Abstract

Background
Platelets stored at 1–6 °C are hypothesized to be more hemostatically active than standard room temperature platelets (RTP) stored at 20–24 °C. Recent studies suggest converting RTP to cold-stored platelets (Delayed Cold-Stored Platelets, DCSP) may be an important way of extending platelet lifespan and increasing platelet supply while also activating and priming platelets for the treatment of acute bleeding. However, there is little clinical trial data supporting the efficacy and safety of DCSP compared to standard RTP.

Methods
This protocol details the design of a multicentre, two-arm, parallel-group, randomized, active-control, blinded, internal pilot trial to be conducted at two cardiac surgery centers in Canada. The study will randomize 50 adult (≥ 18 years old) patients undergoing at least moderately complex cardiac surgery with cardiopulmonary bypass and requiring platelet transfusion to receive either RTP as per standard of care (control group) or DCSP (intervention group). Patients randomized to the intervention group will receive ABO-identical, buffy-coat, pathogen-reduced, platelets in platelet additive solution maintained at 22 °C for up to 4 days then placed at 4 °C for a minimum of 24 h, with expiration at 14 days after collection. The duration of the intervention is from the termination of cardiopulmonary bypass to 24 h after, with a maximum of two doses of DCSP. Thereafter, all patients will receive RTP. The aim of this pilot is to assess the feasibility of a future RCT comparing the hemostatic effectiveness of DCSP to RTP (defined as the total number of allogeneic blood products transfused within 24 h after CPB) as well as safety. Specifically, the feasibility objectives of this pilot study are to determine (1) recruitment of ≥ 15% eligible patients per center per month); (2) appropriate platelet product available for ≥ 90% of patients randomized to the cold-stored platelet group; (3) Adherence to randomization assignment (> 90% of patients administered assigned product).

Discussion
DCSP represents a promising logistical solution to address platelet supply shortages and a potentially more efficacious option for the management of active bleeding. No prospective clinical studies on this topic have been conducted. This proposed internal pilot study will assess the feasibility of a larger definitive study.

Background

Platelets are one of the most commonly used blood products and as such are frequently in short supply. Currently, platelets are stored at room temperature (20–24 °C) to retain post-transfusion circulatory longevity but at the cost of reduced shelf-life, which is part of the reason for the supply challenges. Cold storage (at 1–6 °C) of platelets prolongs their shelf-life while maintaining hemostatic effectiveness in acutely bleeding patients. Thus, converting room temperature-stored platelets (RTSP) before their shelf-life expires to cold-stored platelets may be a good strategy for extending their shelf-life and addressing the platelet supply challenges, but the safety and comparative effectiveness of this strategy in bleeding patients has not been robustly assessed. This pilot study will assess the feasibility of conducting a definitive comparative study of standard room temperature-stored platelets (RTSP) and delayed cold-stored platelets (DCSP).

Platelet transfusion is the primary therapy for platelet-related bleeding (i.e., excessive bleeding due to platelet deficiency or dysfunction). Platelets are one of the most commonly used blood products, particularly in major cardiothoracic surgery with cardiopulmonary bypass where platelet deficiency and dysfunction occur in all patients to varying degrees [1, 2]. As a result, approximately one in four cardiac surgical patients receive at least one platelet transfusion to treat active bleeding in the operating room or soon thereafter, with high levels of variability across institutions. Approximately 10% of the total platelet supply is directed to cardiac surgery alone [3,4,5]. Since the 1970s, standard international practice has been to store platelet units at room temperature (20–24 °C). This preserves the longevity of platelets post-transfusion but limits their storage shelf-life to 7 days for both pooled buffy-coat bacterially cultured and pooled buffy-coat pathogen-inactivated platelets [6]. The short shelf-life of room-temperature platelets (RTP) creates major supply challenges for blood suppliers and hospitals and leads to wastage of up to 30% of platelet units due to outdating [7]. Additionally, existing data suggests that storage at room temperature, while prolonging circulatory survival after transfusion, may in fact impair hemostatic function [8].

Discussion

Cold-stored platelets have been extensively studied in preclinical settings, and pilot trials in humans suggest at least comparable efficacy with no increased risk for adverse outcomes compared to room-temperature platelets [9, 18, 24, 39]. However, the safety and efficacy of cold-stored platelets have not been evaluated in large clinical trials and these products are not currently approved for use in Canada. Although they may have hemostatic superiority over conventional room-temperature platelets, there is a possibility that cold-stored platelets may increase the risk of thromboembolic events (as they are hemostatically more activated upon transfusion). However, this risk is largely theoretical and has not been demonstrated in prior studies [18, 40]. Nevertheless, we have taken several steps to minimize this risk and to identify it early should it occur. Additionally, while cohort studies have been published examining the impact on patient care of introducing delayed cold-stored platelets during times of shortages, large studies systematically measuring efficacy and safety are lacking [18].

The co-primary feasibility endpoints are adequate enrollment, adequate cold-stored platelet supply, and adequate clinician adherence to randomization assignment. We selected these outcomes because they will indicate what, if any, are the most important protocol modifications required before undertaking a large, definitive trial. Specifically, recruitment and protocol adherence are key common progression criteria for internal pilots of efficient RCTs [33], and confirming an adequate supply of cold-stored platelets at the time of transfusion is a critical metric for ensuring the feasibility of the definitive trial.

The planned primary outcome for the definitive study will be the mean number of ABCs transfused (including red cells, plasma, and platelets) within 24 h of CPB end. This outcome is an accepted measure of hemostatic efficacy that captures clinically relevant differences between study arms. It has been used as a primary outcome in a large randomized controlled trial comparing fibrinogen concentrate to cryoprecipitate in cardiac surgical patients in Canada [26, 28]. This outcome was used to support Canadian regulatory approval of fibrinogen concentrate in cardiac surgical patients, demonstrating its validity and importance for key regulatory stakeholders, and was a recommended outcome from the recent NHLBI Hemostasis Clinical Trial Outcomes Working Group [41].

Abstract

     Cancer screening is a source of much debate. At the interface between public health, specialist care, economics and public health policy, it creates tensions between professional groups, politicians, the media and the public. A screening test may be cheap but applying it to a population (with rigorous quality control and effective downstream processing of patients with abnormal results) creates a huge workload and cost. Screening can also have profound psychological effects. People with false-positive results require investigation yet are usually eventually found not to have cancer. Unless screening can be shown to reduce mortality from specific cancers, the resources used are better spent on improving care, and this has led to disparities in screening recommendations between countries. Advances in understanding the genetic basis of cancer are likely to provide new approaches to cancer risk assessment and new challenges for developing screening strategies, by risk-banding populations based on polymorphisms in low-penetrance cancer risk genes. The American Cancer Society guidelines for cancer screening, reviewed annually, represent a global gold standard that is difficult to emulate in most healthcare economies because of cost and under-capacity for downstream processing of abnormal findings. Tailoring cancer screening recommendations to a country’s health economy is an essential public health intervention.

Introduction

     Cancer screening seems so logical to all healthcare workers and patients alike. We all know that early cancer is curable in the majority of cases and later stage disease is not. So, picking up cancer before a patient has symptoms would seem ideal. The problem is that none of the tests available are perfect. And the resources spent on screening programmes may well be better spent on speeding up appropriate referral of symptomatic patients. Here, we will consider the advantages of screening along with the downside for the common cancers.

     The long-awaited publication of the independent review on national cancer screening programmes in England makes grim reading.1 Two disastrous information technology failures e one in breast cancer and the other in cervical cancer e were revealed in 2018. Thousands of patients were simply deleted from the computer database by accident. New technologies such as the faecal immunochemical test (FIT) and once-only colonoscopy programmes are still not fully rolled out even though plans were unveiled 8 years ago. And although much talked about, artificial intelligence currently plays little part in data interpretation except in research settings. Crucially, the consumer uptake of each of the three major programmes e breast, colon and cervix e is in decline, especially in deprived areas. The impact of coronavirus disease (COVID-19) has been severe and services are only just beginning to clear the huge backlog generated.2

The future

     New technology such as the microanalysis of circulating DNA e so-called liquid biopsy e could radically change the situation. Future changes in cancer screening will lead to profound ethical, educational, commercial and medical challenges. Completion of the Human Genome Project, the ability to handle large volumes of sequence data, and rapid and inexpensive assays for mutations using gene-chip technology will transform the assessment of cancer risk. Commercial pressures have caused the major pharmaceutical companies to invest heavily in genomics, and their interest will lead to the discovery of new drugs and more specific tailoring of therapies to individual patients. It is likely that groups of individuals with no family history of cancer will be identified as being at significantly increased risk of developing cancer. Devising optimal screening schedules for such groups will be a major challenge.

     The biggest problem of all is motivating the customers. The compliance rate varies enormously across the world, driven by education, socioeconomic factors and deprivation.5 The educated worried well are likely to go for every free test offered by the health system. The socially excluded residents of the neighbouring poorer districts on the wrong side of the tracks will not visit the doctor until they have advanced stage 4 cancer. And yet private clinics offer top of the range health screening for >£3000 of scans and tests to the gullible wealthy with no evidence of benefit. To save lives most effectively, we must target the poor.

Abstract

Cancer vaccines based on tumor cell components have shown promising results in animal and clinical studies. The vaccine system contains abundant tumor antigen components, which can activate the immune system by antigens. However, their efficacy has been limited by the inability of antigens delivery, which are the core components of vaccines, further fail to be presented and activation of effective cells. Nanotechnology offers a novel platform to enhance the immunogenicity of tumor-associated antigens and deliver them to antigen-presenting cells (APCs) more efficiently. In addition, nanotreatment of tumor cells derivate active ingredients could also help improve the effectiveness of cancer vaccines. In this review, we summarize recent advances in the development of cancer vaccines by the combination of nanotechnology and tumor-based ingredients, including liposomes, polymeric nanoparticles, metallic nanoparticles, virus-like particles and tumor cells membrane, tumor lysate, and specific tumor antigens. These nanovaccines have been designed to increase antigen uptake, prolong antigen presentation, and modulate immune responses through codelivery of immunostimulatory agents. We also further discuss challenges and opportunities in the clinical translation of these nanovaccines.

Introduction

Cancer immunotherapy has revolutionized cancer treatment by harnessing the immune system to recognize and attack cancer cells [1–3]. Among various immunotherapeutic approaches, cancer vaccines have attracted significant attention due to their potential to induce long-lasting and specific immune responses against tumor cells [4–7]. By comparison with surgery, it hardly produce large wounds, nor does it cause higher toxicity in normal tissues and drug tolerance like chemotherapy in the treatment of tumor. However, the clinical efficacy of cancer vaccines based on tumor cell components, such as peptides and proteins, is limited by their poor immunogenicity and inefficient delivery to antigen presentation cells (APCs). Although, many cancer vaccines were applied with the immune-stimulatory agents, such as the programmed cell death protein 1 (PD-1), CpG oligonucleotide, etc. The clinical response rates remain low, especially in the hypoimmunogenic tumors. As we all know, pancreatic cancer is a more difficult type for immunotherapy as a low immunogenic tumor. Therefore, there are few effective cancer vaccines that can actively promote the pancreatic cancer treatment. Meanwhile, limited by the specific tumor antigens, the development of cancer vaccines was extremely difficult.

The field of cancer vaccines has seen significant advancements in recent years, with numerous studies focusing on different aspects of vaccine development and application [8–12]. These advances have been facilitated by the exploration of various types of cancer vaccines, including those targeting viral antigens, neoantigens, and other tumor-specific antigens [13–16]. One approach in cancer vaccine research involves targeting shared antigens from viral infections linked to certain cancer types, such as Epstein–Barr virus and HPV. Studies have shown promising results with vaccines targeting viral antigens like Epstein–Barr nuclear antigen 1 and latent membrane proteins, as well as HPV-related antigens, demonstrating favorable antitumor efficacy and the potential to establish durable T cell memory in rapidly progressing HPV-positive tumors [17]. Another significant area of research is neoantigen cancer vaccines. Neoantigens, derived from nonsynonymous cell variants, are only expressed in tumor cells and can bypass thymus-negative selection, leading to robust neoantigen-specific T cell responses [14]. Advances in genomic and transcriptional profiling have made identifying putative neoantigens possible, although challenges remain in predicting which neoantigens can effectively induce neoantigen-specific T cell responses [18–20]. Cancer vaccines are being developed to stimulate antitumor immunity with tumor antigens delivered in various forms, such as cells, peptides, viruses, and nucleic acids [21–24]. These vaccines aim to overcome tumor heterogeneity and reverse the immunosuppressive microenvironment. Challenges in the field include single antigen targeting, weak immunogenicity, off-target effects, and impaired immune response [25–27]. Current research and reviews provide insights into the principle of action, components, classification, delivery methods, and progress of cancer vaccines, offering a broader perspective for future vaccine design.

Recent studies have shown that tumor antigens can be used for the design of cancer vaccines without the necessity to identify, parse, and reconstruct certain antigens [28–31]. A novel concept has been proposed that the whole antigen vaccine systems derived from tumor cells could be designed to conquer cancer treatments [32–34]. The tumor cells themselves are a huge antigen pool with countless tumor antigen epitopes, which can be used to activate antitumor immune response. Among them, more studies have focused on the application of tumor cell membrane as tumor antigens to stimulate APCs and further activate the antitumor immune response of T cells. In addition, the activation of T cells in immune response requires the involvement of costimulatory molecules. Some studies are based on this theoretical foundation, using genetic engineering to modify tumor cell membranes. By retaining antigen on the cell membrane and inducing the expression of costimulatory molecule CD80, T cells can be directly activated, thereby achieving antitumor immune response [35] (Figure 1). Of course, many studies combine tumor cell membranes that retain tumor antigens with other functional molecules to directly activate dendritic cells (DCs) for antigen presentation, leading to the activation of T cell immune response. These are two different approaches aimed at achieving the same goal [36–38]. A series of nanovaccines developed on this basis have been widely used in the treatment of different tumor cells and preclinical experiments.

Abstract

Axillary surgery for patients with breast cancer (BC) in 2024 is becoming increasingly specific, moving away from the previous ‘one size fits all’ radical approach. The goal is to spare morbidity whilst maintaining oncologic safety. In the upfront surgery setting, a first landmark randomized controlled trial (RCT) on the omission of any surgical axillary staging in patients with unremarkable clinical examination and axillary ultrasound showed non-inferiority to sentinel lymph node (SLN) biopsy (SLNB). The study population consisted of 87.8% postmenopausal patients with estrogen receptor-positive, human epidermal growth factor receptor 2-negative BC. Patients with clinically node-negative breast cancer and up to two positive SLNs can safely be spared axillary dissection (ALND) even in the context of mastectomy or extranodal extension. In patients enrolled in the TAXIS trial, adjuvant systemic treatment was shown to be similar with or without ALND despite the loss of staging information. After neoadjuvant chemotherapy (NACT), targeted lymph node removal with or without SLNB showed a lower false-negative rate to determine nodal pathological complete response (pCR) compared to SLNB alone. However, oncologic outcomes do not appear to differ in patients with nodal pCR determined by either one of the two concepts, according to a recently published global, retrospective, real-world study. Real-world studies generally have a lower level of evidence than RCTs, but they are feasible quickly and with a large sample size. Another global real-world study provides evidence that even patients with residual isolated tumor cells can be safely spared from ALND. In general, few indications for ALND remain. Three randomized controlled trials are ongoing for patients with clinically node-positive BC in the upfront surgery setting and residual disease after NACT. Pending the results of these trials, ALND remains indicated in these patients.

Introduction

Axillary surgery for breast cancer (BC) has evolved significantly from a previous “one size fits all” approach that involved radical surgery, including lymph node dissection extending from the axilla to the neck, to an increasingly granular and individualized surgical treatment. Axillary lymph node dissection (ALND) was the standard of care for all patients with BC until the nineties, which was considered to be a therapeutic procedure. The rationale behind it was that a complete surgical removal of locoregional tumor residues would result in improved survival, a hypothesis that has never been proven and was already questioned by the NSABP-04 trial [1,2,3]. In this landmark study, patients with clinically node-negative and node-positive BC were shown to have similar 10-year overall survival outcomes, no matter whether ALND or axillary radiotherapy (ART) were performed [3]. These results could be confirmed in clinically node-negative patients, who underwent breast-conserving surgery (BCS) and adjuvant radiotherapy of the breast [4]. Therefore, radical surgery and its associated morbidity was increasingly questioned. Axillary staging information was still deemed necessary, leading to the development of the sentinel lymph node (SLN) biopsy (SLNB). Whilst showing a false-negative rate of around 10%, excellent oncologic outcomes were achieved [5,6,7,8]. Notably, SLNB dramatically reduced surgical morbidity and improved quality of life [5,9,10,11,12,13,14,15,16,17]. Nevertheless, approximately 5% of patients still experience surgery-related morbidity [9]. Therefore, studies to identify patients in whom surgical axillary staging can be altogether abandoned have been initiated.

Conclusions

Efforts to de-escalate axillary surgery in BC have led to major changes in treatment paradigms, sparing thousands of women the associated morbidity of ALND whilst remaining oncologically safe, as shown in randomized controlled trials with a high level of evidence. Few indications for ALND remain, with real-world studies being indicative of safe omission possibilities even if ITCs are found after NACT. Such studies generally have a lower level of evidence. However, they can address clinically relevant questions in a global manner, quickly, with the largest number of participants, and therefore the strongest statistical power available. For patients with clinically node-positive BC, the results of three randomized controlled trials—namely, the Alliance A011202 trial, the ADARNAT trial, and the OPBC-03/TAXIS trial—are eagerly awaited.

Abstract

One in eight women will develop breast cancer in the US. For women with moderate (15–20%) to average (12.5%) risk of breast cancer, there are few options available for risk reduction. For high-risk (>20%) women, such as BRCA mutation carriers, primary prevention strategies are limited to evidence-based surgical removal of breasts and/or ovaries and anti-estrogen treatment. Despite their effectiveness in risk reduction, not many high-risk individuals opt for surgical or hormonal interventions due to severe side effects and potentially life-changing outcomes as key deterrents. Thus, better communication about the benefits of existing strategies and the development of new strategies with minimal side effects are needed to offer women adequate risk-reducing interventions. We extensively review and discuss innovative investigational strategies for primary prevention. Most of these investigational strategies are at the pre-clinical stage, but some are already being evaluated in clinical trials and others are expected to lead to first-in-human clinical trials within 5 years. Likely, these strategies would be initially tested in high-risk individuals but may be applicable to lower-risk women, if shown to decrease risk at a similar rate to existing strategies, but with minimal side effects.

Introduction

For women in the US, breast cancer (BC) is the most prevalent cancer and the second-leading cause of cancer-related deaths. Projections for 2023 estimate that 55,720 women will be diagnosed with carcinoma in situ, 297,790 with invasive carcinoma, and 43,170 women will die from BC [1]. With the number of new diagnoses still on the rise, one in eight women will develop BC within their lifetime, but all women are at risk. Therefore, there is a need to develop new strategies for primary prevention with a focus on high-risk (>20%) individuals, but that can also be applied to moderate- (15–20%) and average (12.5%)-risk individuals.

There are well-established risk factors that contribute to the absolute risk of developing BC [2,3]. There are modifiable risk factors such as having a healthy diet, regular exercise, and limiting alcohol consumption [2,4]. Cumulative exposure of breast tissue to estrogen is an important risk factor for BC. This risk can be minimized by various actions such as having their first-born before age 30, limiting the use of hormonal birth control medications, and avoiding hormone replacement therapy. Non-modifiable risk factors that increase cumulative exposure to estrogen include younger age at menarche and older age at natural menopause [2]. There are non-modifiable genetic risk factors that include known mutations in a high-penetrant BC gene such as BRCA1 and BRCA2, cumulative interaction of risk-associated alleles of BC susceptible SNPs, and/or family history with multiple incidences of BC [5]. There are also non-modifiable risk factors related to the personal history of radiation therapy to the chest, and the number of breast biopsies [4].

Conclusions and Future Directions

BC is the leading cause of new cancer cases and is the second leading cause of cancer-related deaths in women. The limited, approved prevention interventions available for high-risk individuals can have severe and long-term side effects that deter many women from making proactive choices. Regrettably, BC prevention is an area of translational research that is currently underfunded by federal agencies [182]. Therefore, emerging and novel approaches for the primary prevention of BC that provide the same or superior protection while minimizing the side effects of current interventions should be pursued and prioritized. These approaches seek to eradicate BC and align well with NIH’s All of US Research Program—a nationwide initiative for precision health interventions that proactively prevent rather than treat disease in high-risk individuals. We provide a comprehensive review of emerging approaches for BC prevention based on non-modifiable risk factors that put women at a higher risk of developing BC. Virtually all of these studies were performed in rodent models of BC, which have some limitations and challenges for direct translation to at-risk individuals. Additional scalability and validation studies in larger animal models will be an important step in bridging the gap between discovery and clinical evaluation. Although currently underutilized, rabbit studies should be considered as an appropriate intermediate model. Evolutionarily, anatomically, and physiologically, rabbit mammary glands are more similar to humans than those of rodent models or other large animals such as cows and sheep [183,184]. Female rabbits have four pairs of mammary glands each containing four ductal trees [177], which can be cannulated for ID injection [177,185,186,187,188,189] using a procedure very similar to ID administration of contrast agents in clinical ductography [190,191] and chemotherapeutic agents in first-in-human clinical research [92,145]. Alternatively, or complementary to validation studies in larger animals, judicious determination based on the scientific rigor and clinical feasibility of these emerging approaches should be applied to prioritize those interventions more likely to have an impact on primary prevention of BC.

Abstract

Breast cancer affected more than 2.3 million women in 2022 and is the most diagnosed cancer among women worldwide. The incidence rates are greater in developed regions and are significantly higher among women with higher education and socioeconomic status. Therefore, it is reasonable to assume that the way women live their lives may impact their risk of being diagnosed with breast cancer. This systematic review aimed to identify what is known about the causes and risk factors of breast cancer, excluding genetic causes. A comprehensive systematic search identified 2387 systematic reviews, 122 were included and six overall themes identified. In our “top list” with the 36 most important findings, a study of breast density had the highest effect size for increasing the risk of breast cancer, and a high sex-hormone-binding globulin level was the most protective factor. Many of the included studies investigating the same topics had conflicting results. The conclusion from this evidence synthesis reveals a lack of consensus of factors associated with the causes and risk of breast cancer. These findings suggest that recommendations about lifestyle and breast cancer should be made with caution.

Introduction

Breast cancer affected more than 2.3 million women in 2022 and is the most diagnosed cancer among women worldwide [1,2]. Breast cancer is also the number one cause of death from cancer in women; 670,000 women died from this disease in 2022 [2]. That is approximately 7% of all cancer deaths worldwide. The incidence rates are greater than 80 per 100,000 in developed regions of the world, such as Europe and North America, Australia, and New Zealand, and less than 40 per 100,000 in developing countries [3,4]. However, statistics from some developing countries may be attributed to underreporting [5]. The differences in incidence between countries could be due to changes in exposure to environmental risk factors, behavior, and lifestyle factors of different population groups [6]. These facts provide good reasons to study the causes and risk factors of breast cancer.

The causes of breast cancer in women are still unclear, and nonhereditary causes and risk factors predominate [7]. These include early menarche, hormone intake, nutrition, alcohol consumption, smoking, and obesity, all of which are commonly reported as risk factors [6]. Heredity accounts for only 5–10% of breast cancer cases, with germline mutations in BRCA1 or BRCA2 accounting for 30% of inheritable breast cancer cases [7]. Several researchers are working on the identification of specific genes as a cause of breast cancer, while others are conducting studies on the combinations of genes and other factors [8]. A study published in the Lancet in 2005 concluded that 21% of all breast cancer deaths worldwide were attributable to physical inactivity, overweight and obesity, and alcohol use [9]. An update from 2017 examined the connection between breast cancer incidence and environmental factors such as chemicals and radiation and found that exposure to these substances may lead to an increased risk of developing breast cancer [10]. However, numerous studies have identified late age of first full-term (if any) pregnancy, short periods of breast-feeding, dietary habits, quality and composition of meals, physiologic factors, lower age at menarche, and later menopause as causes and risk factors of breast cancer in women [11].

Conclusions

Six overall themes and more than 27 topics were identified. In our “top list” of the 36 most important findings, high breast density had the highest effect size for increasing the risk of breast cancer, and a high sex-hormone-binding globulin level was identified as the most protective factor in decreasing breast cancer risk. Notwithstanding the comprehensive work in performing these studies, there is still a large degree of uncertainty with respect to what exactly triggers or may influence or cause breast cancer. Unfortunately, this extensive work has not provided a clear and convincing answer as to why women develop breast cancer. Based on our review, however, it is important to point out this lack of consensus because the recommendations from some health authorities use several uncertain consensus statements to guide us to a healthy lifestyle. We therefore argue that this review of systematic reviews provides a valuable contribution to the research portfolio regarding breast cancer in women. We also argue that it highlights that health professionals should be careful because there still remains a great deal of uncertainty regarding the risk factors and causes of breast cancer in women.

Abstract

Purpose
There is scarce comparative effectiveness research on the new treatment modalities for localized prostate cancer. We aim to compare through Patient-Reported Outcome Measures (PROMs) the impact of active surveillance, robot-assisted radical prostatectomy (RARP), intensity-modulated radiotherapy (IMRT), and real-time brachytherapy, considering side effects (incontinence, irritative/obstructive urinary symptoms, sexual dysfunction and bowel symptoms) and physical and mental health.

Materials and Methods
Prospective cohort of men diagnosed with clinically localized prostate cancer (age 50-75y, T1-T2, and low risk including Gleason 3 + 4 in T1c) from 18 Spanish hospitals, followed up to 24 months. Treatment decisions were jointly made by patients and physicians (n = 572). The Expanded Prostate cancer Index Composite (EPIC-26) and Short-Form 36 (SF-36v2) were administered through telephone interviews before and three, six, 12, and 24 months after treatment. To account for correlation among repeated measures, generalized estimating equation models were constructed. All analyses were performed with propensity score weights to solve treatment selection bias.

Results
The PROMs completion rate at 24 months was 95.0 %. Active surveillance entails the fewest side effects, but with significant sexual (0.4 standard deviations [SD], p < 0.001) and physical health deterioration (0.5 SD, p < 0.001); and moderate mental health improvement (0.4 SD, p = 0.001) at 24 months. Compared with active surveillance, RARP presented greater urinary incontinence (p = 0.030), and IMRT and real-time brachytherapy worse bowel symptoms (p = 0.027 and p = 0.007) at 24 months.

Conclusions
Most side effects of the new treatment modalities seem to be limited to short-term deteriorations, except for moderate-large urinary incontinence in patients who had undergone RARP and moderate bowel deterioration in patients treated with IMRT or with real-time brachytherapy. Furthermore, patients under active surveillance, IMRT, and real-time brachytherapy showed a moderate improvement in mental health.

Introduction

Prostate cancer is the most frequently diagnosed non-cutaneous cancer among men in USA and Europe [1], and most patients are diagnosed in localized stages [2], becoming long-term survivors [3]. Randomized controlled trials of curative intention treatments for localized prostate cancer are mainly restricted to the ProtecT (Prostate Testing for Cancer and Treatment) trial [4], [5]. This study showed similar very high rates of survival at ten years of follow-up [4] for radical prostatectomy, external beam radiotherapy and active monitoring, though differing in their side effects’ patterns, evaluated with Patient-Reported Outcome Measures (PROMs) [5]. ProtecT patients were treated in the early 2000s with open retropubic radical prostatectomy, external beam 3D-conformal radiotherapy (delivered at 74 Gy in 37 fractions), and active monitoring.

New modalities of the same treatments are being widely used, such as robot-assisted radical prostatectomy (RARP), intensity-modulated radiation therapy (IMRT), or real-time brachytherapy, with the theoretical justification that they are less aggressive and could achieve maximum efficacy in oncological results with a lower rate of side effects. RARP has shown to be an easily acquired laparoscopic technique, with shorter learning curves than the open procedure [6]. IMRT has allowed treating patients with higher doses of radiation, without increasing toxicity in surrounding healthy tissues [7]. Real-time brachytherapy allows correcting radioactive seed distribution and doses at the time of their implantation, achieving better target coverage and sparing normal tissues [8].

The rapid adoption of newer modalities has introduced additional uncertainty to the decision-making process. On the one hand, despite the theoretical advantages, the randomized clinical trial comparing RARP with open radical prostatectomy did not find significant benefits in PROMs [9]. On the other hand, the randomized clinical trial comparing IMRT with 3-D conformal radiotherapy reported differences in urinary, bowel and other treatment-related symptoms, in favor of the new technique [7]. The only recent study comparing real-time with pre-planned low-dose rate brachytherapy as a monotherapy did not show any differences in toxicity, though PROMs were not included [8].

Conclusions

In conclusion, in this cohort of men with localized prostate cancer strictly treated with new treatment modalities, side effects mainly disappeared by the 24-month follow-up, except for the moderate-large urinary incontinence in patients who underwent RARP and the moderate bowel deterioration in those treated with IMRT and brachytherapy. Therefore, most side effects of new treatment modalities seem to be limited to short-term deteriorations. On the other hand, patients under active surveillance, IMRT, and real-time brachytherapy showed a moderate improvement in mental health. It is important to consider each patient’s preferences regarding their treatment strategy, with personalized information about the potential risks and benefits, during the shared decision-making process.

Abstract

Cancer vaccines, designed to activate the body’s own immune system to fight against tumors, are a current trend in cancer treatment and receiving increasing attention. Cancer vaccines mainly include oncolytic virus vaccine, cell vaccine, peptide vaccine and nucleic acid vaccine. Over the course of decades of research, oncolytic virus vaccine T-VEC, cellular vaccine sipuleucel-T, various peptide vaccines, and DNA vaccine against HPV positive cervical cancer have brought encouraging results for cancer therapy, but are losing momentum in development due to their respective shortcomings. In contrast, the advantages of mRNA vaccines such as high safety, ease of production, and unmatched efficacy are on full display. In addition, advances in technology such as pseudouridine modification have cracked down the bottleneck for developing mRNA vaccines including instability, innate immunogenicity, and low efficiency of in vivo delivery. Several cancer mRNA vaccines have achieved promising results in clinical trials, and their usage in conjunction with other immune checkpoint inhibitors (ICIs) has further boosted the efficiency of anti-tumor immune response. We expect a rapid development of mRNA vaccines for cancer immunotherapy in the near future. This review provides a brief overview of the current status of mRNA vaccines, highlights the action mechanism of cancer mRNA vaccines, their recent advances in clinical trials, and prospects for their clinical applications.

Introduction

Cancer is currently one of the most challenging problems adversely affecting human health. The unique immunosuppressive state of the tumor microenvironment (TME) attracts much attention in the field of cancer therapy. Cancer immunotherapy aims to boost the patient’s anti-tumor immune system, change the TME, promote cancer cell death and ultimately improve the cancer survival rate. Although ICIs have been proved to be effective in treating a variety of cancers, the overall response rate in patients is quite moderate. So, there is an urgent need to enhance the efficacy of current cancer immunotherapies.

Cancer vaccine is a major breakthrough in use of antigens to activate the human immune system against malignant tumors. Cancer vaccines fall into several broad categories, including oncolytic viruses (OVs), cellular vaccine, peptide vaccine, and nucleic acid vaccine.

OVs are natural or genetically engineered viruses that can infect and replicate in cancer cells, thereby directly killing infected cells and inducing systemic anti-tumor immunity [1,2]. Several OVs have entered into clinical trials such as adenovirus, poxviruses, herpes simplex virus type I (HSV-1), and coxsackievirus [3]. Talimogene laherparepvec (T-VEC), the first attenuated HSV-1 vaccine approved by the FDA, encodes granulocyte-macrophage colony-stimulating factor (GM-CSF) and promotes anti-tumor immune response and prolongs the median survival rate of patients with melanoma [2,[4], [5], [6]]. In addition, OVs have a synergistic effect on cancer therapy in combination with chemotherapy, radiotherapy or chimeric antigen receptor T cell (CAR-T) immunotherapy [1,7,8]. It also shows the potential of transforming immunosuppressive “cold” tumors into “hot” tumors [9]. However, OVs are live viruses prone to propagation, which may lead to uncontrollable dose changes and suffering from the host antiviral immune response [10].

Conclusion and perspectives

With the development of molecular biology, mRNA vaccines have brought unprecedented hopes for cancer immunotherapy. Historically, the use of mRNA vaccines has been limited by instability, innate immunogenicity and low efficiency of in vivo delivery. Improvements in mRNA structure (e.g., codon optimization, nucleotide modification, selfamplifying mRNA; etc.) and delivery vehicles (e.g., LNPs, polymers, peptides;etc.) have largely overcome these barriers. Compared to other cancer vaccines, mRNA vaccines stand out for several reasons: (1) An mRNA vaccine can encode multiple antigens simultaneously which bind to both MHC-I and MHC-II to promote humoral and cellular immune responses. (2) Compared to DNA vaccines, mRNA vaccines are nonintegratable, therefore free of mutagenic risk. (3) mRNA produced by IVT is free of pathogenic viral components and with no potential of infection. (4) Cancer mRNA vaccines offer the advantages with low costs, rapid production, and convenient renewal.

However, the mRNA field still faces challenges in terms of immunogenicity and effectiveness. Systemic inflammatory response may be the main concern for mRNA cancer vaccines, as mRNA inherently possesses immunostimulatory functions by activating the TLR7/8 pathway and inducing an IFN-I response. Currently, the innate immune response mediated by IFN-I can be largely reduced by removal of dsRNA contaminants, codon optimization and nucleotide modification. Another challenge is to determine the most feasible administration route for the vaccine. The administration route dictates the distribution of mRNA and influences the vaccine’s efficacy. Muscle injection is a common and viable administration route, currently, FDA-approved SARS-CoV-2 mRNA vaccines are delivered through muscle injection [114]. However, intravenous injection allows mRNA to reach many lymphoid organs, and this administration method has been proven to stimulate a robust CD8+ T cell anti-tumor immune response. Therefore, intravenous injection is the most commonly used direct administration route in mRNA cancer vaccine trials.

Abstract

Lymphoma and leukemia are fatal syndromes of cancer that cause other diseases and affect all types of age groups including male and female, and disastrous and fatal blood cancer causes an increased savvier death ratio. Both lymphoma and leukemia are associated with the damage and rise of immature lymphocytes, monocytes, neutrophils, and eosinophil cells. So, in the health sector, the early prediction and treatment of blood cancer is a major issue for survival rates. Nowadays, there are various manual techniques to analyze and predict blood cancer using the microscopic medical reports of white blood cell images, which is very steady for prediction and causes a major ratio of deaths. Manual prediction and analysis of eosinophils, lymphocytes, monocytes, and neutrophils are very difficult and time-consuming. In previous studies, they used numerous deep learning and machine learning techniques to predict blood cancer, but there are still some limitations in these studies. So, in this article, we propose a model of deep learning empowered with transfer learning and indulge in image processing techniques to improve the prediction results. The proposed transfer learning model empowered with image processing incorporates different levels of prediction, analysis, and learning procedures and employs different learning criteria like learning rate and epochs. The proposed model used numerous transfer learning models with varying parameters for each model and cloud techniques to choose the best prediction model, and the proposed model used an extensive set of performance techniques and procedures to predict the white blood cells which cause cancer to incorporate image processing techniques. So, after extensive procedures of AlexNet, MobileNet, and ResNet with both image processing and without image processing techniques with numerous learning criteria, the stochastic gradient descent momentum incorporated with AlexNet is outperformed with the highest prediction accuracy of 97.3% and the misclassification rate is 2.7% with image processing technique. The proposed model gives good results and can be applied for smart diagnosing of blood cancer using eosinophils, lymphocytes, monocytes, and neutrophils.

Introduction

Leukemia and lymphoma are the most frequent kinds of blood cancer in people of all ages, particularly young people. This abnormal situation is induced by red blood cell proliferation and immature growth, which can harm red blood cells, bone marrow, and the immune system [1]. Leukemia accounts for more than 3.5% of new cancer cases in the United States, with over 50,000 new cases diagnosed in 2018 [2]. Cancerous lymphoblasts in the blood travel to other organs, including the heart, brain, lungs, and arteries, before spreading to important tissues throughout the body. Red blood cells are normally in charge of transporting oxygen from the heart to all organs. They make up half of the total blood volume. White blood cells, on the other hand, serve an important role in the human immune system, serving as the first line of protection against a variety of diseases and disorders [3]. As a result, accurately identifying these white blood cells is crucial in understanding the symptoms of the problem. Their categorization is determined by their cytoplasmic composition. Changes in lymphocytes, a kind of white blood cell, cause acute lymphoblastic leukemia [4]. Acute or chronic leukemia are the two types of leukemia. Without treatment, the typical recovery period for acute myeloid leukemia is roughly three months; however, the time of appearance of chronic leukemia is longer than that of acute leukemia. Chronic lymphoblastic leukemia is the most common kind of acute leukemia, accounting for around 25% of all juvenile malignancies [5, 6]. Early detection of leukemia and lymphoma has always been difficult for researchers, clinicians, and hematologists. Leukemia symptoms include enlarged lymph nodes, paleness, fever, and weight loss, although these symptoms can also be caused by other diseases [7]. Because of the moderate nature of the symptoms, diagnosing leukemia and lymphoma in its early stages is challenging. PBS microscopic assessment is the most often used leukemia and lymphoma diagnostic approach, while the gold standard for leukemia and lymphoma diagnosis only entails obtaining and analyzing white blood cell samples [8]. Several research have utilized machine learning and deep learning and machine diagnostics approaches to laboratory image processing during the last two decades in the hopes of pushing the boundaries of late diagnosis of leukemia and lymphoma and establishing their subtypes [9]. In this research, blood smear pictures were evaluated to diagnose, distinguish, and count cells in distinct kinds of leukemia and lymphoma [10].

Conclusion

The early detection of blood cancer using white blood cells can help meritoriously in its cure. The study’s proposed framework consists of three transfer learning models AlexNet, MobileNet, and ResNet empowered with SGDM, ADAM, and RMSPROP. The proposed framework applies all transfer learning models with varying learning rates effectively to white blood cancerous cells for early classification. To enhance the results, the proposed study used image processing techniques incorporating transfer learning and achieved the highest CA of 97.3% and 2.7% MCR. All experiments in the proposed study are comprehensively explained with respect to every model training and testing phase. This study helps health 5.0 to predict blood cancer in its early stages for early treatment. Furthermore, in the future, federated machine learning using the fed average technique will play a major role in better early prediction of blood cancer empowered with fuzzed machine learning and deep learning techniques will also apply more statistical techniques such as ANOVA and Chi-Square.

Abstract

Aim. This study investigated the effect of tumor size and other factors on the survival and prognosis of hepatocellular carcinoma (HCC). Methods. All HCC populations based on the National Cancer Institute’s SEER database to receive from 2010 to 2016 were employed in the study. Results. This study enrolled a total of 14,634 HCC. Among them, 1,686 patients had tumors ≤ 2 cm, 6,169 patients had tumors 2–5 cm, and 6,779 patients had tumors > 5 cm. The results using univariate analysis showed that all factors were significant prognostic factors for overall survival and specific survival. Patients with tumor size ≤ 2 cm were more likely to survive, while patients with tumor size > 5 cm had a lower survival rate. Patients who had surgery or surgery plus chemotherapy had a higher chance of survival in stages I-II, and the survival rate declined smoothly during the 80 months. The change rate of the mortality rate increased rapidly during the period of 1–12 cm; afterwards, the mortality rate’s HR was basically and smoothly maintained at a high level. Conclusions. Tumor size was positively correlated with the mortality rate of HCC. Survival rates were greater in patients with tumors ≤ 2 cm who underwent surgery or surgery plus chemotherapy. Patients with HCC in the early stage had a higher survival probability particularly when they had experienced surgery or surgery plus chemotherapy.

Introduction

Hepatocellular carcinoma (HCC) with an extremely high mortality rate is one of the most common malignant tumors. Previous study [1] showed the HCC has the poor of prognosis, and its survival rate of 5-year was under 20%. HCC has a special feature: growth with metastasis to distant organs, which accounts for poor survival. The HCC with distant metastasis is commonly found in the lungs, bones, and brain [2]. Moreover, the most common risk factor for HCC globally is the hepatitis B virus. In a previous study, the most common causative agent was the hepatitis C virus [3]. More than 90% of primary liver cancers are HCC [4]. In recent years, relevant research studies confirmed that specific therapeutic regimens, including surgical resection, chemotherapy, and radiotherapy, provided HCC patients favorable prognosis and long-term survival. The current meta-analysis from Francesca’s study [5] found that regorafenib was a safe and effective treatment option for patients with advanced HCC. In addition, the efficacy and safety of microwave ablation and radiofrequency ablation were similar, but microwave ablation reduced the long-term recurrence rate [6]. A review summarized the trajectory of various aspects of HCC management over the last 15 years, providing additional information for clinicians to aggregate [7]. Previous research studies [8] found that HCC patients were more likely to feel hopeless, depressed, and even have serious suicidal thoughts. HCC monitoring for national minority and individuals of lower socioeconomic status was poorly performed, further exacerbating the difference in HCC prognosis among these disadvantaged populations [9]. Current therapeutic regimens, including surgery of liver resection, transplantation, radiotherapy, percutaneous ethanol injection, transarterial chemoembolization, microwave ablation, radiofrequency ablation, cryoablation, irreversible electroporation, combination therapies (such as postoperative adjuvant chemoradiotherapy and nutrition supportive therapy) and palliative care, will create high costs for HCC [10].

Conclusions

This study revealed that the age of majority in HCC was over 50 years old, and the majority of HCC had solid tumor sizes of 2–5 cm and not otherwise specified histology. The incidence of HCC in males was much higher than that in females, and whites also proved to be more than half the population at risk for HCC. Based on different stages, the majority of patients were in the early stages of HCC. Furthermore, HCC patients were distributed in above 2 cm, and the distribution of basic information for different tumor sizes was consistent with the overall populations. Single patients had more challenges than married patients. Otherwise, survival rates were greater in patients with tumor size ≤2 cm who underwent surgery or surgery with chemotherapy. Patients with HCC in the early stage had a higher survival probability, particularly when they had undergone surgery or surgery plus chemotherapy. The most important thing was that we further determined that the larger the tumor, the greater the risk, and that surgical treatment was the major and critical of the three methods.

Abstract

     5-10% of all breast cancers are associated with mutations in hereditary breast cancer genes several of which are involved in the DNA damage response.

     BRCA1 and BRCA2 mutation is not associated with poor prognosis in breast cancers, but infact better prognosis when treated with chemotherapy in comparison to similar non BRCA mutated breast cancers.

    Treatment with the small molecule PARP inhibitor olaparib after chemotherapy improves overall survival in patients with early breast cancer and germline BRCA1 or BRCA2 mutations.

     Platinum based chemotherapy is highly active in those with germline BRCA1 or BRCA2 mutations but cross resistance between platinum agents and PARP inhibitors can be mediated by somatic “reversion mutations” in BRCA1 or BRCA2 and is a clinical challenge.

     Understanding the underlying mechanisms of overlapping or distinctive resistance is vital to therapy development in this evolving area of translational medicine.

Introduction

     Approximately 5% to 10% of the 2.3 million breast cancer cases diagnosed annually are associated with a mutation in a known hereditary breast cancer predisposition gene such as BRCA1 or BRCA2.1,2 The integration of genomics into the standard diagnostic pathways for breast cancer patients and the availability of targeted treatment approaches for those with hereditary breast cancer predisposition gene mutations means that the management of these patients is now distinct to that a decade ago. In this review, we discuss the recent advances made in systemic treatments for hereditary breast cancer and highlight future challenges that must be addressed for improvements in clinical outcomes to be achieved in this distinct subgroup.

Hereditary Breast Cancer Genes

     Many of the germline mutations associated with hereditary breast cancer occur in “caretaker” tumor suppressor genes (genes whose normal function is to maintain the integrity of the genome and whose dysfunction leads to genome instability) and include BRCA1, BRCA2, PALB2, ATM, CHEK2, and p53.3 For example, germline deleterious mutations in BRCA1 (gBRCA1m) or BRCA2 (gBRCA2m), which play key roles in DNA repair by homologous recombination (HR), are associated with an increased lifetime risk of developing breast, ovarian, prostate and pancreatic cancer.2,4,5 gBRCA1m carriers have a cumulative lifetime breast cancer risk of 46% to 60% and when diagnosed with breast cancer typically have the basal-like, triple negative (B-L, TNBC), subtype of the disease. gBRCA2m carriers have a cumulative lifetime breast cancer risk of 43% to 55% and tend to develop estrogen receptor-positive (ER+), luminal B subtype, breast cancers (significantly more so than for gBRCA1m carriers).6, 7, 8, 9 gBRCA1/2m breast cancers in those who have a strong family history are usually detected at a younger age than sporadic breast cancers.

Disclosure

     E.H.-J. is a clinical PhD fellow funded by Cancer Research UK and AstraZeneca. A.T. is a consultant for AstraZeneca, Merck KGaA, Artios, Pfizer, Vertex, GE Healthcare, Inbiomotion, MD Anderson Cancer Centre; has received grant/research support from AstraZeneca, Myriad, Medivation, and Merck KGaA; and is a stockholder in Inbiomotion. Stands to gain from the use of PARP inhibitors as part of the ICR’s “rewards to inventors” scheme. C.J.L. makes the following disclosures: receives and/or has received research funding from: AstraZeneca, Merck KGaA, Artios. Received consultancy, SAB membership or honoraria payments from: Syncona, Sun Pharma, Gerson Lehrman Group, Merck KGaA, Vertex, AstraZeneca, Tango, 3rd Rock, Ono Pharma, Artios, Abingworth, Tesselate, Dark Blue Therapeutics. Has stock in: Tango, Ovibio, Enedra Tx., Hysplex, Tesselate. C.J.L. is also a named inventor on patents describing the use of DNA repair inhibitors and stands to gain from their development and use as part of the ICR “Rewards to Inventors” scheme.

Abstract

Breast cancer is one of the main cause of cerebral and leptomeningeal metastases, the prognosis of which remains poor to this day. Most studies excluded patients with active brain metastases (BM) and particularly with leptomeningeal metastases (LM) explaining the lack of therapeutic innovation in this area. Currently, the standard management of patients with BM of breast cancer is based on the combination of surgery, radiotherapy and systemic treatments. Recently, third-generation of Antibody-Drug Conjugates (ADCs), have revolutionized the management of metastatic breast cancer. Trastuzumab deruxtecan and Sacituzumab govitecan have indeed shown significant improvements of survival outcomes and can now be used in a wide range of breast cancer subtypes. However, few data are available on the efficacy of third-generation ADCs on BM and LM of breast cancer. As the field of ADCs is rapidly evolving, with new constructs entering the late clinical development, in this review we describe the efficacy of approved and novel promising conjugates on patients with BM and LM of breast cancer.

Introduction

Brain metastases (BM) frequently occur in patients with advanced solid tumors, leading to significant morbidity and mortality. Although the incidence of BM varies across tumor histologies, it is estimated that 10 to 25% of patients with metastatic cancer will develop BM during the course of their disease [1], [2], [3]. Among these tumors, breast cancer (BC) ranks as the second most common cause of BM, following lung cancer. Autopsy studies, considering both symptomatic and asymptomatic lesions, estimate the incidence of BM in BC to be around 20 to 30% [4], [5]. Among metastatic breast cancers (mBC), HER2 positive and triple-negative subtypes are associated with a higher risk of BM (about 30% for each) than luminal subtype (15%) [5].Typically, BM is a late event in the disease course. The median time between the diagnosis of mBC and the onset of BM is approximately 53 months for luminal subtype, 34 months for HER2-positive subtype, and 25 months for triple-negative breast cancer (TNBC) [6]. With the availability of more effective systemic therapies for breast cancer, patients are living longer, resulting in a steady increase in the incidence of BM [7]. Despite therapeutic advancements, patients with BM from BC continue to have a poor prognosis. The median survival varies depending on tumor subtypes, ranging from 7 to 9 months for hormone-receptor positive (HR+)/HER2-negative BC, 16 to 19 months for HR+/HER2-positive BC, 11 to 13 months for hormone-receptor negative (HR-)/HER2-positive BC, and less than 5 months for TNBC [8], [9], [10].

Conclusions and perspectives

In recent years, the advent of novel ADC has significantly transformed the treatment landscape for metastatic breast cancer and holds great promise for improving survival outcomes [62].

However, the management of brain metastases remains a significant challenge. Many studies have either excluded patients with central nervous system involvement or failed to report specific intracranial data when included. Furthermore, there is a paucity of studies specifically investigating the efficacy of third-generation ADC in patients with active brain metastases or leptomeningeal disease.

Nonetheless, the limited available data thus far present promising findings, demonstrating notable activity of ADC in patients with active brain metastases. Given the poor prognosis associated with central nervous system involvement and the effectiveness of ADC, it is imperative to intensify the exploration of these novel treatments in this patient population. Therefore, substantial efforts should be dedicated to designing well-designed clinical trials in this context.

Abstract

Introduction

Materials and Methods

Results

Discussion

Conclusions

Data Availability

Disclosure

Conflicts of Interest

Acknowledgments

Supplementary Materials

References

Copyright

Related articles

Abstract

     Background. Estimation of survival requires follow-up of patients from diagnosis until death ensuring complete and good quality data. Many population-based cancer registries in low- and middle-income countries have difficulties linking registry data with regional or national vital statistics, increasing the chances of cases lost to follow-up. The impact of lost to follow-up cases on survival estimates from small population-based cancer registries (<500 cases) has been understudied, and bias could be larger than in larger registries. Methods. We simulated scenarios based on idealized real data from three population-based cancer registries to assess the impact of loss to follow-up on 1-5-year overall and net survival for stomach, colon, and thyroid cancers—cancer types with very different prognosis. Multiple scenarios with varying of lost to follow-up proportions (1-20%) and sample sizes of (100-500 cases) were carried out. We investigated the impact of excluding versus censoring lost to follow-up cases; punctual and bootstrap confidence intervals for the average bias are presented. Results. Censoring of lost to follow-up cases lead to overestimation of the overall survival, this effect was strongest for cancers with a poor prognosis and increased with follow-up time and higher proportion of lost to follow-up cases; these effects were slightly larger for net survival than overall survival. Excluding cases lost to follow-up did not generate a bias on survival estimates on average, but in individual cases, there were under- and overestimating survival. For gastric, colon, and thyroid cancer, relative bias on 5-year cancer survival with 1% of lost to follow-up varied between 6% and 125%, 2% and 40%, and 0.1% and 1.0%, respectively. Conclusion. Estimation of cancer survival from small population-based registries must be interpreted with caution: even small proportions of censoring, or excluding lost to follow-up cases can inflate survival, making it hard to interpret comparison across regions or countries.

Introduction

     Population-based cancer registries (PBCR) are the gold standard source of population-based incidence and survival statistics [1, 2]. Estimation of survival requires follow-up of a cohort of cancer patients until their moment of death or study closure, ensuring complete follow-up and good quality data. Many PBCR, contrary to the situation of clinical trials, do not perform routine follow-up of all patients when they perform survival analyses. Usually, they cross-link information from civil registration and vital statistics of their population to be informed regarding date (and cause) of death. If the completeness or quality of the vital statistics is suboptimal, deceased patients may not be reported and therefore considered erroneously being alive at the date of administrative follow-up. The quality of the death-registry is relatively complete in Colombia [3]; therefore, absence of a death certificate is usually considered as an indicator to consider the patient alive. However, in Colombia and low- and middle-income countries (LMIC), this cross-linking between registries and vital statistics is difficult and often only possible for the regional vital statistics data—if a patient died in another city, the registries would not be notified. Sometimes strict personal data protection policies [4] inhibit this linkage altogether, and registries have to rely on notes made by registrars when coincidentally encountering patients already in the registry.

Results and analyses

     Records of 3,455 incident cancer patients were collected from the three PBCR, 1,528 (44.2%) for stomach, 902 (26.1%) for colon, and 1,025 (29.7%) for thyroid gland cancer. After applying the exclusion criteria, 2,924 cases remained: 1,188 for stomach, 759 for colon, and 977 for thyroid gland cancer (details for reasons for exclusion in table S1). The proportion of excluded tumors was 22.3% for stomach, 15.9% for colon, and 4.7% for thyroid gland. The mean age for stomach cancer cases was 63.8 years (standard deviation (SD): 15.0), for colon 64.8 years (SD 14.1), and for thyroid gland 48.4 years (SD 14.3). The proportion of women was 41.5, 60.5, and 86.4% for stomach, colon, and thyroid gland, respectively.

     Table 1 shows overall one-, three-, and 5-year all-cause and net survival for the complete case analysis of the three cancer types (reference scenario). For stomach cancer, one-year overall and net survival were 0.39 and 0.40; corresponding figures were 0.66 and 0.67 for colorectal cancer and 0.96 and 0.96 for thyroid cancer. Five-year overall and net survival were 0.19 and 0.21 for stomach cancer, 0.44 and 0.50 for colon cancer, and 0.92 and 0.95 for thyroid gland cancers, respectively. Net survival was always slightly higher than overall survival.