by small and large next-generation sequencing panels. • CGP identifies more level II/III alterations and potentially germline variants. • The rate of patients receiving a therapy matched to the genomic profile is low. [ABSTRACT FROM AUTHOR]

As an efficient, cheap and durable cocatalyst, CuP has been a the research hotspot in the field of light-driven water decomposition for hydrogen production. In this study, the amorphous CuP cocatalyst with defects and unsaturated edge sites was deposited on the surface of CdS nanorods by in-situ photodeposition strategy, strategy to synthesize CuP/CdS composite photocatalyst materials. The CuP/CdS composite with 10% CuP loading content presents high hydrogen evolution activity (906 μmol g−1h−1), 16 times of single CdS. In addition, the characterization shows that the coupling of CuP nanoparticles with CdS as a cocatalyst can not only enhance the visible light absorption, effectively shorten the band gap width, but also improve the separation efficiency of h+-e- pairs and enhance the photocatalytic hydrogen production performance. This work provides a new approach to design and develop CdS based photocatalytic materials with low cost, strong stability and high efficiency. • CuP/CdS was synthesized in an environmentally friendly manner for the first time. • CuP/CdS photocatalyst has excellent photocatalytic hydrogen production performance. • CuP/CdS photocatalyst can effectively accelerate the ability of carrier separation. • The unsaturated edge site of CuP cocatalyst can provide more active sites. [ABSTRACT FROM AUTHOR]

Cancer of unknown primary (CUP) is a heterogeneous entity with limited overall survival (OS) in most patients. Prognostic biomarkers are needed, particularly for treatment stratification. We investigated the impact of programmed death-ligand 1 (PD-L1) expression as prognostic marker in immunotherapy-naïve CUP patients. Clinical data from patients with confirmed CUP diagnosis according to ESMO guidelines, treated at the West German Cancer Center, Essen from 2015 to 2021, were analyzed. Patients treated with checkpoint inhibitors were excluded. PD-L1 expression was assessed in tumor tissues following established guidelines. Of a cohort of 132 patients, 62 patients, including 30 patients with prognostically unfavorable CUP, met inclusion criteria and were evaluable for PD-L1 expression. Comparing PD-L1 Tumor Proportional Score (TPS) and Combined Positive Score (CPS) revealed almost complete concordance (96.2 %). Patients with PD-L1-positive CUP (TPS ≥1 %; n = 36; 58 %) had superior overall survival (median not reached) as compared to patients with PD-L1-negative CUP (median 14 months, 95 %CI 10.0–18.0; HR 0.3, p < 0.001). The benefit of PD-L1 positivity (n = 12; 40 %) was maintained in the unfavorable CUP subgroup (median 20 months, 95 %CI 3.0–37.0 versus 10 months, 95 %CI 3.1–16.9; HR 0.4, p = 0.032). In PD-L1-positive CUP there was a positive correlation between the level of PD-L1 expression and survival (TPS ≥50 %: median survival not reached, HR 0.1; TPS 1 to 49 %: OS: 77 months, HR 0.4). PD-L1 expression associates with favorable survival in checkpoint inhibitor-naïve CUP patients. This implies a role of cancer immunity in CUP biology and may nominate PD-L1 for patient stratification in further studies and clinical care. [Display omitted] • Favorable OS in checkpoint inhibitor-naïve CUP patients with PD-L1 expression. • In patients with CUP the level of PD-L1 expression correlates with survival. • PD-L1 expression could be used as a biomarker for prognosis in CUP patients. [ABSTRACT FROM AUTHOR]

Cancer of unknown primary (CUP) has a poor prognosis. Given the recent approval of immune checkpoint inhibitors for several cancer types, we carried out a multicenter phase II study to assess the efficacy of nivolumab for patients with CUP. Patients with CUP who were previously treated with at least one line of systemic chemotherapy constituted the principal study population. Previously untreated patients with CUP were also enrolled for exploratory analysis. Nivolumab (240 mg/body) was administered every 2 weeks for up to 52 cycles. The primary endpoint was objective response rate in previously treated patients as determined by blinded independent central review according to RECIST version 1.1. Fifty-six patients with CUP were enrolled in the trial. For the 45 previously treated patients, objective response rate was 22.2% [95% confidence interval (CI), 11.2% to 37.1%], with a median progression-free survival and overall survival of 4.0 months (95% CI, 1.9-5.8 months) and 15.9 months (95% CI, 8.4-21.5 months), respectively. Similar clinical benefits were also observed in the 11 previously untreated patients. Better clinical efficacy of nivolumab was apparent for tumors with a higher programmed death-ligand 1 expression level, for those with a higher tumor mutation burden, and for microsatellite instability-high tumors. In contrast, no differences in efficacy were apparent between tumor subgroups based on estimated tissue of origin. Adverse events were consistent with the known safety profile of nivolumab. No treatment-related death was observed. Our results demonstrate a clinical benefit of nivolumab for patients with CUP, suggesting that nivolumab is a potential additional therapeutic option for CUP. • Nivolumab demonstrated clinical benefits in a statistically assessable number of patients with CUP. • Objective response rate was 22.2% in previously treated patients with CUP, which met the study primary endpoint. • Benefits were more apparent in patients with known biomarkers for ICIs, but also observed in those without such markers. • No differences in efficacy were apparent between tumor subgroups based on estimated tissue of origin. • Nivolumab could be an additional therapeutic option for these unmet medical needs. [ABSTRACT FROM AUTHOR]

Current guidelines recommend combination chemotherapy for treatment of patients with unfavorable cancer of unknown primary (CUP). Biomarker-guided targeted therapies may offer additional benefit. Data on the feasibility and effectiveness of comprehensive genomic biomarker profiling of CUP in a standard clinical practice setting are limited. This analysis included 156 patients with confirmed unfavorable CUP diagnosis according to ESMO guidelines, who were treated at the West German Cancer Center, Essen, Germany, from 2015 to 2021. Clinical parameters and outcome data were retrieved from the electronic hospital information system. Genomic biomarker analyses were performed in formalin-fixed paraffin-embedded tumor tissue whenever possible using the QIAseq Multimodal-Pancancer-Panel. Non-squamous histologies, high tumor burden, and age above 60 years associated with poor survival outcome. Tissue availability restricted comprehensive biomarker analyses to 50 patients (32%), reflecting a major limitation in the real-world setting. In those patients a total of 24 potentially actionable alterations were identified in 17 patients (34% of profiled patients, 11% of total population). The most prevalent biomarkers were high tumor mutational burden and BRCA-mutations. In a real-world setting precision medicine for patients with CUP is severely restricted by tissue availability, and a limited spectrum of actionable alterations. Progress for patients may require emphasizing the need for sufficient biopsies, and prospective exploration of blood-based biomarker profiling. [Display omitted] • Real-world setting: 1/3 of patients had sufficient tissue for molecular analyses. • 34% of molecular analysed patients showed potentially treatable alterations. • 41% of targeted treatable patients had a rationale for an immunotherapeutic regime. [ABSTRACT FROM AUTHOR]

The UK National Health Service has well-developed site-specific referral pathways for patients with suspected cancer, but historically there has been inequality of access for patients with suspected Metastatic malignant disease of Unknown primary Origin (MUO). The Brighton cancer of unknown primary (CUP) clinic covers a population of about 650 000. As well as 'in-house' referrals, direct general practitioner referrals are also accepted (since 2015), aiming to shorten the diagnostic pathway and improve patient support. We present data from the first 3 years of activity. Referrals were screened by an oncologist, ensuring adherence to the strict referral criterion of imaging evidence of a suspected diagnosis of MUO. A standardised data collection form was completed at each clinic appointment by the CUP team. Outcomes were cross-checked against clinic lists, letters and multidisciplinary meeting (MDM) records. A data analysis was carried out of all referrals to the CUP clinic (2015–2018), including general practitioner referrals. In total, 258 patients were seen in the CUP clinic in the first 3 years. The median age was 71 years (range 23–95 years). Source of referral: general practitioner (30%); physician (27%); acute oncology (24%); other MDM (16%); surgeon (3%). A final diagnosis of cancer was made in 83% of referrals, with a primary site identified in 83% of those cancer cases: 19% haematological, 11% lung, 9% urological, 8% upper gastrointestinal, 6% breast, 5% skin, 4% gynaecological, 4% lower gastrointestinal, 0.3% thyroid and 0.3% sarcoma. 10% of referrals remained with a MUO diagnosis (not fit for further investigation) and 7% had confirmed CUP. 17% had a benign diagnosis (of which 56% were general practitioner referrals). Of the general practitioner referrals: 55% were seen in the CUP clinic, 31% did not meet referral criteria and 14% were declined after MDM review of imaging confirmed benign appearances. The development of direct general practitioner referrals to CUP clinics nationally should be encouraged (as supported by the National Institute for Health and Care Excellence) – they are feasible and manageable within a tertiary CUP clinic, resulting in high rates of cancer diagnoses, with attendant early support from specialist nursing teams and oncological review. • Historically there has been inequality of access for patients with suspected MUO. • Direct GP referrals are feasible and manageable within a tertiary CUP clinic. • MUO patients benefit from early specialist nurse support and oncologist input. [ABSTRACT FROM AUTHOR]

The CO 2 -concentrating mechanism (CCM) in cyanobacteria supports high rates of photosynthesis by greatly increasing the concentration of CO 2 around the major carbon fixing enzyme, Rubisco. However, the CCM remains poorly understood, especially in regards to the enigmatic CO 2 -hydration enzymes which couple photosynthetically generated redox energy to the hydration of CO 2 to bicarbonate. This CO 2 -hydration reaction is catalysed by specialized forms of NDH-1 thylakoid membrane complexes that contain phylogenetically unique extrinsic proteins that appear to couple CO 2 hydration to NDH-1 proton pumping. The development of the first molecular genetic system to probe structure-function relationships of this important enzyme system is described. A CO 2 -hydration deficient strain was constructed as a recipient for DNA constructs containing different forms of the CO 2 -hydration system. This was tested by introducing a construct to an ectopic location that gives constitutive expression, rather than native inducible expression, of the ndhF3-ndhD3-cupA-cupS , ( cupA operon) encoding high affinity CO 2 -hydration complex, NDH-1 3 . Uptake assays show the restoration of high affinity for CO 2 uptake, but demonstrate that the CupA complex can drive only modest uptake fluxes, underlining the importance of its tandem operation with the CupB-containing complex NDH-1 4 , the complementary high flux, low affinity CO 2 hydration system. Experiments with the carbonic anhydrase inhibitor, ethoxyzolamide, indicate that the NDH-1 3 complex is strongly inhibited, yet the remaining NDH-1 4 activity in the wild-type is less so, suggesting structural differences between the low affinity and high affinity CO 2 –hydration systems. This new construct will be an important tool to study and better understand cyanobacterial CO 2 uptake systems. [ABSTRACT FROM AUTHOR]

Highlights • Cancer of unknown primary (CUP) is metastatic without a known primary. • Investigated the efficacy of S. typhimurium A1-R combined with CAR on the CUP PDOX model. • S. typhimurium A1-R combined with CAR inhibited the tumor growth significantly more compared to monotherapy. • S. typhimurium A1-R can increase the efficacy of a standard drug used for CUP in a PDOX model. Abstract Cancer of unknown primary (CUP) is metastatic disease without a known primary and therefore very difficult to identify effective therapy. Previously, we demonstrated partial efficacy of Salmonella typhimurium A1-R (S. typhimurium A1-R) alone and carboplatinum alone (CAR) on a CUP patient tumor in the patient-derived xenograft (PDOX) model. The aim of the present study was to investigate the efficacy of S. typhimurium A1-R combined with CAR on the CUP PDOX model. The CUP tumors were implanted orthotopically into the left supraclavicular fossa of nude mice to match the site from which they were resected from the patient. CUP PDOX models were divided randomly into the following 4 groups after the tumor volume reached 100 mm3: G1: untreated group; G2: CAR (30 mg/kg, i.p., weekly, 2 weeks); G3: S. typhimurium A1-R (5x107 CFU/body, i.v., weekly, 2 weeks).; G4: S. typhimurium A1-R combined with CAR (S. typhimurium A1-R; 5x107 CFU/body, i.v., weekly, 2 weeks; CAR, 30 mg/kg, i.p., weekly, 2 weeks). Each group comprised 7 mice. All mice were sacrificed on day 15. Tumor volume and body weight were measured twice a week. S. typhimurium A1-R and CAR moderately inhibited tumor growth compared to the untreated group on day 15 (P < 0.001 and P < 0.001, respectively). S. typhimurium A1-R combined with CAR inhibited the tumor growth significantly more compared to S. typhimurium A1-R monotherapy or CAR monotherapy on day 15 (P = 0.004 and P = 0.001, respectively). The present report demonstrates that S. typhimurium A1-R can increase the efficacy of a standard drug used for CUP in a PDOX model. [ABSTRACT FROM AUTHOR]

Background: Acetabular osteolysis is a major complication of total hip arthroplasty. It is caused in part by wear debris. It has been suggested that this debris can migrate through screw holes in the acetabular component. Solid-backed components have been used to prevent this migration and reduce osteolysis. Newer materials, however, have reduced wear debris. This study aimed to evaluate whether using solid-backed instead of cluster-hole components actually reduces osteolysis. This could open up the possibility of screws being used for greater stability where required.Methods: This prospective trial randomized 100 patients undergoing cementless total hip arthroplasty to receive either cluster-hole or solid-backed acetabular components. A cementless cup and highly cross-linked polyethylene was used in all patients. Computed tomography, performed at 5 and 10 years after surgery, was assessed by a blinded radiologist for the presence of osteolysis.Results: Of the 100 patients, 14 required screws for stability, and so were moved into a third "screw" group for per-protocol analysis. At 10 years after surgery, osteolytic lesions were discovered in 18.2% of patients. There was no difference in incidence or volume of osteolysis between patients with cluster-hole acetabular components and those with solid-backed components.Conclusion: This study reveals a low number of patients with osteolytic lesions 10 years after total hip arthroplasty performed with a modern cup design and highly cross-linked polyethylene liner. There was no clear benefit to using solid-backed acetabular components. Cluster-hole components, however, offer the option of screw augmentation when required. [ABSTRACT FROM AUTHOR]

Objective: It is unclear whether hydroxyapatite (HA) coating of uncemented cups used in primary total hip arthroplasty (THA) improves bone ingrowth and reduces the risk of aseptic loosening. We therefore investigated survival of different uncemented cups that were available with or without HA coating.Method: We investigated three different cup types used with or without HA coating registered in the Nordic Arthroplasty Register Association (NARA) database that were inserted due to osteoarthritis (n = 28,605). Cumulative survival rates and adjusted hazard ratios (HRs) for the risk of revision were calculated.Results: Unadjusted 13-year survival for cup revision due to aseptic loosening was 97.9% (CI: 96.5-99.4) for uncoated and 97.8% (CI: 96.3-99.4) for HA-coated cups. Adjusted HRs were 0.66 (CI 0.42-1.04) for the presence of HA coating during the first 10 years and 0.87 (CI 0.14-5.38) from year 10-13, compared with uncoated cups. When considering the endpoint cup revision for any reason, unadjusted 13-year survival was similar for uncoated (92.5% [CI: 90.1-94.9]) and HA-coated (94.7% [CI: 93.2-96.3]) cups. The risk of revision of any component due to infection was higher in THA with HA-coated cups than in THA with uncoated cups (adjusted HR 1.4 [CI 1.1-1.9]).Conclusions: HA-coated cups have a similar risk of aseptic loosening as uncoated cups, thus the use of HA coating seems to not confer any added value in terms of implant stability. The risk of infection seemed higher in THA with use of HA-coated cups, an observation that must be investigated further. [ABSTRACT FROM AUTHOR]

To use liquid lubricants for cold forging and extrusion operations causing severe deformation without phosphate-conversion coatings, automatic re-lubricating using pulsating motion of a servo press was enhanced. In backward extrusion of a cup with internal splines, negative pressure for supplying the lubricant to the inner surface of the cup was generated under the punch bottom by the pulsating motion. Since the punch grooves are not fully filled with metal during extrusion, the gaps are formed in the grooves, and thus the liquid lubricant is supplied through these gaps up to the punch bottom without completely taking the punch from the cup. The effects of the holding time after each punch upstroke, the viscosity of the lubricant and the number of cycles on the seizure prevention and the surface quality of the formed cup were examined from experiments of extrusion with pulsating motion. To shorten the forming time, lubricant pockets on a punch bottom and billet top and increase in punch upstroke were employed. [ABSTRACT FROM AUTHOR]

Patients with neck squamous cell carcinomas of unknown primary tumour (NSCCUP) present with lymph node metastasis without evidence for a primary tumour. Most patients undergo an aggressive multimodal treatment, which induces severe, potentially unnecessary toxicity. Primary tumours of NSCCUP can be hidden in the oropharynx. Human papillomavirus (HPV) is causally involved in a subgroup of oropharyngeal squamous cell carcinomas (OPSCC) associated with early lymph node metastasis and good prognosis. Detection of markers for HPV transformation in NSCCUP could allow focussing on the oropharynx in primary tumour search and could be of value for choice and extent of treatment. In a retrospective multicentre study (Germany, Italy and Spain), we analysed metastatic lymph nodes from 180 NSCCUP patients for the presence of HPV DNA, HPV E6*I mRNA and cellular p16 INK4a overexpression, a surrogate marker for HPV-induced transformation. HPV status, defined as positivity for viral mRNA with at least one additional marker, was correlated with clinical parameters and survival outcome. A substantial proportion (16%) of NSCCUP were HPV-driven, mainly by HPV16 (89%). HPV prevalence increased with year of diagnosis from 9% during 1998–2004 to 23% during 2005–2014 (p = 0.007). HPV-driven NSCCUP had significantly better overall and progression-free survival rates (p ≤ 0.008). Based on this survival benefit, it is contended that HPV RNA status should be included in NSCCUP diagnosis and in therapeutic decision-making. Deintensification of radiation in patients with HPV-driven NSCCUP, while concurrently concentrating on the oropharynx appears to be a promising therapeutic strategy, the efficacy of which should be assessed in prospective trials. To our knowledge, this is the largest study on HPV in NSCCUP. [ABSTRACT FROM AUTHOR]

Although the incidence of Cancer of Unknown Primary (CUP) is estimated to be 1–2 % of all cancers worldwide, no international standards for diagnostic workup are yet established. Such an international guideline would facilitate international comparison, provide adequate incidence and survival rates, and ultimately improve care of patients with CUP. Participants for a four round modified Delphi study were selected via a CUP literature search in PubMed and an international network of cancer researchers. A total of 90 CUP experts were invited, and 34 experts from 15 countries over four continents completed all Delphi survey rounds. The Delphi procedure resulted in a multi-layer CUP classification for the diagnostic workup. Initial diagnostic workup should at least consist of history and physical examination, full blood count, analysis of serum markers, a biopsy of the most accessible lesion, a CT scan of chest/abdomen/pelvis, and immunohistochemical testing. Additionally, the expert panel agreed on the need of an ideal diagnostic lead time for CUP patients. There was no full consensus on the place in diagnostic workup of symptom-guided MRI or ultrasound, a PET/CT scan, targeted gene panels, immunohistochemical markers, and whole genome sequencing. Consensus was reached on the contents of the first diagnostic layer of a multi-layer CUP classification. This is a first step towards full consensus on CUP diagnostics, that should also include supplementary and advanced diagnostics. [Display omitted] • Cancer of Unknown Primary (CUP) has an incidence of 1–2 % of all cancers worldwide. • No global standards for the diagnostic workup for CUP are yet established. • A Delphi study with experts from 15 countries was conducted • Consensus was reached on a multi-layer CUP classification for diagnostic workup • This study is a first step towards full consensus on CUP diagnostics [ABSTRACT FROM AUTHOR]

We established a mathematical method to precisely calculate the radiographic anteversion (RA) and radiographic inclination (RI) angles of the acetabular cup based on anterior–posterior (AP) pelvic radiographs after total hip arthroplasty. Using Mathematica software, a mathematical model for an oblique cone was established to simulate how AP pelvic radiographs are obtained and to address the relationship between the two-dimensional and three-dimensional geometry of the opening circle of the cup. In this model, the vertex was the X-ray beam source, and the generatrix was the ellipse in radiographs projected from the opening circle of the acetabular cup. Using this model, we established a series of mathematical formulas to reveal the differences between the true RA and RI cup angles and the measurements results achieved using traditional methods and AP pelvic radiographs and to precisely calculate the RA and RI cup angles based on post-operative AP pelvic radiographs. Statistical analysis indicated that traditional methods should be used with caution if traditional measurements methods are used to calculate the RA and RI cup angles with AP pelvic radiograph. The entire calculation process could be performed by an orthopedic surgeon with mathematical knowledge of basic matrix and vector equations. [ABSTRACT FROM AUTHOR]

Background: Hydroxyapatite (HA) has been applied to joint prostheses as a bioactive coating to prolong their durability. However, HA benefits for cup survival in total hip arthroplasty (THA) remain controversial. In this study, we compared the survival of cups with and without HA coating during a minimum follow-up of 18 years.Methods: In total, 183 THA cases in 163 patients were analyzed, including 73 cups with HA coating (HA(+) group) and 110 without HA coating (HA(-) group); otherwise, the cups had identical titanium-sprayed rough surfaces and were fixed with screws. In both groups, the same conventional polyethylene liners were applied. Zirconia and alumina ceramic heads were used in the HA(+) and HA(-) groups, respectively. We retrospectively analyzed cup survival based on cup revision for any reason or aseptic loosening as end points.Results: In total, 7 and 8 revisions were performed in the HA(-) and HA(+) groups with survival rates of 86.3% and 90.1%, respectively. Among them, 3 cups in the HA(-) group and 1 cup in the HA(+) group were revised for aseptic loosening in 20 years (survival rates 94.1% and 98.7%, respectively). No significant difference was detected in cup survival rates between the groups based on both end points. There were no stem revisions during the observation period.Conclusion: The results suggested that HA coating did not have either beneficial or adverse effects on the long-term cup survival in primary cementless THA. [ABSTRACT FROM AUTHOR]

Glaucoma is an eye disease that results in irreversible loss of vision. The manual examination of optic disk (OD) is a standard procedure used for detecting glaucoma. This paper presents a glaucoma expert system based on the segmentations of OD and optic cup attained from color fundus images. A novel implicit region based active contour model is proposed for OD segmentation which incorporates the image information at the point of interest from multiple image channels to have robustness against the variations found in and around the OD region. A novel optic cup segmentation method is also proposed based on the structural and gray level properties of cup. Based on the precise information about the contours of OD and cup different parameters are calculated for glaucoma assessment. The proposed system is evaluated on 59 retinal images comprising 17 normal and 42 glaucomatous images against the groundtruths given by an experienced ophthalmologist. The proposed OD segmentation method achieved an average F -score of 0.975, average boundary distance of 10.112 pixel and average correlation coefficient of 0.916. The cup segmentation method attained an average F -score of 0.89, average boundary distance of 18.927 pixel and average correlation coefficient of 0.835. The mean error and standard deviation of the error σ for all the parameters are much smaller in glaucomatous images compared to normal images. This indicates high sensitivity of the proposed method in glaucoma assessment. [ABSTRACT FROM AUTHOR]

Screws, pegs and hydroxyapatite-coating are used to enhance the primary stability of uncemented cups. We present a 14-year follow-up of 48 hips randomized to four groups: press-fit only, press-fit plus screws, press-fit plus pegs and hydroxyapatite-coated cups. Radiostereometric migration measurements showed equally good stability regardless cup augmentation. The mean wear rate was high, 0.21 mm/year, with no differences between the groups. Seven hips had radiographical osteolysis but only in hips with augmented cups. Cups without screw-holes compared with cups with screw-holes resulted in better clinical outcome at the 14-year follow-up. Thus, augmentation of uncemented cups with screws, pegs, or hydroxyapatite did not appear to improve the long-term stability compared with press-fit only. [ABSTRACT FROM AUTHOR]

Background: Cancer of unknown primary (CUP) is a common cancer yet little is known about the reliability of incidence data. Methods: We audited 574 CUP (C80.9) diagnoses (median age 81 years) registered by the New South Wales (NSW) Central Cancer Registry (2004-2007) in a cohort of Australian Government Department of Veterans' Affairs clients. The registry did not clarify diagnoses with notifiers during this period due to interpretation of privacy legislation. For the audit, current registry practice was applied by seeking additional information from CUP notifiers and reclassifying diagnoses as necessary. In addition, clinicopathological characteristics were extracted from notifications. Fisher's exact test and Student's t-test were used to compare the demographic and clinicopathological characteristics of the CUP subgroups. Age/sex-standardised CUP incidence rates and 95% confidence intervals were calculated, standardised to the 2001 Australian population. Results: 172 (30.0%) cases were reclassified to a known primary site, mostly cutaneous, and nine (1.6%) were found to be non-malignant diagnoses. After the audit the age/sex-standardised CUP incidence rates decreased from 26.0 (95% CI 21.2-30.8) to 15.9 (95% CI 12.5-19.3) per 100,000 person-years. Of the 393 remaining CUP cases, 202 (51%) were registered on the basis of a clinical diagnosis (46 by death certificate only) and 191 (49%) by pathological diagnosis (79 by cytology alone). Compared to cases with a pathological diagnosis, cases with a clinical diagnosis were older (85.6 vs. 82.0 years, p<0.001), and the reported number and location of metastases differed (p<0.001); metastatic sites were more likely to be unspecified for clinical diagnoses (36.1% vs. 4.2%). Conclusions: Cancer registry processes can markedly influence CUP incidence. Future population-based CUP research should take this into account, and consider stratification by basis of diagnosis due to differences in patient and tumour characteristics. [ABSTRACT FROM AUTHOR]

Use of an oversized “jumbo cup” is an effective technique for revision of most failed acetabular components. The jumbo cup is prepared with hemispherical reamers and provides a large porous ingrowth surface area in direct contact with the host bone. However, since the oversized cup is larger than the native acetabulum, the hip center can be raised, which may require use of a longer femoral head to maintain soft tissue tension and leg length. The anterior edge of the cup may also protrude through the anterior wall, which could be a cause of iliopsoas tendonitis resulting in groin pain. [ABSTRACT FROM AUTHOR]

Abstract: Colloidal Unimolecular Polymer, CUP, particles were synthesized and characterized as a potential new and useful spheroidal polymer conformation for a variety of applications. Also known as single chain nanoparticles, these nanomaterials are gaining in popularity. The route to CUP particle formation is an innovative approach utilizing a small number of hydrophilic groups along a hydrophobic polymer backbone which transitions from a random coil conformation in organic solvent to a hard sphere in water through a slow gradient with subsequent solvent removal. The CUP particles have diameters which are proportional to their molecular weights and range typically from 3 nm to over 9 nm. These CUP particles were stable in water and free of solvent or surfactants. The sodium or potassium salts of CUP particles are spheroidal and are able to be dried then re-dissolved in water with no aggregation, unlike the original polymer. The diameters of the CUP particles correlate with the absolute number average molecular weight (M n) and distributions from the GPC. Molecular weights from 28K to 122K are reported here and are based on an acrylic copolymer having a molar ratio of 9:1 MMA:MAA. [Copyright &y& Elsevier]

Abstract: Background: Cancer of unknown primary (CUP) is a fatal cancer for which incidence trends have changed but detailed survival trends remain unexplored. These could point out successful diagnostic and therapeutic approaches. We investigate survival trends in CUP according to histology, locations of metastases and site-specific causes of death. Patients and methods: A total of 20,523 CUP patients with nodal and extranodal metastases were identified from the Swedish Cancer Registry. Hazard ratios (HRs) were estimated, comparing three different time periods (1987–1993, 1994–2000 and 2001–2008) with respect to histological subtype, CUP location and the cause of death. Results: Survival for patients with CUP increased over the study period (HR=0.91 [95% confidence interval (CI): 0.78–0.84], p <0.001 for trend). Adenocarcinoma was the only histology associated with increased survival (0.78 [0.74–0.82], p <0.001 for trend). Survival was improved most clearly for CUP of the pelvis (0.55 [0.36–0.83]), peritoneum (0.58 [0.53–0.65]) and nervous system (0.46 [0.29–0.72]). Survival improved substantially in patients with ovarian (0.57 [0.46–0.70]), peritoneal (0.39 [0.24–0.65]) and biliary system cancers (0.67 [0.52–0.87]). Kaplan–Meier curves showed significant survival gains for all CUP and adenocarcinoma patients (p <0.001). Conclusions: Over time, survival for patients with CUP increased for adenocarcinoma and for CUP of the pelvis, peritoneum and nervous system. Survival trends in CUP may be related to (1) similar trends in other common metastatic tumours, particularly pancreatic and hepatobiliary cancers, which are common ‘hidden’ primaries for CUP, (2) earlier detection and (3) advances in the management of metastatic cancers. The improvement in survival at specific locations suggests true therapeutic gains. [Copyright &y& Elsevier]

abstract: Total hip arthroplasty (THA) has been associated with excellent functional outcomes and survival rates (Cushner et al., 2010 [1]). Selection of acetabular shell and technique of implantation is an important factor as is the stem for a successful THA. Both cemented all-polyethylene cups and cementless sockets have benefited from improvements in surgical techniques, cup designs, and bearing surfaces. This paper is a review of the current literature that focuses on the options for the acetabular components of a modern total hip replacement, aiming to answer common questions and controversies on this topic. [Copyright &y& Elsevier]

Abstract: Background: Radiostereometry is a well documented method to measure the polyethylene wear after total hip replacements. Wear is measured according to the point motion of the head center in relation to the polyethylene as the reference segment. Increasing head sizes and new cup materials may diminish visibility of markers deteriorating the segment and leading to study drop outs. Alternatively markers in the periacetabular bone may be easier to detect rendering this segment more stable. Our aim was to compare wear measurements against the cup, the acetabuluar bone and a calculated wear estimation including cup migration. Methods: A prospective randomized controlled trial comparing reverse hybrid with cemented total hip replacement was conducted. 31 patients had tantalum markers in the polyethylene and in the periacetabular bone making it possible to measure wear using both as reference segments. We used a uniplanar radiostereometric technique. Findings: Wear in the y-axis was overestimated by 53% when markers in the periacetabular bone were used (P <0.001). Proximal wear was 0.34mm (95% CI of mean: 0.29–0.38) when using the polyethylene as the reference and 0.52mm (95% CI of mean: 0.38–0.65) using the acetabular bone. Migration of the cup seemed to influence the wear calculations, overestimating wear when markers in the periacetabular bone were used as the reference segment. Interpretation: Wear measured with periacatebular bone markers is influenced by cup migration, overestimating wear measurements. We therefore recommend not using the acetabular bone as the reference segment. [Copyright &y& Elsevier]

Abstract: This review will summarize the levels of selected current use pesticides (CUPs) that have been identified and reported in Arctic media (i.e. air, water, sediment, and biota) since the year 2000. Almost all of the 10 CUPs (chlorothalonil, chlorpyrifos, dacthal, diazinon, dicofol, lindane, methoxychlor, pentachloronitrobenzene (PCNB), pentachlorophenol, and trifluralin) examined in the review currently are, or have been, high production volume chemicals i.e. >1M lbs/y in USA or >1000t/y globally. Characteristic travel distances for the 10 chemicals range from 55km (methoxychlor) to 12,100km (PCNB). Surveys and long-term monitoring studies have demonstrated the presence of 9 of the 10 CUPs included in this review in the Arctic environment. Only dicofol has not been reported. The presence of these chemicals has mainly been reported in high volume air samples and in snow from Arctic ice caps and lake catchments. There are many other CUPs registered for use which have not been determined in Arctic environments. The discovery of the CUPs currently measured in the Arctic has been mainly serendipitous, a result of analyzing some samples using the same suite of analytes as used for studies in mid-latitude locations. A more systematic approach is needed to assess whether other CUPs might be accumulating in the arctic and ultimately to assess whether their presence has any significance biologically or results in risks for human consumers. [Copyright &y& Elsevier]

Cancer of unknown primary (CUP) is the finding of a metastatic cancerous lesion without an established primary source localized within the body. CUP can be of any cancer cell type, however, adenocarcinoma is most often identified by histology. Up to 5% of all malignant diagnoses are classified as CUP. PET is an imaging modality often utilized to distinguish a primary source in the setting of CUP, yet often a primary is never identified. CUP can be further stratified using specific qualifiers as favorable and unfavorable, indicating the potential therapeutic response to treatment regimens. Treatment approach to CUP relies heavily on the cell type identified by histology, the location of the lesion, and the amount of spread within the body. In the typical setting and presentation, per current literature, CUP arises in the 7th decade of life in patients with multiple comorbidities, and often has a poor prognostic value. This case report identifies an atypical presentation of CUP, a 38-year-old Caucasian female with an axillary mobile mass, and no associated systemic symptoms. Biopsy of the node and immunohistochemical staining showed histology consistent with metastatic carcinoma. Mammography, MRI, and PET scan found no evidence of tumor primary or distant metastasis. Further staining confirmed metastatic carcinoma consistent with breast origin, without an established breast primary. As in this case, CUP may present in an atypical manner, warranting a thorough investigation aiming to identify the tumor primary to aid in identification of a proper treatment regimen and approach. [ABSTRACT FROM AUTHOR]

Abstract: Press-fit acetabular cups without screw holes can limit migration of particulate wear debris and reduce risk of acetabular osteolysis and device loosening. The Tri-Spike cup (Biomet, Inc, Warsaw, Ind) includes a titanium alloy plasma spray porous surface and does not require screw fixation. We retrospectively examined the incidence of cup loosening and acetabular osteolysis after implantation of 45 cups (44 patients) with mean follow-up of 7.3 years (range, 4-9 years). Only one patient (one cup) had evidence of less than 1 mm of retroacetabular radiolucency at 3 years (nonprogressive), which was found to remain firmly fixed during revision of the aseptically loosened femoral component. No cups were removed or revised at latest follow-up. Projected Kaplan-Meier survivorship at 9 years was 100% for cup loosening/revision and 97.8% for radiolucency. [Copyright &y& Elsevier]

Abstract: Objective: The L1 adhesion molecule (L1-CAM,CD171) is over expressed in ovarian and endometrial carcinomas and other tumors derived from the Mullerian tract. Here we evaluated whether L1-CAM could serve as a novel tumor marker for the diagnosis of metastatic abdominal-pelvic cancers of uncertain origin in women. Patients and methods: During a 6-year period we investigated 28 patients with metastatic abdominal or pelvic cancer with uncertain primary-origin. In all these cases a thorough clinical, surgical, pathologic and immunohistochemistry evaluation was performed and correlated to the L1-CAM expression as determined by immunohistochemical staining. Results: In 20 patients where the differential diagnosis was primary ovarian or endometrial cancer and primary or recurrent colon cancer, L1 immunohistochemistry staining allowed or supported the correct diagnosis. In four cases L1 staining allowed the correct diagnosis between breast and ovarian cancer. In two cases vaginal metastases of unknown origin were positive to L1 immunohistochemistry staining implying their mullerian origin and one case each of inguinal lymph node metastases and abdominal wall cancer that were positive for L1-CAM, allowed the correct diagnosis of primary ovarian cancer. In a whole, L1-CAM was of crucial role of delinating the final diagnosis in 17 of the 28 cases described. Conclusions: L1-CAM, a new tumor marker, was found to be specific for metastatic cancer originating from mullerian origin. Its incorporation into the conventional immunohistochemistry analysis in cases of cancer of unknown primary in women, allows a correct diagnosis and subsequent treatment in the majority of cases with abdominal-pelvic carcinomatosis. [Copyright &y& Elsevier]

Abstract: This paper deals with the hydromechanical deep drawing of metal cups with complex stepped geometries. Two materials, a low-carbon steel (DC04) and stainless steel (DIN 1.4301), have been researched. A die set with a maximum possible deep drawing ratio β 0,max =3.0 for a punch diameter ∅ 100mm has been designed and constructed. The die set is designed to withstand fluid counter pressures up to 200MPa. Pressure control is achieved using a micro-metering pressure control valve. The process is initially simulated using the FEM solver LS-DYNA. Experiments have been conducted with two punch geometries. The punch geometries consist of cylindrical and conical wall segments. Complex positive and negative features are manufactured in the punch bottom face. The ability of transferring complex features from the punch onto the blank surface with high deep drawing ratios is investigated. Extended limiting deep drawing ratios of β 0,max =3.0 for DC04 and β 0,max =2.875 for DIN 1.4301 have been achieved. [Copyright &y& Elsevier]

Abstract: Background: Dislocation following total hip arthroplasty is a major complication and malorientation of the acetabular cup is one of the primary factors affecting dislocation. Different conventions used to describe the cup orientation produce significant variations in the recommendations for correct positioning, which in turn make it difficult for clinicians to properly interpret and apply previously reported studies. Methods: We examined nine articles presenting recommendations for the range of target orientations of the acetabular cup to minimize the risk of dislocation (referred to as the ‘safe zone’). Those studies included five ways to define the cup orientation and two methods to define the reference frame. We converted those recommendations to a single representation based on the radiographic angles expressed in the pelvic frame reference. Findings: After conversion, the mean recommended anteversion angle was shifted downward by 5° (P <0.01). Also, the target orientation recommendations became more consistent, especially for the anteversion angles where the standard errors of the upper and lower limits were reduced by 61% (P =0.02) and 23% (P =0.04), respectively. Interpretation: The choice of reference frame and the definition for acetabular cup orientation angles can have a significant effect on the target orientation for the acetabular cup. Recommendations for the target orientation should always explicitly state which reference frame and angle definition is being used. The averaged recommendation of the studies assessed here is 41° inclination and 16° anteversion in radiographic angles or 39° inclination and 21° anteversion in operative angles, both expressed in the pelvic reference frame. [Copyright &y& Elsevier]

Abstract: Objectives: The variable frontal geometry of the carpus has been known for many years, however there is no unanimity as to whether to describe the dynamic model of the carpus as comprising row or columnar functional units. The place of the scaphoid is also discussed. This study attempts to understand the organization and the composition of the functional units of the carpus. Methods: We took radiographs of 40 normal right wrists in radial and ulnar deviation and measured the displacement in the coronal plane of each carpal bone except the pisiform. We measured the angular movements of each carpal bone compared to a vertical axis passing through the geometric centre of the carpus. This axis is parallel to the radial axis which is defined as the line joining the midpoints of the radius at 2 and 5cm proximal to the radial articular surface. We studied the movement of each row and each column. Results: Recorded angular movements were the followings: scaphoid 26°, lunate 28°, triquetrum 29°, trapezium 44°, trapezoid 50°, capitate 50°, hamate 56°. Average angular movement within the first row is 27°, within the second row is 50°. Average angular movement within the radial column is 38°, middle column is 39°, ulnar column is 42°. Conclusions: The amplitude of movement are similar for the bones of each row, and different for the bones of each column. The bones of each row tend to move together and can alone account for all movements of the wrist. The movements measured between each column are torsional intrarow movements, allowing congruence between the two rows and the glenoid surface of the radius. The scaphoid movements are superposable with those of lunate and triquetrum. Scaphoid kinematics joins the first row. Radio-ulnar deviation of the wrist is shared equally between the radiocarpal and midcarpal joints. This sharing of wrist movement between the two rows constitutes for us a double cup carpal model. [Copyright &y& Elsevier]

Abstract: STAM (signal-transducing adaptor molecule) is a protein highly conserved from yeast to mammals. In Drosophila melanogaster the basic molecular architecture of the protein is comprised of a N-terminal VHS domain, an ubiquitin-interacting motif and a central Src homology-3 domain. In this paper we examine the expression pattern of the stam gene and the localisation of the STAM protein during D. melanogaster oogenesis. Its transcript is present throughout egg chamber development in all germ-line cells, including the oocyte. dSTAM is firstly detected in germarial region 2, where the protein is present in the newly formed germ-line cysts and is mainly accumulated into the oocyte. As oogenesis proceeds, dSTAM is enriched in the perinuclear region of the nurse cells and is also found in the somatic polar follicular cells. In the oocyte, the protein is more abundant posteriorly and becomes restricted to the posterior pole just before disappearing at stage 10b. We show that dSTAM localisation is unaffected in the oocyte of grk mutant egg chambers, indicating that it is not dependent on the polarity of the microtubule network. In contrast, dSTAM distribution is remarkably altered in cup mutant oocytes where the protein accumulates in a round central spot and never reaches the posterior pole. [Copyright &y& Elsevier]

Abstract: A deformable-model based approach is presented in this paper for robust detection of optic disk and cup boundaries. Earlier work on disk boundary detection up to now could not effectively solve the problem of vessel occlusion. The method proposed here improves and extends the original snake, which is essentially a deforming-only technique, in two aspects: knowledge-based clustering and smoothing update. The contour deforms to the location with minimum energy, and then self-clusters into two groups, i.e., edge-point group and uncertain-point group, which are finally updated by the combination of both local and global information. The modifications enable the proposed algorithm to become more accurate and robust to blood vessel occlusions, noises, ill-defined edges and fuzzy contour shapes. The comparative results on the 100 testing images show that the proposed method achieves better success rate (94%) when compared to those obtained by GVF-snake (12%) and modified ASM (82%). The proposed method is extended to detect the cup boundary and then extract the disk parameters for clinical application, which is a relatively new task in fundus image processing. The resulted cup-to-disk (C/D) ratio shows good consistency and compatibility when compared with the results from Heidelberg Retina Tomograph (HRT) under clinical validation. [Copyright &y& Elsevier]

Abstract: In metazoans, translational regulation of a set of maternal mRNAs directs oocyte maturation and early embryogenesis. These transcripts are often kept dormant until their products are spatially and temporally required in development. The interaction between general translation factors (i.e. eIF4E) and their specific interactors influences translation initiation. A search of the protein database for a mouse homologue of the Drosophila Cup protein, a translational repressor during female germ-line development, identified the product of the Clast4 gene. In this report, we show that Clast4 mRNA and protein are highly expressed within the cytoplasm of growing oocytes. The Clast4 protein is stable during this developmental window and post-translationally modified by phosphorylation upon oocyte meiotic maturation. Additionally, we show that Clast4 and eIF4E directly interact by means of a canonical and functional eIF4E-binding motif. Our results suggest that Clast4, similar to Drosophila Cup, may act at the translational level during murine female germ-line development. [Copyright &y& Elsevier]

Abstract: A novel, highly efficient, plastic scintillator detector has been constructed. The primary application of the detector is to act as a veto device in heavy-ion-induced fusion-evaporation reactions, in which the structure of proton-rich nuclides is investigated by -ray spectroscopy methods. The detector rejects events in which light charged particles, like protons and particles, are emitted in the evaporation process, facilitating selection of reaction channels associated with emission of only neutrons. The detector was used in a EUROBALL experiment, with achieved efficiencies of 80% and 63% for protons and particles, respectively. The design of the detector, its performance and limitations are discussed. [Copyright &y& Elsevier]

A recently introduced redrawing process enables the redrawing of cups at a redraw ratio of 3. In this process, a cup drawn by the conventional deep drawing process is directly redrawn by repeatedly squeezing an annular urethane pad held inside (at the bottom of) the cup. The cup itself is held inside a cylindrical container. The redrawing action is similar to that of Maslennikov’s technique for drawing cups from flat sheet metal; the difference being that the present process makes use of a cup instead of the flat blank. Redrawing experiments conducted with annealed aluminium cups indicate that with sufficient friction at the urethane–cup interface and proper lubrication of the die, very deep cups can be produced by this process. Results from these experiments are reported in this paper. [Copyright &y& Elsevier]

Objective: To determine the impact of diagnostic TORS lingual tonsillectomy (DTLT) on objective swallowing measures for carcinoma of unknown primary (CUP).Methods: Between 10/2016-1/2020, 27 patients with p16+ squamous cell carcinoma (SCC) level 2a nodal disease underwent DTLT and ipsilateral neck dissection for CUP. No patient had a history of cutaneous SCC. Patients participated in Modified Barium Swallow (MBS) three weeks post-TORS, which were then compared to those from a contemporaneous cohort of 40 patients with clinically-identified p16+ base of tongue (BOT) primary tumors. DIGEST scores were retrospectively calculated. Univariate and multivariate analysis performed, stratified by BOT glossectomy (n = 40) versus lingual tonsillectomy for CUP (n = 27). Radiation to the resected primary or potential primary sources was omitted if margins were ≥3 mm or if no primary identified.Results: Twenty-seven consecutive patients with clinical stage cT0N1 HPV-associated OPSCC had a BOT primary pathologically identified in 18/27 (67%). Univariate analysis of functional swallow assessment on MBSImP correlated with improved post-TORS DIGEST scores for CUP. On multivariate analysis (MVA) DIGEST safety scores were improved for CUP than cT1 BOT glossectomy [Odds Ratio (OR) 0.28, p = 0.038]. MVA on matched pT1 CUP (n = 27) vs. pT1 BOT (n = 19), OR of moderate/severe dysphagia for CUP was 0.54 [0.12-2.38, p = 0.417] for DIGEST safety scores and 0.27 [0.06-1.18, p = 0.082] for DIGEST efficiency scores. Moderate/severe dysphagia as determined by DIGEST overall scores for CUP compared to cT1 and pT1 yielded an OR of 0.39 (p = 0.081) and 0.42 (p = 0.195), respectively. Twenty-six total patients received adjuvant RT, and 18 (11 with ≥3 mm margins, 9 with negative specimens) were spared intentional RT to the oropharynx. Median follow-up was 22.6 months with 100% PFS.Conclusions: Patients undergoing DTLT for CUP demonstrated acute swallow defecits in the post-operative setting. A comparison of long-term functional results between DTLT and elective irradiation of the primary site should be studied.Level Of Evidence: Level III. [ABSTRACT FROM AUTHOR]

In animal embryos, the maternal-to-zygotic transition (MZT) hands developmental control from maternal to zygotic gene products. We show that the maternal proteome represents more than half of the protein-coding capacity of Drosophila melanogaster 's genome, and that 2% of this proteome is rapidly degraded during the MZT. Cleared proteins include the post-transcriptional repressors Cup, Trailer hitch (TRAL), Maternal expression at 31B (ME31B), and Smaug (SMG). Although the ubiquitin-proteasome system is necessary for clearance of these repressors, distinct E3 ligase complexes target them: the C-terminal to Lis1 Homology (CTLH) complex targets Cup, TRAL, and ME31B for degradation early in the MZT and the Skp/Cullin/F-box-containing (SCF) complex targets SMG at the end of the MZT. Deleting the C-terminal 233 amino acids of SMG abrogates F-box protein interaction and confers immunity to degradation. Persistent SMG downregulates zygotic re-expression of mRNAs whose maternal contribution is degraded by SMG. Thus, clearance of SMG permits an orderly MZT. • Early Drosophila embryos degrade 2% of their maternally encoded proteome • The Cup-TRAL-ME31B-Smaug post-transcriptional repressive complex is cleared • Distinct E3 ubiquitin ligases target Cup-TRAL-ME31B (CTLH E3) versus Smaug (SCF E3) • Failure to degrade Smaug abrogates an orderly maternal-to-zygotic transition Cao et al. show that 2% of the proteome is degraded in early Drosophila embryos, including a repressive ribonucleoprotein complex. Two E3 ubiquitin ligases separately act on distinct components of this complex to phase their clearance. Failure to degrade a key component, the Smaug RNA-binding protein, disrupts an orderly maternal-to-zygotic transition. [ABSTRACT FROM AUTHOR]

• CUP accounts for approximately 1–3 % of all malignant neoplasms. • CUP patients are categorized according to their clinicopathological characteristics. • Empiric CUP regimens may be suboptimal in some patients within the unfavorable subsets. • CUP with colorectal, lung and renal - profiles seem to arise as distinct CUP entities. Cancers of Unknown Primary Site (CUP) account for approximately 1–3 % of all malignant neoplasms. It represents a heterogeneous group of malignancies without a detectable primary and is characterized by aggressive clinical behavior. Patients with CUP are presumably categorized into prognostic subsets according to their clinical and pathological characteristics. The majority of these patients are chemoresistant and treated with empiric chemotherapy regimens which yield limited survival. Recent diagnostic advances have led to the identification of a higher percentage of culprit primaries among which colorectal, lung and renal tumors. The empiric CUP regimens may be suboptimal in these patients which explain in part their poor prognosis. In the absence of prospective randomized studies to prove the benefit of site-specific therapy in these subsets, we reviewed the literature to assess whether CUP with colorectal, lung and renal - profiles should be treated similarly to the correspondent primary tumors. [ABSTRACT FROM AUTHOR]