Magnetic Breakdown and Topology in the Kagome Superconductor CsV_{3}Sb_{5} under High Magnetic Field.

The recently discovered layered kagome metals of composition AV_{3}Sb_{5} (A=K, Rb, Cs) exhibit a complex interplay among superconductivity, charge density wave order, topologically nontrivial electronic band structure and geometrical frustration. Here, we probe the electronic band structure underlying these exotic correlated electronic states in CsV_{3}Sb_{5} with quantum oscillation measurements in pulsed fields up to 86 T. The high-field data reveal a sequence of magnetic breakdown orbits that allows the construction of a model for the folded Fermi surface of CsV_{3}Sb_{5}. The dominant features are large triangular Fermi surface sheets that cover almost half the folded Brillouin zone. These sheets have not yet been detected in angle resolved photoemission spectroscopy and display pronounced nesting. The Berry phases of the electron orbits have been deduced from Landau level fan diagrams near the quantum limit without the need for extrapolations, thereby unambiguously establishing the nontrivial topological character of several electron bands in this kagome lattice superconductor.

Observing the Suppression of Superconductivity in RbEuFe_{4}As_{4} by Correlated Magnetic Fluctuations.

In this Letter, we describe quantitative magnetic imaging of superconducting vortices in RbEuFe_{4}As_{4} in order to investigate the unique interplay between the magnetic and superconducting sublattices. Our scanning Hall microscopy data reveal a pronounced suppression of the superfluid density near the magnetic ordering temperature in good qualitative agreement with a recently developed model describing the suppression of superconductivity by correlated magnetic fluctuations. These results indicate a pronounced exchange interaction between the superconducting and magnetic subsystems in RbEuFe_{4}As_{4}, with important implications for future investigations of physical phenomena arising from the interplay between them.

Canadian cohort expanded-access program of nivolumab plus ipilimumab in advanced melanoma.

Background: The combination of nivolumab and ipilimumab is approved in several jurisdictions (United States, European Union, Canada) for the first-line treatment of patients with advanced melanoma. CheckMate 218 is a North American expanded-access program (eap) of nivolumab plus ipilimumab in patients with advanced melanoma. Here, we report safety and survival outcomes for the Canadian cohort in the eap. Methods: Eligible patients were those 18 years of age or older with unresectable stage iii or iv melanoma, an Eastern Cooperative Oncology Group performance status of 0 or 1, and no prior anti-PD-1 or anti-ctla-4 therapy. Patients were treated with nivolumab 1 mg/kg and ipilimumab 3 mg/kg every 3 weeks for 4 cycles (induction phase); they then continued with nivolumab 3 mg/kg every 2 weeks (maintenance phase) until progression, unacceptable toxicity, or a maximum of 48 weeks, whichever occurred first. Safety and overall survival (os) data were collected. Results: Of 194 patients enrolled, 174 were treated, and 51% continued on nivolumab maintenance. Median follow-up was 12.9 months. All-grade and grades 3-4 treatment-related adverse events were reported in 98% and 60% of patients respectively and led to treatment discontinuation in 40% and 28% of patients. Two treatment-related deaths were reported. The 12- and 18-month os rates were 80% [95% confidence interval (ci): 73% to 86%] and 76% (95% ci: 67% to 82%) respectively. Conclusions: In this Canadian population, nivolumab plus ipilimumab demonstrated a safety profile and survival outcomes consistent with phase ii and iii clinical trial data.

Use of immuno-oncology in melanoma.

Treatment options for patients with metastatic melanoma have expanded rapidly since the approval of ipilimumab by the U.S. Food and Drug Administration in 2011. Cytokines such as interferon and interleukin-2 were approved in 1995 and 1998 respectively. However, the effect on survival was marginal, and the toxicity, substantial. Multiple vaccine studies likewise failed to show improvements in survival. The "Holy Grail" came with the discovery of immune checkpoints, and the first metastatic melanoma trial to show an improvement in overall survival involved the use of an immune checkpoint inhibitor against ctla-4: ipilimumab. Since then, the field of immuno-oncology has exploded, with approvals for PD-1 inhibitors and discovery, in clinical trials, of several novel checkpoints such as tim-3, lag-3, and others. In fact more than 950 novel immunotherapy drugs are currently being trialled. Recently, combinations of ctla-4 and PD-1 inhibitors have been associated with 1-year survival rates exceeding 80% and 4-year survival rates greater than 50%. In no tumour has as much progress been made in the last 5 years as in melanoma, and the efforts to unravel and exploit mechanisms used by the tumour to avoid immune detection are just beginning.

Current landscape of immunotherapy in the treatment of solid tumours, with future opportunities and challenges.

Immunotherapy has emerged as a new standard of care, showing survival benefit for solid tumours in multiple disease sites and indications. The survival improvements seen in diseases that were highly resistant to traditional therapies, with a poor prognosis, are unprecedented. Although the benefits observed in clinical trials are undeniable, not all patients derive those benefits, leading to emerging combination strategies and an ongoing quest for biomarker selection. Here, we summarize the current evidence for immunotherapy in the treatment of solid tumours, and we discuss emerging strategies at the forefront of research. We discuss future challenges that will be encountered as experience and knowledge continue to expand in this rapidly emerging field.

Superconducting and normal-state anisotropy of the doped topological insulator Sr0.1Bi2Se3.

SrxBi2Se3 and the related compounds CuxBi2Se3 and NbxBi2Se3 have attracted considerable interest, as these materials may be realizations of unconventional topological superconductors. Superconductivity with Tc ~3 K in SrxBi2Se3 arises upon intercalation of Sr into the layered topological insulator Bi2Se3. Here we elucidate the anisotropy of the normal and superconducting state of Sr0.1Bi2Se3 with angular dependent magnetotransport and thermodynamic measurements. High resolution x-ray diffraction studies underline the high crystalline quality of the samples. We demonstrate that the normal state electronic and magnetic properties of Sr0.1Bi2Se3 are isotropic in the basal plane while we observe a large two-fold in-plane anisotropy of the upper critical field in the superconducting state. Our results support the recently proposed odd-parity nematic state characterized by a nodal gap of Eu symmetry in SrxBi2Se3.

Prey composition and ontogenetic shift in coastal populations of longnose gar Lepisosteus osseus.

Longnose gar Lepisosteus osseus were collected from May 2012 to July 2013 in the Charleston Harbor and Winyah Bay estuaries (SC, U.S.A.). This study examined trends in stomach fullness, described major prey components and their importance in the diet of L. osseus, compared stomach content-based trophic level estimates with the stable-isotope-based proxy: δ(15) N and tested for the occurrence of an ontogenetic diet shift using stomach content analysis and stable C and N isotopes (δ(13) C and δ(15) N). Dominant prey families were Clupeidae, Sciaenidae, Penaeidae, Fundulidae and Mugilidae, with the highest consumption rates in autumn. Trophic levels calculated using stomach contents did not correspond to δ(15) N (P > 0·05). Stomach contents and stable-isotope signatures indicate ontogenetic prey composition shifts from low trophic level benthic prey (fundulids) to higher trophic level pelagic prey (clupeids) as the fish grow between 400 and 600 mm in standard length. Due to their biomass, abundance and top predator status, L. osseus play a significant ecological role in the estuarine community composition, although this effect has often been overlooked by past researchers and should be considered in future estuarine community studies.

High-dose mitoxantrone-vinblastine-cyclophosphamide and autologous stem cell transplantation for stage III breast cancer: final results of a prospective multicentre study.

BACKGROUND: Stage III breast cancer patients continue to suffer high relapse and death rates despite standard chemotherapy regimens. High-dose alkylator chemotherapy does not further improve outcome. This phase II study evaluated a novel high-dose chemotherapy regimen which combined active breast cancer agents with differing mechanisms of action. PATIENTS AND METHODS: Eligibility included at least seven involved axillary nodes (AxLNs) for tumours <5 cm, at least four AxLNs for tumours >5 cm or locally advanced breast cancer (LABC). Patients received four cycles of fluorouracil-adriamycin-cyclophosphamide (FAC) followed by one cycle of mitoxantrone 63 mg/m(2)-vinblastine 12.5 mg/m(2)-cyclophosphamide 6 g/m(2) (MVC) with autologous blood stem cell transplantation (ASCT). RESULTS: Between April 1995 and December 1998, 92 patients aged 21-65 years (median 45 years) were enrolled, of whom 25 were treated preoperatively for LABC and 67 were treated postoperatively. Although there was no early treatment-related mortality, one late death occurred from secondary acute myeloid leukaemia. The 7-year event-free and overall survival rates were 53% (95% confidence interval 42-64%) and 62% (95% CI 52-73%), respectively, with no significant difference between pre- and postoperative groups. CONCLUSION: FAC followed by MVC-ASCT is feasible and reasonably well tolerated, but does not result in improved survival rates compared with other conventional or high-dose regimens for stage III breast cancer.

Radioiodinated N-[3-(4-morpholino)propyl]-N-methyl-2-hydroxy-5-iodo-3-methylbenzylamine (ERC9): a new potential melanoma imaging agent.

The role of nuclear medicine in the management of patients with malignant melanoma has expanded in recent years with the introduction of lymphoscintigraphy and sentinel lymph node biopsy, intense interest in positron emission tomography (PET) imaging using 2-[18F]fluoro-2-deoxyglucose (18F-FDG) as a tracer, and encouraging reports of several new single-photon-emitting radiopharmaceuticals. While PET imaging with FDG exhibits a high sensitivity for imaging patients with melanoma, specificity may not be as high and access to the technology remains limited. Single-photon emission tomography (SPET) imaging remains standard technology for most nuclear medicine departments. We report a novel radiopharmaceutical--radioiodinated N-[3-(4-morpholino)-propyl]-N-methyl-2-hydroxy-5-iodo-3-methylbenzylamine (ERC9)--which appears to show a sensitivity and specificity that are commensurate with expectations of a radiopharmaceutical for routine clinical imaging. In this phase II trial, 110 patients at risk for recurrence, with suspected recurrence or being restaged have been imaged with this novel tracer, demonstrating an overall sensitivity of 91% and specificity of 89%. The results of our study support a phase III trial to establish the clinical role of ERC9 in staging melanoma patients at presentation who are at high risk for metastasis, or restaging patients with known relapse to assess the extent of their disease, particularly if therapy or enrollment into a clinical trial is being considered.

Phase II study of docetaxel, doxorubicin, and cyclophosphamide as first-line chemotherapy for metastatic breast cancer.

PURPOSE: This pilot phase II study investigated the efficacy and toxicity of docetaxel with doxorubicin and cyclophosphamide (TAC) as first-line chemotherapy for anthracycline-naive patients with metastatic breast cancer. PATIENTS AND METHODS: Fifty-four patients received a total of 359 courses consisting of docetaxel 75 mg/m2 given intravenously (IV) over 1 hour, preceded by IV doxorubicin 50 mg/m2 and cyclophosphamide 500 mg/m2 for a maximum of eight 3-week cycles. RESULTS: After an independent panel review, the overall objective response rate was 77% (complete response, 6%). Overall objective response rates in patients with visceral, bone, and liver involvement were 82%, 82%, and 80%, respectively. Median duration of response was 52 weeks, and median time to progression was 42 weeks. With a median follow-up of 32 months, the median survival had not yet been reached, whereas the 2-year survival was 57%. The main toxicities were hematologic (neutropenia grade 3/4 in 100% of patients and 95% of cycles; febrile neutropenia in 34% of patients and 9% of cycles). Documented grade 3 infection was seen in one patient (2%) in one cycle, and no toxic death was reported. Severe acute or chronic nonhematologic adverse events were infrequent, and docetaxel-specific toxicities (such as fluid retention and nail changes) were mild, with only one patient being discontinued for fluid retention. Congestive heart failure was seen in two patients (4%). CONCLUSION: TAC is an active and manageable regimen that has been chosen as the basis of five randomized phase III trials, including two pivotal studies comparing TAC to fluorouracil plus doxorubicin and cyclophosphamide in the metastatic and adjuvant treatment of breast cancer.

Phase I study of the BLP25 (MUC1 peptide) liposomal vaccine for active specific immunotherapy in stage IIIB/IV non-small-cell lung cancer.

Active specific immunotherapy with liposomal vaccines targeted to the mucinous carcinoma-associated glycoprotein MUC1 have shown promising results in animal models. The aim of this phase I study was to evaluate the safety and immunogenicity of 2 dose levels of the MUC1 liposomal vaccine preparation BLP25. Patients with stage IIIB or IV non-small-cell lung cancer received either 20 microg or 200 microg of the liposomal BLP25 vaccine preparation. Injections were administered subcutaneously at weeks 0, 2, 5, and 9. Immunological responses to vaccination were measured by antibody production, cytotoxic T lymphocytes (CTL), and proliferative T-helper cells. Seventeen patients were entered on study; 12 patients completed the vaccination protocol. Two patients, 1 in each dose group, developed clinically insignificant grade 3 lymphopenia during the study. Nonhematologic toxicities were mild and self-limiting, and there were no significant long-term injection site reactions. Immunological assays revealed the generation of CTLs against MUC1-positive tumor cell lines in 5 of 12 evaluable patients. These patients did not have CTLs prior to receiving the vaccine. No significant humoral response to the vaccination was observed. No objective antitumor responses were observed. Of the 12 patients completing all the vaccinations, 4 had stable disease. Median survival time was 5.4 months in the 20 microg group and 14.6 months in the 200 microg group. In summary, the BLP25 liposomal vaccine was well tolerated and elicited a primarily cellular immune response in these lung cancer patients. This study forms the basis for further clinical exploration of the MUC1 liposomal vaccine, BLP25.

Docetaxel (Taxotere) in combination with anthracyclines in the treatment of breast cancer.

Considering the single-agent activity of docetaxel (Taxotere; Rhône-Poulenc Rorer, Antony, France) and doxorubicin in breast cancer and their potential non-cross-resistance, several docetaxel/anthracycline-based combination chemotherapies were developed in phase I and II programs for metastatic breast cancer patients. The rationale for these combinations was also reinforced by the fact that docetaxel showed significant activity in phase III trials in patients previously exposed or having failed anthracycline chemotherapy. In a pivotal randomized phase III study of doxorubicin plus docetaxel versus doxorubicin plus cyclophosphamide as first-line chemotherapy for 429 patients with metastatic breast cancer, doxorubicin/docetaxel emerged as the more effective regimen. Despite a lower-dose intensity of doxorubicin, patients receiving doxorubicin/docetaxel experienced a higher response rate as well as a significantly longer time to progression and time to treatment failure. This difference was seen even in patients with poor-prognosis disease. Febrile neutropenia was more common in doxorubicin/docetaxel-treated patients. However, there were no septic deaths among 213 patients receiving doxorubicin/ docetaxel. Extrahematologic toxicity appeared mild for both regimens and the combination docetaxel/doxorubicin did not increase the cardiac toxicity expected for an anthracycline-containing regimen. Docetaxel plus doxorubicin is the first regimen, involving a newly developed agent, proven superior to a standard anthracycline-containing combination in metastatic breast cancer and its potential is now being investigated in the adjuvant setting.

Chemotherapy of breast cancer: are the taxanes going to change the natural history of breast cancer?

Among the novel chemotherapeutic drugs introduced in the last decade, taxanes have emerged as the most powerful compounds and results available to date suggest that they will be remembered in the future as the breast cancer chemotherapy of the 1990s. The two taxanes (paclitaxel, Taxol, Bristol-Myers Squibb and docetaxel, Taxotere, Rhône-Poulenc Rorer) share some characteristics, but are also significantly different both in preclinical profile and, most importantly, in clinical characteristics. The main clinical differences are related to their different efficacy-toxicity ratio in relation to dose and schedule; the differing integrability of paclitaxel and docetaxel in anthracycline-taxane containing regimens, secondary to major differences in pharmacokinetic interactions between each taxane and the anthracyclines, and; the potential differences in level of synergism between each taxane and herceptin (HeR2Neu antibody/trastuzumab, Genentech/Roche). In clinical practice, the taxanes are now standard therapy in metastatic breast cancer after prior chemotherapy, in particular anthracyclines, has failed. Their role in combination with anthracyclines in first-line therapy of advanced breast cancer is emerging and sheds new light on the potential role of taxanes in the adjuvant setting. However, the impact of taxanes on the natural history of breast cancer is yet to be defined, despite the trend of results suggesting that these agents have the potential for significant improvements in advanced and, most importantly, adjuvant therapy of breast cancer. The results of all completed or ongoing Phase III trials in first-line metastatic and the adjuvant setting will help determine if taxanes will further improve the outcome of breast cancer or not.

The academic global virtual concept in clinical cancer research and its application to breast cancer: The Breast Cancer International Research Group.

In contrast to previous decades, the 1990s have witnessed an increase of new agents with significant activity in breast cancer, including chemotherapy, hormone therapy, and, more recently, biologic modifiers. All information appears to confirm that such a trend will persist and even accelerate in the coming decades. Unless clear strategies of development for new drugs are strictly followed, it will become difficult to adequately assess the many new agents with potentially important activity against breast cancer, and patient access may become a limiting key factor. The academic, global virtual concept is calling for the definition of a new relationship between the pharmaceutical industry and clinical researchers. The main aspect is related to the creation of partnerships with an academically controlled global strategy of development for promising new agents, in which the quality and independence of processes (adjuvant setting, for example) are critical. The means are based on the globalization of patient access (worldwide network) and the virtuality of the approach (modern means of communication as well as access to subgroups of patients). The Breast Cancer International Research Group is the first academic global virtual cooperative group in breast cancer and is making contributions in the development of new drugs, such as taxanes, new antiestrogens, and new cytokines.

Docetaxel and anthracycline polychemotherapy in the treatment of breast cancer.

Given the single-agent activity of docetaxel and doxorubicin in metastatic breast cancer and their potential non-cross-resistance, several phase I/II pilot studies of either docetaxel/doxorubicin (TA) or TA plus cyclophosphamide (TAC) were conducted. The results of these studies show that the main toxicity is related to neutropenia and its consequences, although documented infections are rarely reported. Other toxicities are mild, while docetaxel-specific toxicities (fluid retention, nail changes, etc) are seldom seen. No significant cardiotoxicity, even when patients are exposed to a cumulative doxorubicin dose greater than 360 mg/m2, has been observed. In terms of efficacy, response rates in the range of 70% to 80% were noted in all studies, even for patients with visceral metastases. Preliminary data suggest that the combination of docetaxel with epirubicin is also feasible, with manageable toxicities and significant activity. Several phase III randomized trials using TA or TAC are presently being performed in first-line metastatic breast cancer and, most importantly, in the adjuvant setting to assess whether TA-based combinations will change the natural history of breast cancer.

Review of docetaxel and doxorubicin-based combinations in the management of breast cancer: from metastatic to adjuvant setting.

Considering the efficacy of docetaxel (Taxotere, Rhône-Poulenc Rorer, Antony, France) and doxorubicin in advanced breast cancer and their potential noncross-resistance, two pilot studies of docetaxel/doxorubicin (TA)-based combinations were conducted, one being a phase I dose-finding study of TA and the second a phase II study of docetaxel/doxorubicin/cyclophosphamide (TAC). The only significant toxicity, seen in both trials, was neutropenia and its consequences such as febrile neutropenia without significant documented infections. Extrahematologic and particularly docetaxel-specific side effects (fluid retention) were mild. Particularly noteworthy was the absence of significant cardiac toxicity; overall, there was only one case of congestive heart failure (1%). In terms of efficacy, response rates in excess of 70% and 80% were noted in both studies, even for patients with visceral metastases. Several phase III randomized trials using TA or TAC are presently being performed in first-line metastatic breast cancer and most importantly in the adjuvant setting to assess whether TA-based combinations will change the natural history of breast cancer.

Taxane-based three-drug combination in metastatic and adjuvant treatment of breast cancer.

Considering the recommended dose of the docetaxel/doxorubicin combination (75 mg/m2 and 50 mg/m2, respectively), we decided to proceed with a pilot program in untreated metastatic breast cancer aimed at defining a multidrug regimen that could be later randomly compared with a standard doxorubicin-containing polychemotherapy regimen with equidoses of doxorubicin such as the FAC protocol (5-fluorouracil 500 mg/m2, doxorubicin 50 mg/m2, and cyclophosphamide 500 mg/m2) in first-line metastatic and adjuvant treatment of breast cancer patients. We proceeded with a pilot phase II study of the TAC combination, which consists of docetaxel 75 mg/m2 as a 1-hour infusion preceded by doxorubicin 50 mg/m2 and cyclophosphamide 500 mg/m2, both given as an intravenous bolus. Three hundred seventy courses were delivered in 54 anthracycline-naive patients, among whom 62% had visceral metastases. Median relative dose intensity was above 98% for all drugs. Grade 4 neutropenia was the main toxicity (70% of cycles) and the incidence of febrile neutropenia and infection was acceptable (6% and 0.8% of cycles, respectively). Acute and chronic extrahematologic toxicities were mild, mostly grade 2, and the docetaxel-specific toxicities (fluid retention, nail changes, etc) were not major clinical problems; no patient was discontinued due to fluid retention. The major response rate was 73% overall and 79% in measurable disease. Time to progression and survival are still under evaluation. The TAC combination is an active and well-tolerated regimen that is the basis of two currently open, pivotal, randomized phase III trials comparing TAC with FAC in the metastatic and adjuvant treatment of breast cancer.

Docetaxel/doxorubicin/cyclophosphamide in the treatment of metastatic breast cancer.

Preliminary results from phase I trials suggest that the use of docetaxel (Taxotere) and doxorubicin (Adriamycin) is a well tolerated and highly active combination regimen for patients with metastatic breast cancer. The maximum tolerated dose of this combination was 50 mg/m2 of doxorubicin given as an intravenous bolus followed 1 hour later with 75 mg/m2 of docetaxel given as a 1-hour intravenous infusion. Because cardiotoxicity was not observed with this combination, we added cyclophosphamide (Cytoxan, Neosar) in a phase II trial to determine the antitumor activity and tolerability of this 3-drug combination as first-line therapy in patients with metastatic breast cancer. Preliminary results from this study indicate that the Taxotere/ Adriamycin/Cyclophosphamide (TAC) combination produces response rates of up to 80%. However, frequent grade 4 neutropenia was seen in 68% of cycles, febrile neutropenia in 5.5% of cycles, and grade 3 to 4 infection in .8% of cycles. Cardiac toxicity was rare, with 1 case of reversible congestive heart failure (2%), which occurred 2 months after completion of chemotherapy. These preliminary data show that TAC is highly active and that docetaxel did not significantly increase the cardiotoxicity of doxorubicin. Phase III studies in both the first-line and adjuvant settings are warranted.

Docetaxel/doxorubicin/cyclophosphamide in the treatment of metastatic breast cancer.

A pilot phase II study examined the feasibility of 75 mg/m2 of docetaxel (Taxotere) in combination with 50 mg/m2 of doxorubicin and 500 mg/m2 of cyclophosphamide (Cytoxan, Neosar) in the first-line treatment of metastatic breast cancer. This study was designed to evaluate the efficacy and toxicity of the docetaxel/doxorubicin/cyclophosphamide combination both alone and as induction before high-dose chemotherapy, supplemented by autologous peripheral blood stem-cell transplantation. Patients were divided into three groups: one group received 8 courses of docetaxel/doxorubicin/cyclophosphamide; the second received 4 to 6 courses of the same combination with cell sampling, followed by high-dose chemotherapy with autologous peripheral blood stem-cell transplantation; and the third group's regimen was identical to that of the second, with additional granulocyte-colony stimulating factor (G-CSF, filgrastim [Neupogen]). Of 28 patients (149 courses) evaluable for toxicity and response, the overall response rate was 82%, with 5 (18%) complete responses and 18 (64%) partial responses. The most frequent hematologic toxicity was neutropenia; grade 4 neutropenia occurred in 86% of patients, with febrile neutropenia in 9 patients (18%). There was no incidence of infection, possibly because of the administration of oral ciprofloxacin (Cipro) from days 5 to 15 of each cycle. Nonhematologic adverse events were not severe; there was no significant cardiotoxicity. Future randomized trials of docetaxel/doxorubicin/cyclophosphamide as first-line adjuvant therapy of high-risk patients and as induction chemotherapy are in development.

Krukenberg tumor complicated by pregnancy.

A 32-year-old female presented with a right ovarian mass, and the unilateral oophorectomy specimen revealed adenocarcinoma with signet-ring cells histology consistent with a Krukenberg tumor. The high-grade gastric primary adenocarcinoma was later identified, but by this time a viable 7-week fetus and left ovarian Krukenberg tumor were present. Second trimester palliative oophorectomy and partial gastrectomy were performed. The patient delivered a healthy infant by cesarean section and is now 36 months after the initial diagnosis of metastatic gastric carcinoma and remains asymptomatic and free of disease. The unexpectedly favorable clinical outcome suggests that a patient may benefit from resection of gastric adenocarcinoma metastatic to ovary when other sites of metastatic disease are not evident.