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PDF file - 83K, JAK1 and JAK3 mutation status in NKTCL cases

PDF file - 110K, Non-synonymous somatic mutations identified in the Discovery set of four NKTCL cases

PDF file - 75K, Sequence analysis summary of tumor and blood samples from four NKTCL cases

PDF file - 74K, Primer sets used for Sanger sequencing and HRM analysis

PDF file - 185K, Representative HRM curves of a NKTCL case confirmed as heterozygous JAK3A573V mutation

PURPOSE:We present the strategy of a comprehensive cancer center organized to make operations pandemic proof and achieve continuity of cancer care during the COVID-19 pandemic.METHODS:Disease Outbreak Response (DORS) measures implemented at our center and its satellite clinics included strict infection prevention, manpower preservation, prudent resource allocation, and adaptation of standard-of-care treatments. Critical day-to-day clinical operations, number of persons screened before entry, staff temperature monitoring, and personal protection equipment stockpile were reviewed as a dashboard at daily DORS taskforce huddles. Polymerase chain reaction swab tests performed for patients and staff who met defined criteria for testing of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection were tracked. Descriptive statistics of outpatient attendances and treatment caseloads from February 3 to May 23, 2020, were compared with the corresponding period in 2019.RESULTS:We performed COVID-19 swabs for 80 patients and 93 staff, detecting three cancer patients with community-acquired COVID-19 infections with no nosocomial transmission. Patients who required chemotherapy, radiotherapy, or surgery and patients who are on maintenance treatment continued to receive timely treatment without disruption. The number of intravenous chemotherapy treatments was maintained at 97.8% compared with 2019, whereas that of weekly radiotherapy treatments remained stable since December 2019. All cancer-related surgeries proceeded without delay, with a 0.3% increase in workload. Surveillance follow-ups were conducted via teleconsultation, accounting for a 30.7% decrease in total face-to-face clinic consultations.CONCLUSION:Through the coordinated efforts of a DORS taskforce, it is possible to avoid nosocomial SARS-CoV-2 transmissions among patients and staff without compromising on care delivery at a national cancer center.

Highlights • Minimising transmission of COVID-19 in immunosuppressed cancer patients is of paramount importance. • Triage criteria and screening clinic can be used to identify and manage suspect cases. • Individual departments have developed unique workflows to adapt to the “new normal”., The COVID-19 pandemic has disrupted current models of healthcare and adaptations will likely continue. With the gradual easing of lockdown measures worldwide, cancer centres must be prepared to implement novel means to prevent repeated waves of infection. There are two limitations unique to oncology – a higher susceptibility of patients to COVID-19 and the multidisciplinary approach required of cancer management. We describe the measures implemented in the largest cancer centre in Singapore to continue optimal cancer care in spite of the ongoing pandemic, with no nosocomial infections reported in our centre to date. We adopted a multipronged approach, with an overall committee supervising the entire COVID-19 management effort. A screening clinic was setup to triage patients prior to entry to the centre. Each Oncology Division within the cancer centre designed solutions tailored to the specific needs of their discipline. We explore in detail the screening criteria and workflow of the screening clinic, as well as modifications by individual divisions to reduce infection risk to patients and healthcare professionals. This approach can be modelled by other cancer centres during this prolonged COVID-19 pandemic.

COVID-19, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), was declared a global pandemic in March 2020. It has impacted the world medically, financially, politically and socially, with countries such as China and Italy adopting a full lockdown of their cities to mitigate the transmission. The current mortality rate is 5.4%, with 1 056 159 people infected worldwide. The disease is reminiscent of SARS in 2002, from which the healthcare system of Singapore has garnered many lessons and applied them in the current climate. As a result of the high transmissibility of the virus, hospitals in Singapore have reduced clinic loads and elective treatments to halt propagation of the virus and also to allow redistribution of healthcare workforce to the frontline. Cancer patients, who are often immunocompromised, are at risk of contracting the disease and becoming seriously ill. At the same time, delaying treatment such as radiotherapy in cancer patients can be detrimental. Here, we describe our experience as a large radiation oncology department in Singapore, including the challenges we encountered and how we managed our patient flow.

In December 2019, pneumonia of unknown cause was reported by China to WHO. The outbreak was found to be caused by a coronavirus which was officially named "severe acute respiratory syndrome coronavirus 2" (SARS-CoV-2), and the disease caused by it was named 'COVID-19'. The first case in Singapore was confirmed on 23rd January 2020. With lessons learnt from the SARS epidemic in 2003 and the H1N1 flu pandemic in 2009, Singapore was much better prepared to deal with the virus outbreak. The government has taken swift measures to contain and break the chain of transmission. Healthcare workers face the challenge of keeping patients and staff safe from the disease. There is a higher risk of mortality of COVID-19 in cancer patients and hence unique considerations for a radiation oncology department operating in an infectious disease outbreak. This article is the recommendations and adapted workflow from the two National Cancer Centres in Singapore with the endorsement by the working committee of the Chapter of Radiation Oncology, Academy of Medicine, Singapore. It highlights the challenges that radiation oncology departments in Singapore face and the appropriate recommended responses. This includes interventions, business continuity plans and workflow in managing a COVID-19 positive patient on radiotherapy.

IntroductionWorkload in oncology during a pandemic is expected to increase as manpower is shunted to other areas of need in combating the pandemic. This increased workload, coupled with the high care needs of cancer patients, can have negative effects on both healthcare providers and their patients.MethodsThis study aims to quantify the workload of medical oncologists compared to internal medicine physicians and general surgeons during the current COVID-19 pandemic, as well as the previous H1N1 pandemic in 2009.ResultsOur data showed decrease in inpatient and outpatient workload across all three specialties, but the decrease was least in medical oncology (medical oncology −18.5% inpatient and −3.8% outpatient, internal medicine −5.7% inpatient and −24.4% outpatient, general surgery −17.6% inpatient, and −39.1% outpatient). The decrease in general surgery workload was statistically significant. The proportion of emergency department admissions to medical oncology increased during the COVID-19 pandemic. Furthermore, the study compared the workload during COVID-19 with the prior H1N1 pandemic in 2009 and showed a more drastic decrease in patient numbers across all three specialties during COVID-19.DiscussionWe conclude that inpatient and outpatient workload in medical oncology remains high despite an ongoing COVID-19 pandemic. The inpatient medical oncology workload is largely contributed by the stable number of emergency department admissions, as patients who require urgent care will present to a healthcare facility, pandemic or not. Healthcare systems should maintain manpower in medical oncology to manage this vulnerable group of patients in light of the prolonged COVID-19 pandemic.

The aim of this retrospective national cohort study is to assess the association between various radiation heart dosimetric parameters (RHDPs), acute myocardial infarct (AMI) and overall survival (OS) outcomes in non-small cell lung cancer (NSCLC) patients treated with post-operative thoracic radiotherapy (PORT) using contemporary radiation techniques. We identified patients with stage I to III NSCLC treated with PORT at the 2 national cancer institutions from 2007 to 2014. We linked their electronic medical records to the national AMI and death registries. Univariable Cox regression was performed to assess the association between various RHDPs, AMI, and OS. We included 43 eligible patients with median follow-up of 36.6 months. Median age was 64 years. Majority of the patients had pathological stage III disease (72%). Median prescription dose was 60Gy. Median mean heart dose (MHD) was 9.4Gy. There were no AMI events. The 5-year OS was 34%. Univariable Cox regression showed that age was significantly associated with OS (hazard ratio, 1.06; 95% confidence interval, 1.01 to 1.10; P = .008). Radiation heart doses, including MHD, volume of heart receiving at least 5, 25, 30, 40, 50Gy and dose to 30% of heart volume, were not significantly associated with OS. There is insufficient evidence to conclude that RHDPs are associated with OS for patients with NSCLC treated with PORT in this study. Studies with larger sample size and longer term follow-up are needed to assess AMI outcome.

Background The survival benefit of PCI in ES-SCLC reported by a European randomized trial (RCT) in 2007 was not replicated by a Japanese RCT published in 2017. This study aimed to evaluate the uptake of PCI before and after publication of the European RCT and its association with survival in ES-SCLC. Methods We identified eligible patients in the only two Singapore national cancer centres from 2003 to 2010. We linked their electronic medical records to the national death registry. We described the utilization of PCI in patients diagnosed from 2003 to 2006 (pre-adoption cohort) with patients diagnosed from 2007 to 2010 (post-adoption cohort). We performed univariable and multivariable Cox regression analysis to assess the association between PCI and survival. Results We identified 224 patients with ES-SCLC with no brain metastases. Among the 71 patients who had at least stable disease after first line chemotherapy, there was an increase in the use of PCI from the period 2007 to 2010 compared with 2003 to 2006 (32% versus 10%, P = 0.044). PCI was associated with improved OS (hazard ratio 0.22, 95% CI 0.10 to 0.47, P

Objectives: In light of studies suggesting that tumor size is a prognostic factor for Stage IIA cervical cancers, FIGO revised the cervical cancer staging criteria, subdividing Stage IIA into Stages IIA1 and IIA2, based on tumor size (4cm). This study aims to determine if the new sub-staging has any impact on overall survival as well as elucidate any other prognostic factors and treatment patterns in this category of patients. Materials and Methods: This is a case series of women diagnosed with Stage IIA cervical cancer in KK Women's & Children's Hospital between 2001 and 2005. Statistical analysis was performed with SPSS version 19. Results: A total of 66 patients were diagnosed with Stage IIA cervical cancer between 2001 and 2005. Of the 50 patients which met the inclusion criteria, 35 (70%) had stage IIA1 and 15 (30%) had Stage IIA2 cervical cancer. The overall 5 year survival was not significantly different between Stage IIA1 and IIA2 (79.6% vs 73.3%, p=0.9). Likewise, progression free survival was not significantly different between Stage IIA1 and IIA2 (76% vs 80%, p=0.86). Patients who underwent radical hysterectomy performed better than those treated by primary radiotherapy (87% vs 69.6%, p=0.043). Cox regression analysis showed that age, tumor grade, histology types, tumor size and lymph node status were not independent predictors of survival. Conclusion: Our preliminary results did not find any difference in overall survival based on the new FIGO sub-staging of IIA1 and IIA2. Larger studies are needed to confirm this finding.

Background and purpose We sought to evaluate the nature and frequency of late toxicities in a cohort of nasopharyngeal cancer (NPC) patients treated with conventional radiotherapy alone. Methods and materials Seven-hundred and ninety-six consecutive NPC patients treated using conventional radiotherapy at a single center from 1992 to 1995 were retrospectively analyzed. Patients with histology proven, completely staged, Stage I–IVB World Health Organization Type I–III NPC and completed radical radiotherapy were included. Patients with incomplete staging investigations, distant metastases at diagnosis, previous treatment, and incomplete radiotherapy were excluded. Radiotherapy-related complications were categorized using the RTOG Late Radiation Morbidity Scoring Criteria. Results Median follow-up was 7.2years. The 5-year overall survival and disease free survival were 69% and 56%, respectively, and the corresponding 10-year rates were 52% and 44%. Among 771 patients with at least 3months of follow-up post treatment, 565 (73%) developed RT-related complications. Diagnosed neurological complications were cranial nerve palsies ( n =70; 9%), temporal lobe necrosis ( n =37; 5%), Lhermitte's syndrome ( n =7; 1%), and brachial plexopathy ( n =2; 0.3%). Non-neurological complications included xerostomia ( n =353; 46%), neck fibrosis ( n =169; 22%), hypo-pituitarism ( n =48; 6%), hearing loss ( n =120; 16%), dysphagia ( n =116; 15%), otorrhea ( n =101; 13%), tinnitus ( n =94; 12%), permanent tube feeding ( n =61; 8%), trismus ( n =45; 6%), second malignancies within treatment field ( n =17; 2%), and osteo-radionecrosis ( n =13; 2%). Conclusions While radiotherapy is curative in NPC, many patients suffer significant late treatment morbidities with conventional radiotherapy techniques.

The molecular pathogenesis of natural killer/T-cell lymphoma (NKTCL) is not well understood. We conducted whole-exome sequencing and identified Janus kinase 3 (JAK3) somatic–activating mutations (A572V and A573V) in 2 of 4 patients with NKTCLs. Further validation of the prevalence of JAK3 mutations was determined by Sanger sequencing and high-resolution melt (HRM) analysis in an additional 61 cases. In total, 23 of 65 (35.4%) cases harbored JAK3 mutations. Functional characterization of the JAK3 mutations support its involvement in cytokine-independent JAK/STAT constitutive activation leading to increased cell growth. Moreover, treatment of both JAK3-mutant and wild-type NKTCL cell lines with a novel pan-JAK inhibitor, CP-690550, resulted in dose-dependent reduction of phosphorylated STAT5, reduced cell viability, and increased apoptosis. Hence, targeting the deregulated JAK/STAT pathway could be a promising therapy for patients with NKTCLs. Significance: Gene mutations causing NKTCL have not been fully identified. Through exome sequencing, we identified activating mutations of JAK3 that may play a significant role in the pathogenesis of NKTCLs. Our findings have important implications for the management of patients with NKTCLs. Cancer Discov; 2(7); 591–7. ©2012 AACR. This article is highlighted in the In This Issue feature, p. 569.

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.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), and120: 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.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.

We present a case of a patient with metastatic nasopharyngeal carcinoma who failed two lines of palliative combination chemotherapy and was treated with allogeneic nonmyeloablative stem cell transplantation (NST). This patient achieved a durable tumor response, dramatic relief of his symptoms, and elimination of tumor in his bone marrow—an effect likely achieved via a graft-versus-tumor response. Although NST has been explored previously in solid tumors, such as renal cell carcinoma and breast cancer, it has not been widely explored in nasopharyngeal carcinoma. We also present data from a flow cytometric immune analysis and cytokine enzyme-linked immunosorbent assay analysis in the pre- and post-NST period.

Introduction: It has been established that combined chemoradiotherapy treatment benefits selected patients with stage III Non Small Cell Lung Cancer (NSCLC). However, locoregional recurrence still poses a problem. The addition of surgery as the third modality may provide a possible solution. We report our experience of using the triple-modality approach in this group of patients. Materials and Methods: This is a retrospective review of 33 patients with stage III NSCLC treated between 1997 and 2005. Patients have good performance status and no significant weight loss. There were 26 males (79 %) with median age of 63 years (range, 43 to 74) and median follow-up of 49 months. Seventy-six percent had Stage IIIA disease. Chemotherapy consisted of paclitaxel at 175 mg/m2 over 3 hours followed by carboplatin at AUC of 5 over 1 hour. Thoracic radiotherapy was given concurrently with the second and third cycles of chemotherapy. All patients received 50 Gray in 25 fractions over 5 weeks. Results: The main toxicities were grade 3/4 neutropenia (30%), grade 3 infection (15 %) and grade 3 oesophagitis (9%). Twenty-five patients (76%) underwent surgery. Of the 8 who did not undergo surgery, 1 was deemed medically unfit after induction chemoradiotherapy and 4 had progressive disease; 3 declined surgery. Nineteen patients (58 %) had lobectomy and 6 had pneumonectomy. The median overall survival was 29.9 months and 12 patients are still in remission. Conclusion: The use of the triple-modality approach is feasible, with an acceptable tolerability and resectability rate in this group of patients. Key words: Chemoradiotherapy, Neoadjuvant treatment, Surgery

This study attempted to evaluate the usefulness of the International Prognostic Index (IPI) as a prognostic model in patients treated with R-CHOP (rituximab, cyclophosphamide, vincristine, adriamycin and prednisolone) chemotherapy. We compared 279 patients with DLBCL. Among them, 183 received CHOP while 96 received R-CHOP. Results showed that there were no statistically significant differences between the two groups of patients in terms of both the patient and the lymphoma characteristics. The estimated 2-year survival was significantly higher among patients treated with R-CHOP compared to CHOP alone (85.6% vs. 64.7%, P = 0.004). Both the IPI and age-adjusted IPI were less useful as prognostic models in patients receiving R-CHOP compared to CHOP. In the multivariate analysis, ageor= 60, elevated serum LDH, low serum albumin and advanced stages of disease were each independently associated with decreased survival in patients treated with CHOP. In contrast, among those treated with R-CHOP, only male sex and advanced stage of disease were each independently associated with decreased survival. Using these two factors, patients treated with R-CHOP could be separated into three prognostic groups with 5-year estimated survival ranging from 47% to 100% (P0.0001). In summary, we can conclude that with the significant improvement in survival following the use of rituximab, the relevance of previously recognized prognostic factors has to be reassessed and re-evaluated.

Natural killer (NK) lymphomas occurring more frequently in the Far East and South America respond poorly to anthracycline-based regimens. Here we report an in vivo NK lymphoma xenograft (NK-S1) derived from the testicular metastasis of a patient with an extranodal NK lymphoma (nasal type). The NK-S1 xenograft, established in severe combined immune deficient (SCID) mice retained the same imunophenotypic features as the original tumor. NK-S1 disseminated intra-abdominally to the testis, intestine and liver. Although doxorubicin, rapamycin, bevacizumab, rapamycin-doxorubicin, and bevacizumab-doxorubicin had no effects on the growth of subcutaneous NK-S1 xenografts, intraperitoneal (IP) delivery of cyclophosphamide caused complete tumor regression; this tumor regression was associated with apoptosis, upregulation of activated caspase-3, and cleaved Poly(ADP-ribose) polymerase (PARP). In an IP model of NK lymphoma, cyclophosphamide also prolonged the survival of mice and potently inhibited tumor dissemination and ascites formation. Our data suggest that the NK-S1 xenograft is a useful tool for screening preclinical drugs, and cyclophosphamide may be a useful drug for the treatment of this disease.

Introduction: The aim of this study was to assess the outcome of radical treatment for stage I non-small cell lung cancer (NSCLC) with external beam radiation therapy. Materials and Methods: A retrospective series of 23 patients with stage I NSCLC treated radically with radiotherapy from September 1997 to December 2004 at the National Cancer Centre, Singapore. Eighteen patients had 3D conformal radiotherapy and 5 patients had 2D planning. The median radiation dose delivered was 55 Gy (range, 50 to 67.5 in 20 to 33 fractions). The estimated median BED10 was 63.9 Gy (range, 57.6 to 70.1). Complete response (CR) rates, overall survival and cause-specific survival rates were analysed for evaluation of treatment results. Local regional failure was defined as disease in the ipsilateral lung and entire mediastinum. Recurrence at the contralateral lung and other distal organs was defined as distant metastases. Survival data were calculated using the Kaplan-Meier method and tested for significance with log-rank statistics. Results: A total of 23 patients (16 males, 7 females) with a median age of 73 years (range, 45 to 88) were analysed. Six (26%) had stage IA and 17 (74%) had stage IB disease. Eleven patients refused surgery and 12 patients were medically inoperable. The median follow-up was 18.9 months (range, 6.2 to 117.4). The overall survival at 2 years and 3 years was 54.7% and 24.3% respectively. The overall cause-specific survival was 57.4% at 2 years and 25.6% at 3 years. Radiological CR was obtained in 6/23 patients (26%) and the median survival was 24.8 months as compared to 20 months in patients who attained partial response (PR) or unknown response (P = 0.24). The median survival for 12 patients who received a BED10 of ≥63.9Gy was not reached as compared to 20 months in 11 patients with BED10 of

Introduction: The survival and epidemiology of small-cell lung cancer (SCLC) in Singapore has not been described. We aim to present the characteristics as well as determine the survival outcome and important prognostic factors for SCLC patients. Materials and Methods: A retrospective analysis of SCLC patients diagnosed from 1999 to 2002 was conducted at the Outram campus, Singapore. Clinical characteristics and treatment data were obtained from case records and survival data were checked with the registry of births and deaths on 30 May 2005. Results: One hundred and eleven patients were analysed. There were 38 (34.2%) limited-disease (LD) patients and 73 (65.8%) extensive-disease (ED) patients. The majority were current or former smokers (94.7% among LD and 94.5% among ED). More patients with LD had good performance status (92% versus 63%, P = 0.0003) and were treated with combined chemo-therapy and radiotherapy (82% versus 48%, P = 0.012). The median survival time of LD patients treated with curative chemoradiotherapy was 14.2 months (95% CI, 10.96 to 17.44). Those given prophylactic cranial irradiation had a median survival time of 16.9 months (95% CI, 11.83 to 21.97). For ED patients, the median survival time was 8.17 months (95%CI, 5.44 to 10.89). None of the factors analysed were significant prognostic factors for LD patients while performance status and type of treatment given were significant among ED patients. Conclusions: We found that the characteristics and survival of SCLC patients in Singapore are fairly similar to that of other countries. Key words: Epidemiology, Prognostic factors, Survival

The aim of this study was to characterize primary central nervous system lymphoma (PCNSL) among Asian patients and to determine their outcomes with different therapeutic modalities.Between 1990 and 2005, 37 patients with PCNSL were analyzed within 5 different treatment groups: radiotherapy alone (arm A), combined chemoradiation (arm B), chemotherapy alone with methotrexate (MTX)or = 1 g/m2 (arm C), miscellaneous therapy (arm D), and best supportive care (arm E).The median age at presentation was 59 years, and the majority of patients were male (68%). All patients had aggressive diffuse large B-cell lymphoma. The number of patients in arms A to E were 6, 16, 3, 8 and 4, respectively. The overall median survival was 7.4 months, 54.1 months, not reached, 8.9 months and 0.9 months, respectively. Use of MTX 1-2.5 g/m2 per cycle and an ECOG performance status of 0-2 were each associated with improved survival on univariate analysis (p = 0.022 and p = 0.049, respectively). Compared to radiotherapy alone, use of combined chemo-radiation was associated with a trend towards improved overall median survival (7.4 vs. 54.1 months, p = 0.058).The clinical characteristics and treatment outcomes in our Asian patients were comparable to those reported in Western series. Use of MTX 1-2.5 g/m2 per cycle and an ECOG performance status of 0-2 were associated with improved survival.

Purpose. To evaluate the efficacy and toxicity of adjuvant combination of sequential chemotherapy followed by radiotherapy in uterine papillary serous carcinoma (UPSC). Methods and materials. From April 1994 to June 2003, 26 patients (median age 61.7 years, range 46.9–78.4) with UPSC were treated with a platinum-based chemoradiation protocol after definitive surgery. 9 patients were assigned as stage I (35%), 4 were stage II (15%), 11 were stage III (42%), and 2 were stage IV (8%) according to the FIGO staging for gynecological cancers. All patients underwent total hysterectomy, salpingo-oophorectomy, pelvic ± perioartic lymph nodes dissection/sampling, omentectomy, and peritoneal washing. The adjuvant chemoradiation protocol consists of 4 cycles of platinum-based chemotherapy followed by pelvic irradiation and vaginal vault brachytherapy. In selected stage I patients with no or minimal myometrial invasion, only vault brachytherapy was given after adjuvant chemotherapy. Results. After a median follow-up of 28 months (range 9–113 months), 14 (54%) patients were alive and free of disease. 12 out of these 14 patients were FIGO stage I/II. 9 patients (35%) had died (8 from distant metastases). The Kaplan–Meier 2-year and 5-year survival estimates were 69.5% and 57%, respectively. Only 4 (15%) patients had pelvic recurrence. None of the patients developed local vault recurrence. The treatment was well tolerated, only 1 patient developed congestive cardiac failure from the chemotherapy and 6 patients had grade 2 peripheral neuropathy on follow-up. Conclusion. In our series of UPSC patients treated with adjuvant chemotherapy followed by radiotherapy, local control can be achieved in a majority of patients. Distant failure remains the major cause of mortality. Further investigations into finding a more effective systemic therapy are required if improvement in outcome for this form of uterine cancer is to be achieved.

Objectives This purpose of this study was to examine clinical-pathologic factors – particularly smoking and brain metastases – in EGFR mutation positive (M+) lung adenocarcinoma (ADC) to determine their impact on survival in patients treated with first line EGFR TKI. Methods A retrospective review of EGFR mutation reflex testing experience for all ADC diagnosed at a tertiary Asian cancer centre from January 2009 to April 2013. Amongst this cohort, patients with advanced EGFR M+ ADC treated with first line EGFR TKI were identified to determine factors that influence progression free and overall survival. Results 444/742 (59.8%) ADC reflex tested for EGFR mutations were EGFR M+. Amongst never-smokers (n=468), EGFR M+ were found in 74.5% of females and 76.3% of males, and amongst ever smokers (n=283), in 53.3% of females and 35.6% of males. Exon 20 mutations were found more commonly amongst heavy smokers (> 50 pack years and > 20 pack years, Pearson’s chi square p=0.044, and p=0.038 respectively). 211 patients treated with palliative first line TKI had a median PFS and OS of 9.2 and 19.6 months respectively. 26% of patients had brain metastasis at diagnosis. This was significantly detrimental to overall survival (HR 1.85, CI 1.09-3.16, p=0.024) on multivariate analysis. There was no evidence that smoking status had a significant impact on survival. Conclusions The high prevalence of EGFR M+ in our patient population warrants reflex testing regardless of gender and smoking status. Smoking status and dosage did not impact progression free or overall survival in patients treated with first line EGFR TKI. The presence of brain metastasis at diagnosis negatively impacts overall survival.

Cancer is a genetic disease, grows exponentially with the development of intrinsic and acquired treatment resistance. Past decade has witnessed a considerable progress towards the treatment and understanding of proposed hallmarks of cancer and together with advances in early detection and various treatment modalities. Radiation therapy is an integral part of cancer treatment armamentarium. In developed countries more than half of all cancer patients receive radiation therapy during their course of illness. Although radiation damages both cancer and normal cells, the goal of radiation therapy is to maximize the radiation dose to abnormal cancer cells while minimizing exposure to normal cells, which is adjacent to cancer cells or in the path of radiation. In recent years, life expectancy increases among cancer patients and this increase is due to the results of early diagnosis, screening efforts, improved treatments and with less late effects mostly secondary cancer development. Therefore, cancer survivorship issues have been gaining prominence in the area of radiation oncology research. Understanding the tradeoff between the expected decreases in normal tissue toxicity resulting from an improved radiation dose distribution to the targeted site is an increasingly pertinent, yet needed attention and research in the area of radiation oncology. In recent years, a number of potential molecular targets that involve either with radiation increased tumor cell killing or protecting normal cells have been identified. For clinical benefits, translating these findings to maximize the toxicity of radiation on tumor cells while safeguarding early or late normal cell toxicities using molecular targeted radioprotectors will be useful in radiation treatment.

This retrospective study aimed to evaluate the clinical characteristics and prognostic factors of Asian patients with primary mediastinal large B-cell lymphoma (PMBCL) and to determine the role of rituximab in this entity. Forty-one consecutive patients from 1997 to 2009 were included: 14 received CHOP chemotherapy (cyclophosphamide, doxorubicin, vincristine, prednisolone), while 27 more recently treated patients received CHOP with rituximab (R-CHOP). All patients with a complete or partial response received consolidation involved field radiotherapy (RT). After a median follow-up of 31.2 months (104.4 months for CHOP and 28.8 months for R-CHOP), the overall survival (OS) and progression-free survival (PFS) for R-CHOP- and CHOP-treated patients were 87% vs. 57% and 88% vs. 36%, respectively. R-CHOP resulted in an improvement of PFS (hazard ratio [HR] 8.27, 95% confidence interval [CI] 2.23-30.74, p = 0.002) and OS (HR 4.20, 95% CI 1.05-16.8, p = 0.04). Nineteen patients had positron emission tomography/computed tomography (PET/CT) evaluation after six cycles of R-CHOP (metabolic complete response 13, partial metabolic response five, and metabolic progression one). All five patients with a metabolic partial response received RT instead of intensive salvage chemotherapy; four remained progression-free. In patients with PMBCL, R-CHOP in combination with involved field radiotherapy portended a 3-year OS rate of 87%, which is comparable to historical survival rates with more intensive chemotherapy regimens.

It is our standard of care to include pelvic lymph node dissection (PLND) in the staging of endometrial cancer, followed by adjuvant vaginal vault brachytherapy. We report our experience and outcome of patients with stage 1C grade 3 endometrial cancer from KK Hospital Singapore.Records of patients with a diagnosis of stage 1C grade 3 endometrial cancer (based on the 1988 FIGO [International Federation of Gynecology and Obstetrics] staging system) from 1995 to 2008 were retrospectively reviewed. Details of surgery, chemotherapy, and radiotherapy were recorded, as were prognostic factors such as histological subtype and number of lymph nodes removed. Dates and sites of relapses were noted.A total of 31 cases were reviewed; 29 had sufficient records to be analyzed, of which one was excluded as she had a second primary cancer (breast). Median follow-up was 50.1 months (15.5-154 months). All cases underwent total hysterectomy and bilateral salpingo-oophorectomy; the majority (22 [76%]) had PLND as well. Those who did not undergo PLND received external beam radiotherapy instead. All but 1 case received postoperative vaginal vault brachytherapy. Eight of 10 patients with nonendometrioid adenocarcinoma (eg, clear cell) histology also received adjuvant chemotherapy. There were 5 systemic relapses (17.9%) and 1 pelvic recurrence (3.6%). The 5-year disease-free survival is 78.6%. No serious (grade 3 or 4) adverse effects were recorded.Pelvic lymph node dissection and vaginal vault brachytherapy seem to be effective in preventing locoregional recurrences, with few associated adverse effects. However, the rate of systemic relapse is relatively high. Adjuvant chemotherapy should also be considered for cases with poor prognostic factors.

While nonmyeloablative peripheral blood stem cell transplantation (NST) has shown efficacy against several solid tumors, it is untested in nasopharyngeal cancer (NPC). In a phase II clinical trial, 21 patients with pretreated metastatic NPC underwent NST with sibling PBSC allografts, using CY conditioning, thymic irradiation and in vivo T-cell depletion with thymoglobulin. Stable lymphohematopoietic chimerism was achieved in most patients and prophylactic CYA was tapered at a median of day +30. Seven patients (33%) showed partial response and three (14%) achieved stable disease. Four patients were alive at 2 years and three showed prolonged disease control of 344, 525 and 550 days. With a median follow-up of 209 (4–1147) days, the median PFS was 100 days (95% confidence interval (CI), 66–128 days), and median OS was 209 days (95% CI, 128–236 days). Patients with chronic GVHD had better survival—median OS 426 days (95% CI, 194–NE days) vs 143 days (95% CI, 114–226 days) (P=0.010). Thus, NST may induce meaningful clinical responses in patients with advanced NPC.\ud

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 d9Obstetrique (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.

Background: Retropharyngeal lymph node (RLN) staging in nasopharyngeal carcinoma (NPC) can be controversial. Methods: We retrospectively reviewed all patients with T2–4, N0–1 NPC treated between 1992 and 1994 to examine if RLN metastasis resulted in an increased incidence of distant metastases. Results: Of the 667 patients with NPC, 395 had T2–4, N0–1 disease, 140 had N0, and 255 had N1. All had staging CT scans and were treated with radiotherapy. Median follow-up was 8.3 years. Seventy-four percent showed undifferentiated histology. In this cohort, 187 (47%) had RLN metastases. Multivariate analysis showed that RLN conferred a higher hazard for distant metastasis (p = .04). Using the Kaplan–Meier method, patients with N0 disease and RLN had a similar hazard for distant metastases as patients with N1 disease when compared with patients with N0 disease and without RLN. Conclusion: Patients with N0 disease and RLN appear to share a similar prognosis to patients with N1 disease. © 2009 Wiley Periodicals, Inc. Head Neck, 2009

This is phase II study evaluating a non-platinum-containing regimen, used in conjunction with radiotherapy, in patients with locally advanced non-small cell lung cancer (NSCLC). Patients with non-resectable stage III NSCLC were treated with two cycles of induction gemcitabine (1000mg/m(2)) and vinorelbine (25mg/m(2)) given on D(1,8) every 21 days, followed by thoracic radiotherapy (60-66Gy) with concurrent weekly vinorelbine (15mg/m(2)). The primary objective was to assess response rate and secondary objectives to assess tolerability and to determine the progression-free survival (PFS) and overall survival (OS). Of the 42 patients enrolled on the study, 15 (36%) achieved a partial response (PR) after induction chemotherapy. After chemo-radiotherapy, five patients had complete response (CR) and 19 patients had PR, giving an overall response rate of 52%. The median PFS was 8 months and median OS was 17 months. The regimen was tolerable, with a 21% grade 3/4 neutropenia rate and 38% grade 2/3 esophagitis rate.

Gastric mucosa-associated lymphoid tissue (MALT) lymphoma and diffuse large B cell lymphoma (DLBCL) show a spectrum of disease characterized by varying proportions of low-grade and high-grade components. While the natural history and optimum treatment for low-grade gastric MALT lymphoma and DLBCL is well established, the prognosis and optimal treatment of patients with both low- and high-grade components is not well established. The purpose of our study was to evaluate the clinical characteristics, survival outcomes, and prognostic factors of patients with gastric MALT lymphoma and gastric DLBCL. A retrospective review of patients with gastric MALT lymphoma, gastric DLBCL, or MALT lymphoma with a high-grade component treated at our centers from 1994 to 2006 was performed. Patients were divided into three categories: "pure MALT lymphoma," "MALT lymphoma with high-grade component" (mixed), and "pure DLBCL." Seventy-six patients were included in our study-26 with pure MALT, 22 with MALT with high-grade component ("mixed"), and 28 with pure DLBCL. Pure MALT lymphoma and mixed lymphoma patients had similar clinical characteristics, whereas pure DLBCL patients had less favorable disease characteristics with significantly poorer performance status, higher number of extranodal sites of disease, higher stage, and larger proportion of bone marrow involvement and international prognostic index (IPI) scores compared with mixed lymphoma. The majority of mixed lymphoma (72.7%) and DLBCL patients (71.4%) were treated with chemotherapy. Of patients receiving chemotherapy, a higher proportion of mixed lymphoma and DLBCL patients received anthracycline-based combination chemotherapy regimens compared with MALT lymphoma (73% vs 71% vs 8%) whereas the proportion of mixed lymphoma and DLBCL patients was similar (p = 0.919). At a median follow-up of 37 months, the 5-year overall survival was 66.9%. The 5-year overall survival was 78% for MALT lymphoma, 84% for mixed lymphoma, and 45% for DLBCL. On univariate analysis, DLBCL histology, age, performance status, serum albumin, lactate dehydrogenase, bone marrow, number of extranodal sites, stage, and IPI score were prognostic for inferior survival. On multivariate analysis, DLBCL histology remained significantly prognostic for inferior survival, independent of chemotherapy regimen (hazard ratio (HR) 6.66, 95% confidence interval (CI) 2.01-21.41, p = 0.001). Mixed histology was not prognostic for inferior survival (HR 1.13, 95% CI 0.28-4.54, p = 0.868). Other factors prognostic for inferior survival were serum albumin

AIM OF THE STUDY This study aims to evaluate the association between hepatitis B virus (HBV) and lymphoma and to characterize HBV-related lymphomas. The efficacy of prophylactic lamivudine on HBV reactivation was also evaluated. METHODS We compared the prevalence rate of HBV infection in 556 patients with lymphoma seen over a 4-yr period with that in a group of 4698 Singapore residents aged 18-69 who participated in the National Health Survey. Next, we compared the clinic-pathologic characteristics of HBV-positive and HBV-negative lymphoma cases. RESULTS The prevalence rate of HBV infection in our study was 10.3% (57/556), higher than the prevalence rate of 4.1% (192/4698) in the general population (P < or = 0.001). The higher prevalence was observed in both sexes and across different age groups. An association was observed for non-Hodgkin's lymphoma (NHL) but not Hodgkin's lymphoma. The characteristics of HBV-infected patients with lymphoma were similar to those who were HBV-uninfected in terms of age, ECOG, extra-nodal involvement, LDH level, stage, complete remission rate and overall survival. Use of prophylactic lamivudine significantly decreased the incidence of HBV reactivation (13% vs. 38%, P = 0.02) and disruption to chemotherapy (43% vs. 4%, P = 0.02), with a trend towards improved overall survival. CONCLUSIONS Our findings suggest that an association exists between HBV infection and NHL. However, HBV infection does not appear to have a significant impact on the clinical characteristics and prognosis of NHL. Prophylactic lamivudine should be considered in all HBV-infected patients receiving antracycline and/or steroid containing chemotherapy.

It is known that smoking increases the risk for all histological subtypes of lung cancer. To date, the factors that determine why some patients develop small-cell lung cancer (SCLC) while others develop non-small-cell lung cancer (NSCLC) remain unknown. We compared the characteristics of 774 smokers with SCLC and NSCLC diagnosed during the period January 1999 till December 2002. Multivariate logistic regression was used to estimate the odds ratio (OR) with 95% CI. Testing of linear trend across categories of pack-years was also conducted. Six hundred and sixty-five NSCLC were compared to 109 SCLC. Among SCLC, there were significantly more females (20.2% versus 12.8%), current-smokers (81.7% versus 71.9%) as well as smokers who had smoked more than 40 pack-years (75.6% versus 50.3%). Comparing SCLC with NSCLC among the men only, having smoked more than 40 pack-years was associated with a significantly elevated odds ratio (OR) of 3.71 of developing SCLC (95% CI, 1.05-13.1; p=0.041). There was a decreasing trend in OR with increasing smoking cessation period. When comparing SCLC with adenocarcinoma, the women had a higher OR of 2.37 of developing SCLC (95% CI, 1.05-5.31; p=0.037) compared to the men. Our findings suggest that cumulative smoking exposure in terms of pack-years smoked is an important determining factor for the preferred development of SCLC among smokers.

Background. This study reviews the outcome of patients with nasal natural killer (NK)/T-cell lymphoma treated at the Therapeutic Radiology Department, National Cancer Centre, Singapore, from 1997 to 2003. Methods. Twenty-one consecutive patients treated with radiotherapy, with or without chemotherapy, were retrospectively reviewed. Results. The median age was 44 years (range, 27–86 years). Thirteen patients had stage I disease, five had stage II disease, and three had stage IV disease. Immunophenotyping was CD 56+ in 18 patients. Median follow-up for patients still alive was 23.4 months (range, 8.9–78.5 months). A median dose of 50 Gy (range, 35–56 Gy) was delivered. Sixteen patients also received chemotherapy. Two-year overall survival was 52.8%. Five patients had rapidly progressive disease, with a median survival of 89 days from diagnosis. The other 16 patients had complete remission, after which four relapsed. There were two local relapses. Conclusions. This disease often carries a poor prognosis, despite multimodality treatment. Radiotherapy may contribute to local control in some patients. © 2005 Wiley Periodicals, Inc. Head Neck27: XXX–XXX, 2005

third cycle of chemotherapy. The axillary mass was no longer palpable, with complete resolution of the arm oedema. The primary tumour remained stable with the fourth cycle of chemotherapy. Consolidation radiotherapy was given to the left axilla and arm 4 weeks after completion of chemotherapy. The left axilla was irradiated with a conventional technique by use of anterior opposed fields. The prescribed dose was 45 Gy in 25 fractions with daily treatment except at weekends, with six megavoltage photon beams. Treatment of the primary tumour on the basis of its original dimensions, would involve a large field of radiation, causing unacceptable morbidity. Therefore, we used one anterior field to encompass the residual nodule with adequate margins. The region was irradiated with a 12 MeV electron beam treating at 90% isodose to a total dose of 54 Gy in 30 fractions. Complete response was achieved, as shown by MRI (figures 1C and 1D). The woman remains free of disease at 20 months after initial diagnosis, without complications of brachial plexiopathy and lymphoedema Merkel-cell carcinoma is a rare cutaneous neoplasm of the elderly population. Patients typically present with a