Thinking with Excerpts: John Locke (1632-1704) and his Notebooks.

In his "Méthode nouvelle," an anonymous article in the Bibliothèque universelle of 1686, John Locke described his way of collecting excerpts in notebooks and retrieving relevant entries. The well-known practice of entering textual passages in commonplace books sits uneasily with Locke's criticism of received opinion and authority. Is it possible that he used any of these notes to think with? I suggest that the conditions for this were provided by Locke's interactions with some of his notes, including those which recorded observations, testimonies and experiments. As well as labelling excerpts and other notes with topical Titles, Locke sometimes added precise bibliographical citations, transferred material across notebooks, interpolated his own signed reflections and queries, and (eventually) dated entries.

Hippocrates' complaint and the scientific ethos in early modern England.

Among the elements of the modern scientific ethos, as identified by R.K. Merton and others, is the commitment of individual effort to a long-term inquiry that may not bring substantial results in a lifetime. The challenge this presents was encapsulated in the aphorism of the ancient Greek physician, Hippocrates of Kos: vita brevis, ars longa (life is short, art is long). This article explores how this complaint was answered in the early modern period by Francis Bacon's call for the inauguration of the sciences over several generations, thereby imagining a succession of lives added together over time. However, Bacon also explored another response to Hippocrates: the devotion of a 'whole life', whether brief or long, to science. The endorsement of long-term inquiry in combination with intensive lifetime involvement was embraced by some leading Fellows of the Royal Society, such as Robert Boyle and Robert Hooke. The problem for individuals, however, was to find satisfaction in science despite concerns, in some fields, that current observations and experiments would not yield material able to be extended by future investigations.

The effect of test kit provision, and individual and family education on the uptake rates of fecal occult blood test in an Asian population: a randomized controlled trial.

PURPOSE: The purpose of the study was to investigate whether fecal occult blood test (FOBT) home-delivery and individual education or combined with family education increases FOBT uptake rates in Singapore. METHODS: This is a randomized controlled intervention study of Singaporean residents aged 50 years and above, conducted in May 2012 till May 2013. Eligible individuals in randomly selected households were screened, and one member was randomly selected and allocated to one of the four arms: Group A (individual and family education, FOBT kits provided), Group B (individual education only, FOBT kits provided), Group C (no education, FOBT kits provided) and Group D (no education or FOBT kits provided). RESULTS: Overall response rate was 74.7 %. The FOBT return rates for groups A, B, C and D were 24.5 % [CI 16.2-34.4 %], 25.3 % [CI 16.4-36.0 %], 10.7 % [CI 4.7-19.9 %] and 2.2 % [CI 0.3-7.7 %], respectively. Respondents who were provided education and home-delivered FOBT kits were 15 times more likely to return FOBT kits [Group A: OR 15.0 (3.4-66.2); Group B: OR 15.5 (3.5-68.8)] and those provided with home-delivered FOBT without education were five times more likely to return FOBT kits [Group C: OR 5.8 (1.2-28.3)] than those without education and FOBT kits (Group D). There was no significant difference in return of FOBT kits whether education was provided to subject with or without a family member. CONCLUSION: Home delivery of FOBT kits increased FOBT return rates and individual education combined with home-delivered FOBT increased FOBT return rates even further. However, additional combination with family education did not increase FOBT rates further.

Oncologic outcomes after MRI-assisted image-guided brachytherapy with hybrid interstitial and intra-cavitary applicators under moderate sedation for locally advanced cervix cancer.

Purpose: To report outcomes of using image-guided hybrid intra-cavitary/interstitial applicators under moderate sedation for locally advanced cervical cancer patients in our institution. Material and methods: A total of 69 fractions of brachytherapy with hybrid applicators were performed in 33 patients from January 2017 to April 2021. All patients underwent MRI pelvis 1 week pre-brachytherapy to determine suitability for interstitial brachytherapy and pre-plan needle placement. All insertion of applicators were performed under moderate sedation with midazolam and/or fentanyl. Fifty-eight (84.1%) fractions were planned with CT alone. Clinical outcomes, dose volume parameters, and toxicities were analyzed. Results: The median follow-up was 28 months. A total of 320 needles (median, 5 needles per fraction) were implanted, with a median insertion depth of 3 cm (range, 1.5-4 cm). The median high-risk clinical target volume (HR-CTV) during initial brachytherapy was 34.5 cc (range, 17.8-74.7 cc). The median total EQD2 D2cc of the rectum, bladder, sigmoid, and small intestine colon was 71.8 Gy, 81.5 Gy, 69 Gy, and 58.3 Gy, respectively. The 2-year local control and overall survival were 80.7% and 77.7%, respectively. Larger volume HR-CTV was significantly associated with worse local control (HR = 1.08, p = 0.005) and overall survival (HR = 1.04, p = 0.015). None of the patients required in-patient admission or blood transfusion post-procedure. Late grade 3 gastrointestinal and genitourinary toxicities were observed in 4 patients (12.2%). Conclusions: Hybrid applicators inserted under moderate sedation are feasible and safe. Image-guided interstitial brachytherapy with CT planning aided by MRI performed 1 week pre-brachytherapy is associated with favorable outcomes and modest toxicities.

Cancer and radiation therapy: current advances and future directions.

In recent years remarkable progress has been made towards the understanding of proposed hallmarks of cancer development and treatment. However with its increasing incidence, the clinical management of cancer continues to be a challenge for the 21st century. Treatment modalities comprise of radiation therapy, surgery, chemotherapy, immunotherapy and hormonal therapy. Radiation therapy remains an important component of cancer treatment with approximately 50% of all cancer patients receiving radiation therapy during their course of illness; it contributes towards 40% of curative treatment for cancer. The main goal of radiation therapy is to deprive cancer cells of their multiplication (cell division) potential. Celebrating a century of advances since Marie Curie won her second Nobel Prize for her research into radium, 2011 has been designated the Year of Radiation therapy in the UK. Over the last 100 years, ongoing advances in the techniques of radiation treatment and progress made in understanding the biology of cancer cell responses to radiation will endeavor to increase the survival and reduce treatment side effects for cancer patients. In this review, principles, application and advances in radiation therapy with their biological end points are discussed.

Tailoring adjuvant radiotherapy for stage IB-IIA node negative cervical carcinoma after radical hysterectomy and pelvic lymph node dissection using the GOG score.

OBJECTIVE: The use of adjuvant radiotherapy for early stage node negative patients varies for different institutions. The recognized factors such as deep stromal invasion, lymph vascular space invasion, and size of tumor are the most common factors cited for adjuvant radiotherapy. Studies done have shown that this increases local control but may increase chronic toxicity rates. We report on our use of the GOG score to tailor our treatment decisions. METHODS: A review of all patients staged IB-IIA who underwent Type 3 Radical Hysterectomy and pelvic lymph node dissection (RH) from 1997 to 2007. The GOG score proposed by Delgado et al. was applied, and patients were stratified into 3 groups; <40: no adjuvant treatment, 40-120: Small Field RT (SmRT), and >120: Standard Field RT (StRT) RESULTS: A total of 126 patients matched these criteria. Sixty one patients underwent either SmRT or StRT. There were only 2 known relapses and one death due to inter current illness. The median follow up was 57 months and the 5 year Disease Free Survival was 98.2%. There were no documented Grade 3 or 4 chronic toxicities. There were significantly less (p=0.025) patients with lower limb lymphedema in the SmRT group compared to StRT. CONCLUSION: Our study confirms the utility of the GOG score to tailor radiotherapy for this cohort of patients. This has been proven to be high in efficacy and low in morbidity.

A Prospective Randomized Controlled Trial to Compare the Use of Conventional Dark-Ink Tattoo and Ultraviolet-Ink Tattoo for Patients Undergoing Breast Radiation Therapy.

PURPOSE: Permanent tattoo marks used in radiation therapy remain for the duration of treatment and essentially for the rest of the patient's life. This study compared the initial positioning setup errors and body image perception between patients with ultraviolet (UV) and conventional dark ink tattoos. METHODS AND MATERIALS: Thirty-four patients from February 2018 to March 2019, who underwent radiation therapy (RT) to the breast or chest wall for ductal carcinoma in situ or breast cancer were prospectively recruited and randomized (1:1) to receive either conventional dark ink or UV ink tattoos. Each patient received the assigned tattoos during computed tomography (CT) simulation and initial treatment setup shifts were compared. A 9-item body-image survey was administered to all patients at 3 time points: CT simulation, last week of RT, and 6 weeks post-RT. Feedback from CT and treatment staff in terms of setup time and challenges were collated. RESULTS: The median age of the patient cohort was 46 years old. No statistically significant difference was observed between the mean setup errors for the conventional dark ink group (0.11 cm inferior, 0.01 cm left, 0.11 cm posterior) and UV ink group (0.01 cm superior, 0.01 cm right, 0.06 cm posterior; P = NS). Similar responses were observed in the body-image survey between the 2 groups across all time points (P = NS). The majority of the patients (dark ink 82.3% vs UV ink 88.2%) did not feel less sexually attractive as a result of the tattoo at 6 weeks post-RT. At 6 weeks post-RT, patients in both groups were satisfied with the appearance of the tattoo and did not feel cautious about their choice of clothes (82.4% vs 88.2%; P = NS). In addition, 88.6% of staff (n = 35) felt minimum effect of UV ink on the overall setup time, and 94.3% found no difficulty localizing the UV ink tattoos during patient positioning. CONCLUSIONS: No difference in setup accuracy was found using UV ink tattoos, and it could be implemented clinically with minimal effect on the existing workflow. Patients expressed high satisfaction and self-confidence with the use of UV ink tattoos.

The implementation of an advanced practice radiation therapy (APRT) program in Singapore.

BACKGROUND: The exploration of Advanced Practiced Radiation Therapists (APRTs) development in Singapore started in 2011. This study aims to provide an overview of the development of the APRT roles, and to discuss the approaches used to develop and implement these roles in Singapore. MATERIALS AND METHODS: A mixed methods approach was used in the development of the APRT program. A literature review was carried out to define the APRT scope of practice and core responsibilities. A competency and assessment framework were setup to assess the core competency areas. With this framework, a structured 1-year residency training program was developed. RESULTS: The scope of practice and core responsibilities of APRTs were defined with five proposed advanced practice profiles being successfully validated. A competency framework was set up to assess the core competency domains: clinical, technical and professional competencies, research, education and leadership. A 4-point scoring system was developed for the competency assessment based on two criteria; the frequency with which RTTs would demonstrate competency, and the ability of performing the task competently. A 1-year structured APRT residency program was developed and implemented. The programme consisted of structured lectures, and clinical practice-based modules where APRT residents receive structured mentoring under a mentorship program. CONCLUSION: The APRT program in Singapore employed an evidence-based implementation process that tested the feasibility of a new practice model. Multidisciplinary involvements, mentorship and clinical training were important factors for the success of the APRT program.

Survival and disease relapse in surgical stage I endometrioid adenocarcinoma of the uterus after adjuvant vaginal vault brachytherapy.

INTRODUCTION: Advanced age, deep myoinvasion, whole cavity or lower uterine segment tumors, poor differentiation, and lymphovascular space invasion are known to increase recurrence risk and adversely affect survival in stage I endometrioid adenocarcinoma of the uterus. OBJECTIVES: To ascertain survival rates, failure patterns, and salvageability and to correlate adverse histopathologic effects to recurrences in these patients. METHODS: Data of 162 patients with surgical stage I endometrioid adenocarcinoma of the uterus with an increased risk of recurrence were reviewed from the year 1997 to 2008 at KK Gynaecological Cancer Centre, Singapore. Each patient underwent surgical staging and histopathologic evaluation and received high-dose rate vaginal vault brachytherapy. The data of all patients were discussed in a multidisciplinary meeting. RESULTS: The mean patient age was 58.9 years. Most patients (54.3%) had surgical stage IC endometrioid adenocarcinoma, whereas the rest had stage IB. Grade 2 tumors were seen in 53.7% of the patients and grade 3 in 21.61%. The mean follow-up duration was 52.9 months, with a maximum of 11.5 years. Five- and 10-year survival rates were 94% and 89%, respectively. There were 9 recurrences (5.56%). Stage IC had 77.78% recurrences, whereas stage IB had 22.22%, the median time being 19 months. The initial 3 years had 77.78% relapses. There was no recurrence in grade 3 tumors, with a 100% 5-year survival rate for stage IC grade 3. Age, lymphovascular space invasion, and tumor volume and location were not significant parameters in surgical stage I endometrioid adenocarcinoma patients who failed. One patient had isolated pelvic failure, whereas 5 had a pure distant relapse. Three patients failed at both locoregional and distant sites. Vault recurrence coupled with distant metastasis occurred in 1 patient. Three patients (33.33%) with recurrences, all with limited relapse sites, were salvaged, with a mean survival of 71.33 months. The median survival for recurrent endometrial cancer was 5 years. CONCLUSIONS: This treatment has excellent survival rates with acceptable morbidity, and recurrence is mostly distant.

Concurrent chemoradiotherapy incorporating high-dose rate brachytherapy for locally advanced cervical carcinoma: survival outcomes, patterns of failure, and prognostic factors.

BACKGROUND: This is a retrospective study evaluating the survival outcomes, patterns of failure, and prognostic factors of chemoradiotherapy incorporating high-dose rate brachytherapy in the treatment of locally advanced cervical cancer. METHODS: A review of 120 consecutive patients with Federation Internationale de Gynecologie et d'Obstetrique (FIGO) stages IB2 to IVA cervical cancer treated with concurrent cisplatin-based chemoradiotherapy between April 1999 and January 2005. Overall (OS) and disease-free survival (DFS) were analyzed using the Kaplan-Meier method. RESULTS: The 5-year OS and DFS rates were, respectively, 65.0% (35.0% IB2, 65.7% IIA-B, 71.0% IIIA-B, and 40.0% IVA) and 57.3% (30.0% IB2, 58.2% IIA-B, 64.0% IIIA-B, and 40.0% IVA). Most patients had squamous cell carcinoma (89.2%) and belonged to FIGO stages IIB (40.8%) and IIIB (30.8%). All but 4 patients completed the planned radiotherapy regimen. There were 48 documented recurrences, of which 13 were locoregional only, 26 were distant only, and 9 were both sites. Five patients (4.2%) experienced late grade 3 to 4 gastrointestinal toxicity. On multivariate analysis, a preradiotherapy hemoglobin level of less than 10 g/dL and tumor size of 4 cm or greater or bulky on computed tomography were independently significant variables for OS, whereas a nadir hemoglobin level of less than 10 g/dL and presence of radiologically enlarged pelvic or paraaortic lymph nodes were independently significant variables for DFS. CONCLUSIONS: We conclude that this regimen is efficacious and feasible, but the safety profile about concurrent administration of high-dose rate brachytherapy and chemotherapy should be studied further. Finally, for cervical cancer patients selected for nonsurgical treatment, radiological assessment of tumor size and lymph node status can provide valuable prognostic information over and above FIGO staging alone.

The Impact of Radiotherapy and Histological Risk Factors on Outcomes in Malignant Phyllodes Tumors.

PURPOSE: Breast phyllodes tumors (PT) are classified into benign, borderline, and malignant grades based on histopathologic characteristics. Specific to malignant PT (MPT), surgery is the mainstay yet relapse rates are high and knowledge gaps in the literature exist regarding adjuvant radiotherapy (RT). We aimed to investigate the outcomes of patients with MPT treated in a tertiary Asian institution. METHODS AND MATERIALS: Patients with nonmetastatic MPT treated from February 1992 to June 2019 were analyzed retrospectively. RT details and relapse fields were studied. Outcomes of patients with and without RT were compared and hazard ratios were calculated using Cox proportional hazard test. Multivariable analysis was performed. RESULTS: Twenty-two of 89 patients received adjuvant RT and the median dose was 60 Gy. In the no-RT group, 4 patients received RT on relapse and had no further recurrences; a further 2 received RT for fungating relapses with good symptomatic relief. RT was only increasingly prescribed after 2004. Median follow-up in the RT group was 3.31 years, compared with 6.17 years in the no-RT group. In the RT group, 15 patients (68.2%) underwent mastectomy, versus 39 (58.2%) in the no-RT group. One patient in the RT group developed an infield local relapse, compared with 21 of 67 patients in the no-RT group. Multivariate model showed that RT decreased risk of locoregional failure (hazard ratio 0.12, 95% confidence interval [CI] 0.02-0.92, P = .04). Three-year locoregional recurrence-free survival was higher in the RT group, 92.3% (95% CI, 78.9-100) versus 73.3% (95% CI, 63.1-85.1) in the no-RT group (P = .03). There were no differences in 3-year survival. CONCLUSIONS: We recommend that adjuvant radiotherapy be discussed for malignant PT for local control, even after mastectomy.

Y-Box-binding protein-1 is a promising predictive marker of radioresistance and chemoradioresistance in nasopharyngeal cancer.

The Y-Box-binding protein-1, a member of the cold-shock domain DNA- and RNA-binding protein superfamily, is known to mediate chemoresistance. The aim of this study was to determine the expression of Y-Box-binding protein-1 in nasopharyngeal cancer in vitro and in tumor tissue samples as well as analyze the clinicopathological significance of Y-Box-binding protein-1 expression in nasopharyngeal cancer, in particular as a predictor of outcome after treatment. The Y-Box-binding protein-1 expression profile was evaluated at the mRNA and protein levels in poorly differentiated CNE-2 nasopharyngeal cancer cells by real-time RT-PCR, western blot analysis and immunohistochemistry. Y-Box-binding protein-1 expression in 143 nasopharyngeal cancer specimens was examined by immunohistochemistry and correlated with clinicopathologic parameters. Y-Box-binding protein-1 mRNA and protein were found to be expressed in CNE-2 nasopharyngeal cancer cells in vitro. Of 143 patient tissue sections, 137 (96%) were stained positive for the Y-Box-binding protein-1 protein. Y-Box-binding protein-1 immunostaining was observed to be predominantly cytoplasmic. A higher recurrence of nasopharyngeal cancer was found in patients whose tissues had increased Y-Box-binding protein-1 expression (P<0.001). The Cox proportionate hazard regression model also established that high Y-Box-binding protein-1 immunoreactivity was significantly correlated with increased risk (2.13 times) of recurrence as compared to low Y-Box-binding protein-1 immunoreactivity (P=0.01). Within groups of patients treated by radiotherapy or chemoradiotherapy, recurrent cases had significantly higher Y-Box-binding protein-1 expression than nonrecurrent cases (P<0.001 and P=0.0035, respectively). These data suggest that Y-Box-binding protein-1 expression has clinicopathological significance with potential as a predictive marker of recurrence in nasopharyngeal cancer patients who undergo radiotherapy or chemoradiotherapy.

Biological response of cancer cells to radiation treatment.

Cancer is a class of diseases characterized by uncontrolled cell growth and has the ability to spread or metastasize throughout the body. In recent years, remarkable progress has been made toward the understanding of proposed hallmarks of cancer development, care, and treatment modalities. Radiation therapy or radiotherapy is an important and integral component of cancer management, mostly conferring a survival benefit. Radiation therapy destroys cancer by depositing high-energy radiation on the cancer tissues. Over the years, radiation therapy has been driven by constant technological advances and approximately 50% of all patients with localized malignant tumors are treated with radiation at some point in the course of their disease. In radiation oncology, research and development in the last three decades has led to considerable improvement in our understanding of the differential responses of normal and cancer cells. The biological effectiveness of radiation depends on the linear energy transfer (LET), total dose, number of fractions and radiosensitivity of the targeted cells or tissues. Radiation can either directly or indirectly (by producing free radicals) damages the genome of the cell. This has been challenged in recent years by a newly identified phenomenon known as radiation induced bystander effect (RIBE). In RIBE, the non-irradiated cells adjacent to or located far from the irradiated cells/tissues demonstrate similar responses to that of the directly irradiated cells. Understanding the cancer cell responses during the fractions or after the course of irradiation will lead to improvements in therapeutic efficacy and potentially, benefitting a significant proportion of cancer patients. In this review, the clinical implications of radiation induced direct and bystander effects on the cancer cell are discussed.

Survival outcome of women with synchronous cancers of endometrium and ovary: a 10 year retrospective cohort study.

OBJECTIVE: Synchronous occurrence of endometrial and ovarian tumors is uncommon, and they affect less than 10% of women with endometrial or ovarian cancers. The aim of this study is to describe the epidemiological and clinical factors; and survival outcomes of women with these cancers. METHODS: This is a retrospective cohort study in a large tertiary institution in Singapore. The sample consists of women with endometrial and epithelial ovarian cancers followed up over a period of 10 years from 2000 to 2009. The epidemiological and clinical factors include age at diagnosis, histology types, grade and stage of disease. RESULTS: A total of 75 patients with synchronous ovarian and endometrial cancers were identified. However, only 46 patients met the inclusion criteria. The median follow-up was 74 months. The incidence rate for synchronous cancer is 8.7% of all epithelial ovarian cancers and 4.9% of all endometrial cancers diagnosed over this time frame. Mean age at diagnosis was 47.3 years old. The most common presenting symptom was abnormal uterine bleeding (36.9%) and 73.9% had endometrioid histology for both endometrial and ovarian cancers. The majority of the women (78%) presented were at early stages of 1 and 2. There were 6 (13.6%) cases of recurrence and the 5 year cumulative survival rate was at 84%. CONCLUSION: In our cohort, we found that majority of women afflicted with synchronous cancer of the endometrium and ovary were younger at age of diagnosis, had early stage of cancer and good survival.

Brachytherapy boost for T1/T2 nasopharyngeal carcinoma.

BACKGROUND: The aim of this study was to review our experience and demonstrate the safety of intracavitary brachytherapy (ICB) in patients with nasopharyngeal carcinoma (NPC). METHODS: Hundred seventy-eight patients with early T1-2b disease underwent radical external beam radiation therapy (EBRT) followed by ICB boost. The primary tumor received 66 Gy of EBRT over 33 fractions using 6 or 10 MV photons. ICB insertions were performed 1 week later, delivering 10 Gy in 2 fractions over 8 days. Kaplan-Meier survival analyses were used to calculate the actuarial 5-year overall survival (OS), cause-specific survival, local control, and disease-free survival (DFS). RESULTS: Five-year local control rates were 91.6%. OS, DFS, and cause-specific survival were estimated to be 85.25%, 81.7%, and 87.9%, respectively. Median follow-up was 86 months. There were no documented serious complications noted with ICB. CONCLUSION: ICB boost supplementing radical EBRT is an excellent method of enhancing local control for patients with NPC with early T1-2b disease.

Treatment of nasopharyngeal carcinoma using intensity-modulated radiotherapy-the national cancer centre singapore experience.

PURPOSE: The aim of this study was to determine the efficacy and acute toxicity of our early experience with treating nasopharyngeal carcinoma (NPC) patients with intensity-modulated radiotherapy (IMRT). METHODS AND MATERIALS: A review was conducted on case records of 195 patients with histologically proven, nonmetastatic NPC treated with IMRT between 2002 and 2005. MRI of the head and neck was fused with CT simulation images. All plans had target volumes at three dose levels, with a prescribed dose of 70 Gy to the gross disease, in 2.0-2.12 Gy/fraction over 33-35 fractions. Cisplatin-based chemotherapy was offered to Stage III/IV patients. RESULTS: Median patient age was 52 years, and 69% were male. Median follow-up was 36.5 months. One hundred and twenty-three patients had Stage III/IV disease (63%); 50 (26%) had T4 disease. One hundred and eighty-eight (96%) had complete response; 7 (4%) had partial response. Of the complete responders, 10 (5.3%) had local recurrence, giving a 3-year local recurrence-free survival estimate of 93.1% and a 3-year disease-free survival of 82.1%. Fifty-one patients (26%) had at least one Grade 3 toxicity. CONCLUSIONS: Results from our series are comparable to those reported by other centers. Acute toxicity is common. Local failure or persistent disease, especially in patients with bulky T4 disease, are issues that must be addressed in future trials.