Complex interactions of lovastatin with 10 chemotherapeutic drugs: a rigorous evaluation of synergism and antagonism

Background Evidence bearing on the role of statins in the prevention and treatment of cancer is confounded by the diversity of statins, chemotherapeutic agents and cancer types included in the numerous published studies; consequently, the adjunctive value of statins with chemotherapy remains uncertain. Methods We assayed lovastatin in combination with each of ten commonly prescribed chemotherapy drugs in highly reproducible in vitro assays, using a neutral cellular substrate, Saccharomyces cerevisiae. Cell density (OD600) data were analyzed for synergism and antagonism using the Loewe additivity model implemented with the Combenefit software. Results Four of the ten chemotherapy drugs – tamoxifen, doxorubicin, methotrexate and rapamycin – exhibited net synergism with lovastatin. The remaining six agents (5-fluorouracil, gemcitabine, epothilone, cisplatin, cyclophosphamide and etoposide) compiled neutral or antagonistic scores. Distinctive patterns of synergism and antagonism, often coexisting within the same concentration space, were documented with the various combinations, including those with net synergism scores. Two drug pairs, lovastatin combined with tamoxifen or cisplatin, were also assayed in human cell lines as proof of principle. Conclusions The synergistic interactions of tamoxifen, doxorubicin, methotrexate and rapamycin with lovastatin – because they suggest the possibility of clinical utility - merit further exploration and validation in cell lines and animal models. No less importantly, strong antagonistic interactions between certain agents and lovastatin argue for a cautious, data-driven approach before adding a statin to any chemotherapeutic regimen. We also urge awareness of adventitious statin usage by patients entering cancer treatment protocols.

Implementing gene curation for hereditary cancer susceptibility in Australia: achieving consensus on genes with clinical utility

BackgroundThe strength of evidence supporting the validity of gene-disease relationships is variable. Hereditary cancer has the additional complexity of low or moderate penetrance for some confirmed disease-associated alleles.MethodsTo promote national consistency in interpretation of hereditary cancer/tumour gene test results, we requested opinions of representatives from Australian Family Cancer Clinics regarding the clinical utility of 157 genes initially collated for a national research project. Viewpoints were sought by initial survey, face-to-face workshop and follow-up survey. Subsequent review was undertaken by the eviQ Cancer Genetics Reference Committee, a national resource providing evidence-based and consensus-driven cancer treatment protocols.ResultsGenes were categorised by clinical actionability as: relevant for testing on presentation of common cancer/tumour types (n=45); relevant for testing in the context of specific rare phenotypes (n=74); insufficient clinical utility (n=34) or contentious clinical utility (n=3). Opinions for several genes altered during the study time frame, due to new information.ConclusionThrough an iterative process, consensus was achieved on genes with clinical utility for hereditary cancer/tumour conditions in the Australian setting. This study highlighted need for regular review of gene-disease lists, a role assumed in Australia for hereditary cancer/tumour predisposition genes by the eviQ Cancer Genetics Reference Committee.

Development of mNavigator: Digital Health Application to Facilitate Compliance With Standardized Pediatric Cancer Treatment Protocols in Tanzania

PURPOSE Use of standardized treatment protocols has been demonstrated to improve outcomes for pediatric patients with cancer. Yet it is challenging to implement standardized treatment protocols in low- and middle-income countries as a result of infrastructure and resource constraints, as well as poor health provider compliance with treatment protocols. At Bugando Medical Centre (BMC) in Tanzania, health provider compliance with standardized paper-based treatment protocols is low at 22%. One-year overall survival rates among pediatric patients with cancer at BMC are 40% and almost one third of patients abandon treatment. We posit that improving protocol compliance in this setting may decrease treatment abandonment and improve survival rates. Use of digital case management systems has been shown to improve compliance with treatment protocols because of the ability to incorporate such features as decision-support algorithms, prompts and alerts, and checklists. The digital health application mNavigator was designed to facilitate health provider compliance with standardized pediatric cancer treatment protocols in Tanzania. METHODS mNavigator was developed by adapting an open-source digital case management platform called CommCare. The three stages of mNavigator development were as follows: workflow mapping and form development; form programming in CommCare; and quality assurance using mock and deidentified patient records to identify errors in information flow or outputs, assess preliminary usability, and determine areas for improvement. Standardized treatment protocols for Burkitt lymphoma and retinoblastoma were initially incorporated into mNavigator. The mNavigator prototype underwent usability testing at BMC before implementation in routine clinical practice. RESULTS Preliminary system usability, acceptance, and satisfaction evaluation demonstrated high usability response scores (> 80%). Perceived benefits of the mNavigator system included a user-friendly interface, improved record keeping, and assistance with patient tracking using standardized treatment protocols. Suggestions for improvement centered on the incorporation of other standardized treatment protocols (eg, Wilms tumor), improving interoperability with existing electronic recordkeeping systems, and making similar systems available for other clinical departments. CONCLUSION To our knowledge, mNavigator is the first digital health case management system specifically developed to improve health provider compliance with pediatric cancer treatment protocols in a low-resource setting. With high usability and acceptability, mNavigator has been implemented in routine clinical practice. Implementation and patient outcomes evaluations are ongoing and will inform the scale-up for use in other low- and middle-income countries.

Complex Interactions of Lovastatin with 10 Chemotherapeutic Drugs: A Rigorous Evaluation of Synergism and Antagonism

Background Evidence bearing on the role of statins in the prevention and treatment of cancer is confounded by the diversity of statins, chemotherapeutic agents and cancer types included in the numerous published studies; consequently, the adjunctive value of statins with chemotherapy remains uncertain. Methods We assayed lovastatin in combination with each of ten commonly prescribed chemotherapy drugs in highly reproducible in vitro assays, using an indifferent cellular substrate, Saccharomyces cerevisiae. Cell density (OD600) data were analyzed for synergism and antagonism using the Loewe additivity model implemented with the Combenefit software. Results Four of the ten chemotherapy drugs – tamoxifen, doxorubicin, methotrexate and rapamycin – exhibited net synergism with lovastatin. The remaining six agents (5-fluorouracil, gemcitabine, epothilone, cisplatin, cyclophosphamide and etoposide) compiled neutral or antagonistic scores. Distinctive patterns of synergism and antagonism, often coexisting within the same concentration space, were documented with the various combinations, including those with net synergism scores. Conclusions The interactions of tamoxifen, doxorubicin, methotrexate and rapamycin with lovastatin suggest clinical utility and merit further exploration in cell lines and animal models. No less importantly, strong antagonistic interactions between certain agents and lovastatin argue for a cautious, data-driven approach before adding a statin to chemotherapeutic regimens. We also urge awareness of adventitious statin usage by patients entering cancer treatment protocols.

CT Pre-Operative Imaging of the Esophagus: Is Inclusion of Abdomen Necessary?

Background: Esophageal carcinoma is the third commonest tumor in Kenya with one of the highest mortality rates. Locally, the 2019 Kenya National Cancer Treatment Protocols recommend CT chest and abdomen as the basic imaging tool. The aim of this study was to determine the necessity of including the abdomen while scanning patients with cancer of the esophagus. Methods: Fifty consecutive patients with esophageal cancer who underwent CT imaging were included. Results: 32 male patients (64%) and 18 (36%) female patients. 4 patients (8%) had a CT diagnosis of upper third cancer of the esophagus; 20 patients (40%) had middle third cancer; and 26 patients (52%) had lower third cancer. Patients with middle and lower third esophagus tumors had nodal and distant metastases to the upper abdomen. Conclusion: Preoperative CT with the inclusion of abdomen is essential for patients with middle and lower third tumors. None of the patients with upper third tumors had metastases to the abdomen. Further studies with a larger sample size are needed to assess the necessity of including abdomen in CT scan in these patients. Keywords: Esophageal cancer, CT scan, Abdomen, Diagnostic yield

Male Breast Cancer: Reevaluate Our Opinion

Male breast cancers (MBCs) are relatively uncommon malignancy with less than 1% incidence. MBC presents at a later age with a more advanced presentation as compared to the female breast cancer. Due to the paucity of the number of cases and trials regarding the MBC, female breast cancer treatment protocols are applied. Mastectomy and hormonal therapy remains the mainstay of treatment. Moreover, the data about prognosis of MBC remains limited.

Molecular-genetic polymorphism of breast cancer

Breast cancer occupies a leading position worldwide in the structure of oncological diseases in terms of morbidity and mortality. The life expectancy of patients has increased significantly due to the development of modern treatment methods such as targeted therapy, hormone and immunotherapy. This kind of treatment became available as a result of studying the molecular genetic features of breast cancer and the emergence of new diagnostic methods for detecting molecular structures. Currently, breast cancer treatment protocols are periodically updated and changed according to the results of modern research and the emergence of a new spectrum of targeted drugs and new targets for the drugs. In this review, we summarized the achievements of modern medicine in the field of molecular genetics and the features of breast cancer pathogenesis, such as luminal types of breast cancer, androgen positive types of breast cancer, new features of Her2/neu and Ki-67 overexpression.

Caregiver Stress, Coping Strategies, and Support Needs of Mothers Caring for their Children Who Are Undergoing Active Cancer Treatments

The diagnosis of childhood cancer not only affects the life of the child but also impacts the lives of the caregivers as well. This study aims to explore the caregiving stress, coping strategies, and support needs of mothers caring for children/adolescents with cancer during the active treatment phase. Individual semi-structured interviews were conducted, and two authors independently and thematically analyzed data. Caregiving mothers went through a process of emotional changes and a change in lifestyles when their children were diagnosed with cancer and undergoing treatments. It is important to ensure that caregiving mothers of children/adolescents with cancer are well supported by family, friends, and healthcare professionals. Healthcare professionals can develop informational booklets on cancer treatment protocols and work together with mothers. Parent support groups and plans for psychoeducational and spiritual care programs for mothers as forms of informational and emotional support may also be established.

Severe Vaginal Bleeding in a Case of Renal Cell Carcinoma

Renal Cell Carcinoma (RCC) accounts for approximately 2-3% of all adult cancers and carries the highest mortality of the genitourinary cancers. Metastatic disease is seen in approximately 16% of cases and when present represents an advanced status. Metastasis of RCC to the vagina has rarely been cited in literature and when present can mimic primary vaginal cancer in clinical presentation and symptoms. Biopsy is performed to delineate the etiology and, in the presence of clear cells and certain immunohistochemistry markers, RCC needs to be included in the differential diagnosis. Treatment protocols are limited due to the rarity of the condition, with retrospective and comparative studies alongside cervical cancer treatment protocols serving as the basis. Herein, we describe a unique case of profuse vaginal bleeding secondary to vaginal metastases of RCC and discuss the relevant aspects of diagnosis and treatment.