Palliative care for patients with heart failure and family caregivers in rural Appalachia: a randomized controlled trial.

BACKGROUND: Heart failure (HF) is a debilitating disease with worsening symptoms and family caregiving burden. HF affects more than 8 million Americans. West Virginia has the highest HF death rate in the U.S. and limited healthcare services. This study tested whether the family HF palliative and end-of-life care intervention (FamPALcare) improved patient and caregiver outcomes at 3- and 6-month study endpoints. METHODS: This study used a randomized controlled trial design. Patients with HF and their caregivers were randomly assigned together to the intervention (n = 21) or control (n = 18) group. The intervention included five telephone coaching sessions on the HF home, palliative, and end-of-life care. The outcome data collected at baseline and at 3 and 6 months were from the patients' (a) HF-related health status and depression/anxiety scale scores; and from caregivers' (b) caregiving burden and depression/anxiety scale scores; and (c) anonymous ratings on the 11-item FamPALcare helpfulness scale, completed by the intervention participants. RESULTS: The mean age of the patients was 65.66 (SD = 13.72) years, and 67% were White males. The mean age of the caregivers was 62.05 (SD = 13.14) years, and 77% were White females. Compared to the controls, patients in the intervention group had significantly greater scores for HF-related health status (p < .05) and lower depression/anxiety scores at 6 months, the study endpoint. The family caregivers in the intervention group had significantly lower scores on caregiving burden (p < .05) and depression/anxiety (p < .01) at 3 months. The mean helpfulness rating was M = 4.46 out of 5 (SD = 0.49). CONCLUSIONS: The FamPALcare intervention was found to be effective at improving patient HF-related health status and reducing caregiver burden and improving both patient and caregiver depression and anxiety scores. The FamPALcare HF intervention was found feasible and consistently delivered (fidelity). The FamPALcare intervention's cost-effectiveness and helpfulness ratings information will be used to plan for subsequent clinical trials. TRIAL REGISTRATION: ClinicalTrials.gov NCT04153890, Registered on 4 November 2019, https://clinicaltrials.gov/ct2/show/NCT04153890 .

Blockade of TGF-ß and PD-L1 by bintrafusp alfa promotes survival in preclinical ovarian cancer models by promoting T effector and NK cell responses.

BACKGROUND: Failure of immunotherapy in high-grade serous ovarian cancer (HGSC) may be due to high levels of transforming growth factor-ß (TGF-ß) in ascites or tumour immune microenvironment (TIME). Here, we test whether coordinated blockade of TGF-ß and PD-L1 with bintrafusp alfa (BA) can provoke anti-tumour immune responses in preclinical HGSC models. METHODS: BA is a first-in-class bifunctional inhibitor of TGF-ß and PD-L1, and was tested for effects on overall survival and altered TIME in syngeneic HGSC models. RESULTS: Using a mouse ID8-derived HGSC syngeneic model with IFNγ-inducible PD-L1 expression, BA treatments significantly reduced ascites development and tumour burden. BA treatments depleted TGF-ß and VEGF in ascites, and skewed the TIME towards cytotoxicity compared to control. In the BR5 HGSC syngeneic model, BA treatments increased tumour-infiltrating CD8 T cells with effector memory and cytotoxic markers, as well as cytolytic NK cells. Extended BA treatments in the BR5 model produced ∼50% BA-cured mice that were protected from re-challenge. These BA-cured mice had increased peritoneal T-effector memory and NK cells compared to controls. CONCLUSIONS: Our preclinical studies of BA in advanced ovarian cancer models support further testing of BA as an improved immunotherapy option for patients with advanced ovarian cancer.

Major Surgery, Brain Injury, and Neurodevelopmental Outcomes in Very Preterm Infants.

OBJECTIVES: We determined whether (1) major surgery is associated with an increased risk for brain injury and adverse neurodevelopment and (2) brain injury modifies associations between major surgery and neurodevelopment in very preterm infants. METHODS: Prospectively enrolled infants across 3 tertiary neonatal intensive care units underwent early-life and/or term-equivalent age MRI to detect moderate-severe brain injury. Eighteen-month neurodevelopmental outcomes were assessed with Bayley Scales of Infant and Toddler Development, third edition. Multivariable logistic and linear regressions were used to determine associations of major surgery with brain injury and neurodevelopment, adjusting for clinical confounders. RESULTS: There were 294 infants in this study. Major surgery was associated with brain injury (odds ratio 2.54, 95% CI 1.12-5.75, p = 0.03) and poorer motor outcomes (ß = -7.92, 95% CI -12.21 to -3.64, p < 0.001), adjusting for clinical confounders. Brain injury x major surgery interaction significantly predicted motor scores (p = 0.04): Lowest motor scores were in infants who required major surgery and had brain injury. DISCUSSION: There is an increased risk for brain injury and adverse motor outcomes in very preterm infants who require major surgery, which may be a marker of clinical illness severity. Routine brain MRI to detect brain injury and close neurodevelopmental surveillance should be considered in this subgroup of infants.

Developing a partnership to improve health care delivery to children <18 years with cancer and blood disorders in the English-speaking Caribbean: lessons from the SickKids-Caribbean Initiative (SCI).

In 2013, the SickKids-Caribbean Initiative (SCI) was formalised among The Hospital for Sick Children in Toronto, Canada, the University of the West Indies, and Ministries of Health in six Caribbean countries (Barbados, The Bahamas, Jamaica, St. Lucia, St. Vincent and the Grenadines, and Trinidad and Tobago). The aim was to improve the outcomes and quality of life of children (<18 years) with cancer and blood disorders in the partner countries. Core activities included filling a human resource gap by training paediatric haematologists/oncologists and specialised registered nurses; improving capacity to diagnose and treat diverse haematology/oncology cases; developing and maintaining paediatric oncology databases; creating ongoing advocacy activities with international agencies, decision makers, and civil society; and establishing an integrated administration, management, and funding structure. We describe core program components, successes, and challenges to inform others seeking to improve health service delivery in a multidisciplinary and complex partnership.

Somatic mutations in facial skin from countries of contrasting skin cancer risk.

The incidence of keratinocyte cancer (basal cell and squamous cell carcinomas of the skin) is 17-fold lower in Singapore than the UK1-3, despite Singapore receiving 2-3 times more ultraviolet (UV) radiation4,5. Aging skin contains somatic mutant clones from which such cancers develop6,7. We hypothesized that differences in keratinocyte cancer incidence may be reflected in the normal skin mutational landscape. Here we show that, compared to Singapore, aging facial skin from populations in the UK has a fourfold greater mutational burden, a predominant UV mutational signature, increased copy number aberrations and increased mutant TP53 selection. These features are shared by keratinocyte cancers from high-incidence and low-incidence populations8-13. In Singaporean skin, most mutations result from cell-intrinsic processes; mutant NOTCH1 and NOTCH2 are more strongly selected than in the UK. Aging skin in a high-incidence country has multiple features convergent with cancer that are not found in a low-risk country. These differences may reflect germline variation in UV-protective genes.

Central Retinal Vein Occlusion 36-Month Outcomes with Anti-VEGF: The Fight Retinal Blindness! Registry.

PURPOSE: To analyze the 3-year outcomes in a broad population of patients starting VEGF inhibitors for central retinal vein occlusion (CRVO) in routine clinical practice. DESIGN: Observational database study. PARTICIPANTS: Overall, 527 treatment-naïve CRVO eyes that commenced VEGF inhibitors between December 1, 2010 and 2018 were tracked in the Fight Retinal Blindness! registry. METHODS: Longitudinal models were used to plot changes in visual acuity (VA) and central subfield thickness (CST). MAIN OUTCOME MEASURES: Mean change in VA from baseline to 36 months, injections, visits, completion, switching, and suspensions of therapy > 180 days at the final review. RESULTS: Overall (527 eyes) mean VA change (95% confidence interval [CI]) was + 10 (7, 12) letters, 37% had final VA ≥ 70 and 30% ≤ 35 letters, mean CST changed -306 µm. Completers (257/527, 49%) had mean 36-month changes in VA and CST of + 12 letters and -324 µm with a median of 18 injections at 26 visits. The adjusted mean VA change was similar to each VEGF inhibitor (mean, + 11.4 letters) despite a greater reduction in CST with aflibercept (-310 µm) versus ranibizumab (-258 µm) versus bevacizumab (-216 µm; P < 0.001). Eyes with baseline VA that was trial-eligible (19-73 letters; 356/527, 68%) gained 7 letters, very poor (< 19 letters; 129/527, 24%) gained 22 letters, or very good (> 73 letters; 42/527, 8%) lost 7 letters. Switching (160/527, 30%) was most often to aflibercept (79 eyes). By using suspensions and discontinuation reasons, we identified similar proportions had ceased therapy (154/527, 29%) and were still receiving it at 36 months (165/527, 31%). Only 62/527 eyes (12%) had resolution of macular edema without treatment for > 6 months. CONCLUSIONS: Patients with CRVO that commenced VEGF inhibitors in routine care for whom follow-up was available had VA improvements of around 12 letters at 3 years, but with > 50% lost to follow-up, the VA outcome for the entire group was likely worse. The choice of VEGF inhibitor influenced CST but not VA outcomes. We estimated that around half of the eyes were still receiving injections after 36 months. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found after the references.

Survey of ptosis practice patterns among surgeons in Asia Pacific Society of Ophthalmic Plastic and Reconstructive Surgery (APSOPRS).

OBJECTIVE: To characterize the preferred ptosis practice patterns and variations among oculoplastic surgeons in the Asia-Pacific region. METHODS: A web-based questionnaire was sent to both members and non-members registered under the Asia Pacific Society of Ophthalmic Plastic and Reconstructive Surgery (APSOPRS)'s email database. The survey included preoperative testing practices, surgical preferences for adult aponeurotic and congenital ptosis, various surgical techniques (anterior and posterior approach ptosis procedures, and frontalis sling procedures) and postoperative practices. RESULTS: A total of 386 survey invitations were sent. There was a response rate of 68.7% from respondents from 20 countries in the Asia-Pacific region. There was variation in the preoperative evaluation and management of ptosis. Anterior approach ptosis surgery (96.6%) and frontalis sling procedures (86.8%) were performed by more surgeons than posterior approach ptosis surgery (47.2%). There was a deviation from the traditional frontalis sling procedures for patients with poor levator function. CONCLUSIONS: Our survey results provide insight into the variation in the assessment and management of ptosis amongst oculoplastic surgeons in the Asia-Pacific region. It also demonstrates some differences between practice patterns in Asia-Pacific and America.

The role of cytoreductive surgery and intraperitoneal chemotherapy in gastric cancer.

Gastric cancer (GC) with peritoneal carcinomatosis (PC) progresses rapidly and has historically dismal survival rates. Given the aggressive tumor biology and poor survival outcomes of patients with GC/PC, additional treatments beyond systemic chemotherapy are needed. Cytoreductive surgery and intraperitoneal chemotherapy have been effective management options for peritoneal surface malignancies, with increasing data to support their use in GC/PC. This review highlights the evolution of the surgical treatment of GC/PC, and discusses critical studies supporting the role of cytoreductive surgery, appropriate patient selection, and various methods in the delivery of intraperitoneal chemotherapy for patients with GC/PC.

Surgical approach to pediatric mediastinal masses based on imaging characteristics.

BACKGROUND: Pediatric mediastinal masses may be resected using an open or video-assisted thoracoscopic surgery (VATS) approach. We sought to define the preoperative imaging findings predicting amenability to VATS. METHODS: This multicenter retrospective study of pediatric patients undergoing either VATS or open surgical mediastinal mass resection between 2008 and 2018 evaluated the preoperative imaging descriptors associated with VATS. Postoperative endpoints included length of stay (LOS), 30-day readmission, 90-day mortality and complication rates. RESULTS: Mediastinal mass resection was performed in 33 patients. Median tumor size was 6 cm, and 51.5% had anterior mediastinal tumors. The 23 (69.7%) patients who underwent VATS were significantly older (144 months vs 32, P = 0.01) and larger (33.6 kg vs 13.8 P = 0.03). Preoperative imaging characteristics in VATS included "well circumscribed", "smooth margins" and "cystic", while the open surgery group were "heterogeneous" and "coarse calcification". The open group had more germ cell tumors (60.0% vs 13.0%, P = 0.16) but no difference in malignancy. VATS patients had shorter LOS (2 days vs 6.5, P = 0.24). Readmission, complication and mortality rates were similar. CONCLUSIONS: Pediatric patients with apparent malignancy frequently underwent open resection compared with the thoracoscopic group, although final malignant pathology was similar. Equivalent outcomes and shorter LOS should favor a minimally invasive approach. LEVEL OF EVIDENCE: Level III.

Dexamethasone Implant for Diabetic Macular Oedema: 1-Year Treatment Outcomes from the Fight Retinal Blindness! Registry.

INTRODUCTION: Phase III clinical trials of dexamethasone intravitreal implant for diabetic macular oedema (DMO) have reported significant improvements in visual acuity (VA). Studies evaluating the treatment of DMO in routine clinical practice provide data to identify areas that need improvement. This study evaluated 12-month treatment outcomes of dexamethasone implant for DMO in routine clinical practice. METHODS: Retrospective data analysis of eyes that started dexamethasone implant for DMO from 1 June 2013 to 30 April 2019 in routine clinical practice tracked in the Fight Retinal Blindness! Registry. RESULTS: Of the 4282 eyes (2518 patients) that started DMO treatment in the specified period, 267 (6%) eyes (204 patients) received 454 dexamethasone implant injections. Two-fifths (106 eyes) had received prior treatment for DMO. The mean (95% confidence interval [CI]) VA change at 12 months was 1.8 (- 0.5, 4.2) letters from the mean (standard deviation [SD]) VA of 56.5 (19.8) letters at baseline, with 41% eyes achieving at least 20/40. The mean (95% CI) change in central subfield thickness over 1 year was - 79 (- 104, - 54) µm from a mean (SD) of 459 (120) µm at baseline. Eyes that completed 1 year of follow-up received a median (Q1, Q3) of 2 (1, 2) dexamethasone implants. One-tenth of phakic eyes received cataract surgery while 2% had a pressure response requiring anti-glaucoma medications. CONCLUSIONS: One-year treatment outcomes of dexamethasone intravitreal implant for DMO in routine clinical practice were inferior to those in the clinical trials perhaps because of fewer treatments in clinical practice.

Prebending of Prefabricated Orbital Implants: Towards Improved Orbital Angle Symmetry Post Craniofacial Trauma Surgery.

PURPOSE: Reconstructive surgery after craniofacial trauma aim to restore orbital anatomy for function and aesthetic reasons. The purpose of this study is to improve postoperative orbital symmetry with the use of prebent prefabricated titanium implants. METHODS: In this retrospective study, patients with combined unilateral medial wall and floor fractures who underwent orbital reconstruction surgery were selected. The angle of inferomedial orbital strut (AIOS) was measured at 3 standard locations on preoperative facial computed tomography guided scans of the nonfractured orbit in the coronal view and used as a guide to bend the prefabricated titanium implants intraoperatively. The corresponding values were measured on the postoperative computed tomography and compared for symmetry. RESULTS: Out of 83 patients recruited for the study, 54 were in the prebent group while 29 were in the control group. All other demographics were similar among the 2 groups. Anterior AIOS has a difference of 4.9° between 2 orbits in the prebent group whereas a difference of 15.5° was noted in the nonprebent group. For middle AIOS, a difference of 4.7° was noted in the prebent group whereas nonprebent group had a difference of 14.1°. For posterior AIOS, the prebent group had a difference of 3.8° versus 14.1° in the nonprebent group. The difference in AIOS at all 3 points between the prebent and nonprebent group were significant. CONCLUSIONS: Anatomical prefabricated titanium plates are versatile implants that facilitate orbital reconstruction. Prebending of these implants according to the fellow orbit can achieve better surgical outcomes in a cost-effective manner.

Intraocular Pressure and Glaucoma in Thyroid Eye Disease.

PURPOSE: Current literature lacks a summary of knowledge on intraocular pressure (IOP) elevation and glaucoma in thyroid eye disease (TED). This review aims to augment existing literature by providing such a summary. It qualitatively evaluates current knowledge on the pathogenesis, prevalence, and management of concomitant ocular hypertension or glaucoma in TED patients. METHODS: In this narrative review, relevant publications were identified through a computerized database search. Search results were screened for relevance. Correspondence, Editorials, and Letters to the Editors were excluded. References cited within the identified articles were used to further augment the search. Information extracted for qualitative analysis included epidemiologic data, methods of IOP assessment, management protocols, and response to treatment. RESULTS: Studies in current literature are relatively heterogenous, differing in country of origin, TED cohort sizes, and IOP measurement techniques. Further studies are required to elucidate the true epidemiologic relationship between TED and ocular hypertension or glaucoma. Proposed models of IOP elevation include elevation of episcleral venous pressure, mucopolysaccharide deposition within the trabecular meshwork, restrictive myopathy, steroid-induced glaucoma, and secondary glaucoma. IOP-reducing effects of TED treatment options are discussed. CONCLUSIONS: While raised IOP in TED is a common phenomenon, the diagnosis of glaucoma in TED requires a high index of suspicion before any intervention.

Prevalence, Risk Factors, and Impact of Preoperative Seizures in Neonates With Congenital Heart Disease.

PURPOSE: The purpose of this study was to assess the prevalence, risk factors, and impact of electrographic seizures in neonates with complex congenital heart disease before cardiac surgery. METHODS: A cohort of 31 neonates with congenital heart disease monitored preoperatively with continuous video-EEG (cEEG) was first reviewed for electrographic seizure burden and EEG background abnormalities. Second, cEEG findings were correlated with brain MRI and 18-month outcomes. RESULTS: Continuous video-EEG was recorded preoperatively for a median duration of 20.5 hours (range, 2.5-93.5 hours). The five neonates (16%; 95% confidence interval, 5.5% to 34%) with seizures detected on cEEG in the preoperative period had a diagnosis of transposition of the great arteries or similar physiology, detected in four of five postnatally. None of the 157 recorded electrographic seizures had a clinical correlate. The median time to first seizure was 65 minutes (range, 6-300 minutes) after cEEG hookup. The median maximum hourly seizure burden was 12.4 minutes (range, 7-23 minutes). Before the first electrographic seizure, a prolonged interburst interval (>10 seconds) was not associated with seizures (coefficient 1.2; 95% confidence interval, -1.1 to 3.6). MRI brain lesions were three times more common in neonates with seizures. Sharp wave transients on cEEG were associated with delayed opercular development. CONCLUSIONS: In this cohort, preoperative electrographic seizures were common, were all subclinical, and were associated with MRI brain injury and postnatal diagnosis of transposition of the great arteries. The findings motivate further study of the mechanisms of preoperative brain injury, particularly among neonates with a postnatal diagnosis of transposition of the great arteries.

Peritoneal Lavage Cytology Following Neoadjuvant Chemotherapy for Gastric Adenocarcinoma: Low Yield in Detecting Peritoneal Metastases.

BACKGROUND: Peritoneal lavage cytology (PLC) can detect advanced disease in gastric adenocarcinoma (GC); however, routine practice remains controversial. Furthermore, the effect of neoadjuvant chemotherapy (NAC) on cytological detection of carcinomatosis is unknown. METHODS: Using a 2012-2020 prospective database, we retrospectively reviewed patients with GC who underwent NAC followed by a staging laparoscopic peritoneal lavage with or without biopsy of suspicious peritoneal nodules. PLC results were considered discordant if they did not align with the peritoneal biopsy results. Patients with benign peritoneal cytology (Cyt-) or biopsy results who had postoperative time to carcinomatosis of <6 months were considered to have diagnostic failure of peritoneal lavage. RESULTS: Fifty-five patients with GC who underwent NAC followed by staging diagnostic laparoscopy with peritoneal lavage were identified. The majority of the patients in the cohort had Cyt- lavage (89.1%). Of the patients who underwent resection, 76.1% had T3 or greater disease on final pathology and 66% had nodal metastases. In 23 patients (41.8%) who had both peritoneal lavage and biopsy, four cases (17.4%) had discordant results. Diagnostic failure rate was 20% at 6 months and 42.2% at 12 months. The median time to carcinomatosis in patients who were Cyt- or biopsy negative was 7.9 months. CONCLUSION: PLC after NAC has a high diagnostic failure rate and inaccurately predicts carcinomatosis in 20% of patients with GC. Novel methods for identifying cytology positive GC after NAC should also be developed and evaluated, since the risk of peritoneal dissemination is high.

Verifying intervention fidelity procedures for a palliative home care intervention with pilot study results.

Fidelity (consistency of intervention implementation) is essential to rigorous research. Intervention fidelity maintains study internal validity, intervention reproducibility, and transparency in the research conduct. The purpose of this manuscript is to describe intervention fidelity strategies/procedures developed for a pilot study testing a new palliative care nursing intervention (FamPALcare) for families managing advanced lung disease. The procedures described herein are based on the fidelity best practices recommendations from the NIH Consortium. An evidence-based checklist guided observational ratings of the fidelity procedures used and the intervention content implemented in each intervention session. Descriptive data on how participants understood (received), enacted, or used the intervention information were summarized. The fidelity checklist observational scores found ≥93% of the planned intervention content was implemented, and the fidelity strategies were adhered to consistently during each intervention session. The small variation (7%) in implementation was expected and related to participants' varying experiences, input, and/or questions. The helpfulness scale items include participants' ability to use home care resources, to anticipate and manage end-of-life symptoms, and to use Advance Directive forms. The high ratings (M = 4.4) on the 1-5 (very helpful) Likert Helpfulness Scale verified participants utilized the information from the intervention. Furthermore, there was an improvement in patients' breathlessness scores and completion of Advance Directive forms at 3 months after baseline. It is essential to plan intervention fidelity strategies to use throughout a study and to report fidelity results.

Neovascular age-related macular degeneration at treatment intervals of 14 weeks or greater.

BACKGROUND: We assessed the proportion of eyes with neovascular age-related macular degeneration (nAMD) in routine clinical practice that reach ≥14 week treatment intervals and their outcomes. METHOD: We analysed data from the Fight Retinal Blindness! (FRB!) Project database, a prospectively designed registry of 'real-world' outcomes. Treatment-naive eyes starting vascular endothelial growth factor (VEGF) inhibitors for nAMD from 1st January 2006 were included. Eyes were defined to have reached the ≥14 week treatment interval if they received ≥2 consecutive injections at treatment intervals of ≥14 week but not exceeding 26 weeks. Outcomes were reported in a subgroup of eyes that had 12 months of follow-up from reaching this interval. RESULTS: Of the 3907 treatment-naïve eyes that started treatment during the identified periods on a treat-and-extend regimen and received at least 8 injections over the first 2 years, 402 (10%) eyes received at least 2 consecutive injections at an interval of ≥14 week during their follow-up. Fifty-two percent of these eyes maintained vision to 12 months, however only 40% stayed at this interval and 25% of the lesions reactivated. CONCLUSION: We found that only 10% of eyes with nAMD were extended beyond a 13-week injection interval and that over half had returned to a shorter interval by 12 months. Eyes that stayed at this extended treatment interval maintained stable vision. More data on the outcomes of eyes treated with intervals longer than 3 months are required to establish whether emerging VEGF inhibitors provide a more sustained effect than the currently available drugs.

Incidence and trends of ophthalmic cancer in Singapore: Data from Singapore Cancer Registry.

INTRODUCTION: Limited data are available on the incidence of primary ophthalmic cancers worldwide. We describe the incidence and trends of primary ophthalmic cancers in Singapore. METHODS: Data on ophthalmic cancers diagnosed in Singapore from 1996 to 2016 were retrieved from the Singapore Cancer Registry for analysis. All were histologically proven primary ophthalmic cancers. Calculations of incidence and age-specific frequency of ophthalmic malignancy were made. RESULTS: A total of 297 cases were included, with males constituting 59.9%. The race distribution was 78.5% Chinese, 16.5% Malay, 3.7% Indians and 1.3% others. There was an overall increase in ophthalmic malignancies. The mean age of onset was 47.4 years. The most common cancers were retinoblastoma (93.3%) in patients younger than 15 years, and lymphoma (71.3%) in patients aged 15 years and older. There has been an increase in lymphomas from 16.7% in 1968-1995 to 71.3% in 1996-2016 in those aged 15 years and older. The most common types of ophthalmic cancer according to location are lymphoma of the orbit, conjunctiva, cornea and lacrimal gland; retinoblastoma of the retina; and malignant melanoma of the choroid and ciliary body. CONCLUSION: Our study reported the incidence and trends of ophthalmic cancer in the Singapore population and showed an overall increase in ophthalmic malignancies in Singapore from 1996-2016. A substantial increase in lymphomas over the last 2 decades was noted. The data could aid clinicians, epidemiologists and policymakers in implementing strategies to address trends in ophthalmic cancers and spur aetiological research to improve quality of life in patients with such cancers.