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Mismatch repair deficient colorectal cancers have high mutation loads and many respond to immune checkpoint-inhibitors. We investigated how genetic and immune landscapes co-evolve in these tumors. All cases had high truncal mutation loads. Driver aberrations showed a clear hierarchy despite pervasive intratumor heterogeneity: Those in WNT/βCatenin, mitogen-activated protein kinase and TGFβ receptor family genes were almost always truncal. Immune evasion drivers were predominantly subclonal and showed parallel evolution. Pan-tumor evolution, subclonal evolution, and evolutionary stasis of genetic immune evasion drivers defined three MMRd CRC subtypes with distinct T-cell infiltrates. These immune evasion drivers have been implicated in checkpoint-inhibitor resistance. Clonality and subtype assessments are hence critical for predictive immunotherapy biomarker development. Cancer cell PD-L1 expression was conditional on loss of the intestinal homeobox transcription factor CDX2. This explains infrequent PD-L1 expression by cancer cells and likely contributes to the high recurrence risk of MMRd CRCs with impaired CDX2 expression.

Pancreatic ductal adenocarcinoma (PDAC) is expected to become the second most common cause of cancer death in the USA by 2030, yet progress continues to lag behind that of other cancers, with only 9% of patients surviving beyond 5 years. Long-term survivorship of PDAC and improving survival has, until recently, escaped our understanding. One recent frontier in the cancer field is the microbiome. The microbiome collectively refers to the extensive community of bacteria and fungi that colonise us. It is estimated that there is one to ten prokaryotic cells for each human somatic cell, yet, the significance of this community in health and disease has, until recently, been overlooked. This review examines the role of the microbiome in PDAC and how it may alter survival outcomes. We evaluate the possibility of employing microbiomic signatures as biomarkers of PDAC. Ultimately this review analyses whether the microbiome may be amenable to targeting and consequently altering the natural history of PDAC.

This abstract is being presented as a short talk in the scientific program. A full abstract is available in the Proffered Abstracts section (PR012) of the Conference Proceedings. Citation Format: Benjamin R. Challoner, Andrew Woolston, David Lau, Marta Buzzetti, Louise J. Barber, Tom Lund, Harold B. Sansano, Katharina von Loga, Héctor Lázare-Iglesias, Ruwaida Begum, Richard Crux, David Cunningham, Ian Chau, Naureen Starling, Juan Ruiz-Bañobre, Tony Dhillon, Marco Gerlinger. Genetic and immune landscape evolution defines subtypes of MMR deficient colorectal cancer [abstract]. In: Proceedings of the AACR Special Conference on the Evolutionary Dynamics in Carcinogenesis and Response to Therapy; 2022 Mar 14-17. Philadelphia (PA): AACR; Cancer Res 2022;82(10 Suppl):Abstract nr A002.

Mismatch repair deficient (MMRd) CRCs have high mutation/neo-antigen loads, leading to high immunogenicity and good immunotherapy response rates. We reasoned that the MMRd hypermutator phenotype should also promote intratumor heterogeneity (ITH) and evolvability; and investigated the genetic and immunological co-evolution in 69 regions from 6 localized and 13 metastatic MMRd CRCs by multi-region DNA-, RNA-sequencing and immunohistochemistry. All tumors had high truncal mutation loads (median: 44 mutations in 191 sequenced genes; whole exome equivalent: 1870 mutations). A median of 16.1% mutations per region were heterogeneous, indicating pervasive ITH. Phylogenetic analyses showed that metastases had diverged before subclonal diversification of the primary tumor in 75% of assessable cases. Thus, the ability to metastasize was frequently acquired early during tumor evolution. Driver aberrations evolved with a clear hierarchy: those in the WNT and RTK-MAPK pathways and in TGFbR-family members were almost always truncal (87.0%, 86.4% and 83.7%), indicating a critical role for cancer initiation. In contrast, genetic aberrations that are known to confer immune evasion (IE) were predominantly subclonal (71.4%) and parallel evolution of IE drivers occurred in 4/6 tumors that harboured any subclonal IE driver. This substantiates immune selection pressure as the main driver of Darwinian evolution during tumor progression. These IE drivers are known to confer resistance to checkpoint-inhibitor immunotherapy. ITH therefore needs to be addressed for predictive biomarker development. We quantified CD8 T-cell infiltrates as a surrogate measure of tumor immunogenicity; distinguishing tumors with low CD8 T-cell infiltrates (mean: 3.9% T-cells of all nucleated cells) and those with high infiltrates (mean: 12.2%). T-cell infiltrates showed high ITH in the latter group. This suggested a tumor-intrinsic setpoint, accompanied by marked variability in tumors with dense infiltrates. T-cell densities did not correlate with truncal mutation loads or heterogeneity metrics, questioning how immunogenicity is regulated. Phylogenetic analysis defined three patterns of IE evolution: tumors with subclonal, with pan-tumor, or without any identifiable IE drivers. CD8 T-cell abundance was highest in tumors with subclonal IE, supporting selection pressure from high CD8 T-cell infiltrates as the proximate cause for IE evolution. Tumors with pan-tumor IE showed low CD8 T-cell infiltrates. Surprisingly, tumors without IE drivers had the lowest CD8 T-cell abundance, indicating an alternative mechanism of immune escape. Low densities of CD8 T-cells at the tumor margin and low expression of T-cell chemo-attractants suggested impaired T-cell recruitment in these. Together, we show that immune recognition is a major driver of Darwinian evolution in MMRd CRCs and that immune infiltrates and IE drivers co-evolve interdependently. Whether sensitivity to checkpoint-inhibitor immunotherapy differs between the three phylogenetic MMRd CRC subtypes needs to be assessed in clinical trials. Citation Format: Benjamin R. Challoner, Andrew Woolston, David Lau, Marta Buzzetti, Louise J. Barber, Tom Lund, Harold B. Sansano, Katharina von Loga, Héctor Lázare-Iglesias, Ruwaida Begum, Richard Crux, David Cunningham, Ian Chau, Naureen Starling, Juan Ruiz-Bañobre, Tony Dhillon, Marco Gerlinger. Genetic and immune landscape evolution defines subtypes of MMR deficient colorectal cancer [abstract]. In: Proceedings of the AACR Special Conference on the Evolutionary Dynamics in Carcinogenesis and Response to Therapy; 2022 Mar 14-17. Philadelphia (PA): AACR; Cancer Res 2022;82(10 Suppl):Abstract nr PR012.

Background After liver resection (LR), patients with hepatocellular cancer (HCC) are at high risk of recurrence. There are no approved anti-cancer therapies known to affect such risk, highlighting the acute need for novel systemic therapies to control the probability of disease relapse. Immunotherapy is expanding as a novel treatment option for HCC. Emerging data from cohort 4 of the CA209–040 study, which investigated the safety and preliminary efficacy of nivolumab/ipilimumab co-administration in advanced HCC, suggest that the combination can be delivered safely with an acceptable proportion of reversible grade 3–4 toxicities (27.1%) and a low discontinuation rate (2%) in patients with HCC. Here, we describe the design and rationale of PRIME-HCC, a two-part, multi-centre, phase Ib study to assess safety and bioactivity of the nivolumab/ipilimumab combination prior to LR in early-stage HCC. Methods The study involves an initial safety run-in phase (Part 1) to allow for preliminary safety characterisation within the first 6 patients enrolled and a subsequent expansion (Part 2). Ipilimumab will be administered once only on Day 1. Nivolumab will be administered on Day 1 and Day 22 (± 3 days) for a total of two 21-day cycles (i.e. 6 weeks of treatment). The primary objective of the study is to determine the safety and tolerability of the nivolumab/ipilimumab combination prior to LR. The secondary objective is to preliminarily characterize the efficacy of the combination prior to LR, including objective response rate (ORR) and pathologic response rates. Additional exploratory objectives include preliminary evidence of long-term disease control and to identify predictive correlates of response to the nivolumab/ipilimumab combination in HCC. Discussion The results of this study will help define the positioning of neoadjuvant nivolumab/ipilimumab combination in the perioperative management of HCC, with potential to improve survival outcomes in this patient population. Trial registration EudraCT Number: 2018–000987-27 Clinical trial registry & ID: ClinicalTrials.gov: NCT03682276.

Background 10%–15% of early-stage colon cancers harbour either deficient mismatch repair (dMMR), microsatellite instability high (MSI-H) or POLE exonuclease domain mutations, and are characterised by high tumour mutational burden and increased lymphocytic infiltrate. Metastatic dMMR colon cancers are highly sensitive to immune checkpoint inhibition, and recent data show POLE-mutant tumours are similarly responsive. We are conducting a phase III randomised trial to determine if the addition of the anti-PD-L1 antibody avelumab following adjuvant chemotherapy improves disease-free survival (DFS) in patients with stage III dMMR/MSI-H or POLE mutant colon cancer and is a cost-effective approach for the UK National Health Service (NHS). Methods We are recruiting patients with completely resected, stage III colon cancer confirmed to have dMMR/MSI-H, locally or POLE exonuclease domain mutation on central testing. Eligible patients are randomised in a 1:1 ratio to standard fluoropyrimidine-based chemotherapy (capecitabine, oxaliplatin for 12 weeks or capecitabine for 24 weeks) or chemotherapy, followed by avelumab (10 mg/kg, 2 weekly for 24 weeks). Stratification is by chemotherapy received and MMR/MSI-H status. The primary endpoint is DFS. Secondary endpoints include overall survival, toxicity, quality of life and health resource use. The 3-year DFS rate in the control arm is expected to be ~75%. Avelumab is expected to improve the 3-year DFS rate by 12% (ie, 87%). Target accrual is 402 patients, which provides 80% power to detect an HR of 0.48 for DFS at a two-sided alpha of 0.05. This national, multicentre phase III trial is sponsored by the Royal Marsden NHS Foundation Trust and it is anticipated that approximately 40 centres in the UK will participate. This study opened to recruitment in August 2018. Trial registration number NCT03827044

499 Background: Regorafenib was the first treatment to demonstrate a survival benefit in patients with HCC after progression on sorafenib. The RESORCE trial found that regorafenib improved overall survival with acceptable toxicity, in patients with disease progression on sorafenib who tolerated ≥400mg sorafenib daily and had Child-Pugh A liver function. Methods: We performed a multicentre, retrospective, observational study of patients with HCC receiving regorafenib in the UK, following its availability in April 2018. Results: Data on a total of 104 patients were included from April 2018–August 2019, and 80.8% were male. Age was collected in 85 patients, with a median of 68 years (range 22–86). 23.5% had NAFLD, 21.2% had ALD, 12.9% had HBV, and 3.5% had HCV. Prior management included sorafenib (100%), TACE (30.8%), resection (12.9%). Duration of sorafenib treatment was evaluable in 99/104 patients, and reported a median of 8.7 months (range 1.8–76.6). Duration of regorafenib treatment was evaluable in 92/104 patients, and reported a median of 3.9 months (range 0.0–15.7). Following treatment with regorafenib, 6 patients (5.8%) achieved partial response, 37 (35.6%) achieved stable disease and 45 (43.3%) had progressive disease as the best response. 15 (14.4%) were not assessed and 1 (1.1%) had mixed response. Survival data is immature with 62/101 (61.4%) patients alive at the time of census with median survival currently 6.5 months. Fatigue was the most frequent AE, with 69/88 patients (85.2%) for all grades. 12/88 patients (14.8%) had Grade 3 fatigue. Other significant AEs include hand-foot syndrome (6/85 patients [7.3%] had Grade 3) and diarrhoea (4/83 patients [4.9%] had Grade 3). Conclusions: The population in our real-world experience of regorafenib for HCC had a similar duration of prior sorafenib to those in the RESORCE trial. However, there was different balance of aetiologies with a lower proportion of patients with HBV and HCV. The rate of partial response is similar to the RESORCE trial with fewer patients achieving stable disease. The incidence of fatigue was higher, but the incidence of hand-foot syndrome and diarrhoea were lower. Further expansion and follow-up of this population is warranted.

Background: The prognosis for unresectable locally advanced pancreatic adenocarcinoma (LAPC) remains poor. There is increasing interest in modern ablative techniques to improve outcomes. We report on the potential value of integrating percutaneous irreversible electroporation (IRE) in patients undergoing systemic chemotherapy. Methods: Seventy-five patients with unresectable pancreatic carcinoma underwent percutaneous IRE after chemotherapy using computerised tomography guidance under general anaesthesia. Postoperative immediate and 30-day morbidity and mortality, progression-free (PFS) and overall survival (OS) were evaluated. Results: Post-procedural immediate and 30-day mortality rates were both zero. All-grade adverse events were 25%. Median in-patient stay was 1 day (range 1–5 days). Median OS and PFS post-IRE for LAPC were 27 and 15 months respectively. Four patients with LAPC down-staged post-IRE ablation to be surgically resectable, with R0 resections in 3 cases. Conclusions: These results suggest that percutaneous IRE ablation of unresectable LAPC is safe to integrate with standard-of-care chemotherapy and may improve survival, which provides a template for further evaluation in prospective randomized clinical trials.

SUMMARY The EGF receptor (EGFR) is important in the regulation of proliferation, apoptosis and angiogenesis in cancer. EGFR inhibitors have become a mainstay of treatment of metastatic colorectal cancer, in particular KRAS wild-type patients in 50–60% of patients. Despite this many patients do not respond to these agents. Over the last few years the molecular basis of resistance to EGFR inhibitors has been elucidated to a certain degree. Mutations in KRAS and the NRAS exon are unlikely to respond to EGFR inhibitors. Other mutations, such as BRAF, PI3KCA/AKT and MET, may also lead to resistance. A greater understanding of the molecular basis for resistance may lead to ways of overcoming this, leading to improvements in care for patients.

TPS3615 Background: Colon cancer with deficient mismatch repair (dMMR) and POLE mutations are characterised by a high tumor mutational burden (TMB) and an immunogenic lymphocyte infiltrate. Approximately 12% of stage III colon cancer have dMMR. POLE mutations occur in 1% of colon cancers, but is enriched in patients

Purpose. Raised serum beta human chorionic gonadotrophin (β-hCG) not due to pregnancy can occur as a consequence of (1) gestational trophoblastic neoplasia (GTN), (2) non-gestational trophoblastic tumours, (3) a false-positive β-hCG, (4) the menopause or (5) a high normal level. Accurate differentiation between these causes is vital to avoid potentially inappropriate investigations and therapies, which may induce infertility or other serious adverse events. Here we report the United Kingdom experience of patients with an elevated β-hCG of initial uncertain cause and provide a clinical algorithm for the management of such cases. Method. The Charing Cross and Weston Park Hospital GTN databases were screened to identify patients referred with an elevated β-hCG who were not pregnant and had no previous diagnosis of GTN. Results. Between 1981 and 2004 fourteen women presented with persistently raised serum β-hCG resulting in diagnostic problems. False-positive β-hCG was excluded in all. Three patients developed gestational choriocarcinoma after 9–29 months. However, in 11 women no cause for the persistently elevated β-hCG was found. One of these achieved chemotherapy-induced normalisation of serum β-hCG, but the remaining 10 underwent surgery and/or chemotherapy without benefit. Thus, 71% (10/14) of patients remain well with unexplained elevated β-hCG levels. Conclusion. Elevated serum and urinary β-hCG levels in healthy women should be investigated systematically to exclude an underlying malignant process and to avoid inappropriate surgical and medical intervention. Long-term follow-up is required as tumours may not become apparent for many months or years.

Purpose of review Three cancers in people with HIV denote an AIDS diagnosis: Kaposi's sarcoma, high-grade B-cell non-Hodgkin's lymphoma and invasive cervical cancer. In addition a number of other cancers occur at increased frequency in this population group but are not AIDS-defining illnesses. This review discusses the impact of highly active antiretroviral therapy on the epidemiology and outcome of AIDS-defining cancers. Recent findings The incidence of both Kaposi's sarcoma and non-Hodgkin's lymphoma has declined in the era of highly active antiretroviral therapy and the outcome of both tumours has improved. Moreover, highly active antiretroviral therapy alone produces a response in a majority of antiretroviral-naive patients with Kaposi's sarcoma. In contrast, highly active antiretroviral therapy has had little impact on the incidence of human papilloma virus-associated tumours (cervical and anal cancer) in people with HIV, although it may improve survival by reducing opportunistic infection deaths. As people with HIV live longer with highly active antiretroviral therapy, an increased incidence of other non AIDS-defining cancers that have no known association with oncogenic infections is becoming apparent. Summary For those with access to highly active antiretroviral therapy, the good news from the AIDS-defining cancers - particularly Kaposi's sarcoma and non-Hodgkin's lymphoma - may be balanced by the increasing numbers of non AIDS-defining cancers.

Objective Since the introduction of highly active antiretroviral therapy (HAART) there has been a dramatic reduction in the incidence of Kaposi sarcoma (KS) and an improvement in survival. We wished to examine whether the outcome in pulmonary KS (pKS) has also altered. Methods In a single-institution cohort of 1140 HIV-positive patients with KS, 305 patients were diagnosed in the HAART era (1996–2004). We examined the clinicopathological features and outcomes of these patients, of whom 25 had pKS and 280 did not. Results Patients with pKS had lower CD4 cell counts at the time of KS diagnosis (Mann–Whitney U-test P=0.005). The incidence of pKS was higher in African patients than in non-African patients in this sample (Fisher's test, P=0.001). There were no significant differences in age, gender, plasma HIV-1 viral load or prior HAART treatment at the time of KS diagnosis. Five-year overall survival in the pKS group was 49% [95% confidence interval (CI) 26–73%] as compared with 82% (95% CI 76–87%) for the non-pKS group (log rank, P

Background A recent study by Dhillon et al. [12] , identified both angioinvasion and mTOR as prognostic biomarkers for poor survival in early stage NSCLC. The aim of this study was to verify the above study by examining the angioinvasion and mTOR expression profile in a cohort of early stage NSCLC patients and correlate the results to patient clinico-pathological data and survival. Methods Angioinvasion was routinely recorded by the pathologist at the initial assessment of the tumor following resection. mTOR was evaluated in 141 early stage (IA-IIB) NSCLC patients (67 – squamous; 60 – adenocarcinoma; 14 – others) using immunohistochemistry (IHC) analysis with an immunohistochemical score (IHS) calculated (% positive cells × staining intensity). Intensity was scored as follows: 0 (negative); 1+ (weak); 2+ (moderate); 3+ (strong). The range of scores was 0–300. Based on the previous study a cut-off score of 30 was used to define positive versus negative patients. The impact of angioinvasion and mTOR expression on prognosis was then evaluated. Results 101 of the 141 tumors studied expressed mTOR. There was no difference in mTOR expression between squamous cell carcinoma and adenocarcinoma. Angioinvasion (p = 0.024) and mTOR staining (p = 0.048) were significant univariate predictors of poor survival. Both remained significant after multivariate analysis (p = 0.037 and p = 0.020, respectively). Conclusions Our findings verify angioinvasion and mTOR expression as new biomarkers for poor outcome in patients with early stage NSCLC. mTOR expressing patients may benefit from novel therapies targeting the mTOR survival pathway.

Introduction The best hope of cure for patients with non-small cell lung cancer (NSCLC) is surgical resection. However, even in stage IA patients, 30% die within 5 years. Further improvements in survival require a biomarker(s), which defines the subset of these patients destined to do badly so that they could be targeted for additional therapies. Here, we investigate whether the immunohistochemical expression of a key kinase implicated in lung cancer biology, the mammalian target of rapamycin (mTOR) can predict survival outcome in patients with early stage resected NSCLC. Materials and Methods One hundred thirty-four patients with resected early stage (IA–IIB) NSCLC were pathologically reviewed centrally before staining for mTOR. Multiple variables including age, sex, stage, angioinvasion, lymph node status, and mTOR staining were assessed by univariate and multivariate analyses. Results Stage ( p = 0.044), lymph node status ( p = 0.049), angioinvasion ( p = 0.017), and mTOR staining ( p = 0.007) were significant univariate predictors of poor survival. However, only angioinvasion ( p = 0.016) and mTOR staining ( p = 0.046) remained significant after multivariate analysis. Moreover, mTOR staining was the only variable to predict poor outcome in patients who either had negative lymph nodes ( p = 0.016) or were stage IA ( p = 0.0016). Conclusions The mTOR staining provides a new biomarker for poor outcome in early stage NSCLC and could enable resected stage IA patients to be selected for novel therapies possibly with an mTOR inhibitor.

Purpose: The Akt/mammalian target of rapamycin (mTOR) pathway is frequently activated in human cancers and plays an important role in small cell lung cancer (SCLC) biology. We investigated the potential of targeting mTOR signaling as a novel antitumor approach in SCLC. Experimental Design: The expression of mTOR in patient specimens and in a panel of SCLC cell lines was analyzed. The effects on SCLC cell survival and downstream signaling were determined following mTOR inhibition by the rapamycin derivative RAD001 (Everolimus) or down-regulation by small interfering RNA. Results: We found elevated expression of mTOR in patient specimens and SCLC cell lines, compared with normal lung tissue and normal lung epithelial cells. RAD001 treatment impaired basal and growth factor–stimulated cell growth in a panel of SCLC cell lines. Cells with increased Akt pathway activation were more sensitive to RAD001. Accordingly, a constitutive activation of the Akt/mTOR pathway was sufficient to sensitize resistant SCLC cells to the cytotoxic effect of RAD001. In the sensitive cells, RAD001 showed a strong additive effect to the proapoptotic action of the chemotherapeutic agent etoposide. Intriguingly, we observed low Bcl-2 family proteins levels in the SCLC cells with a constitutive Akt pathway activation, whereas an increased expression was detected in the RAD001-resistant SCLC cells. An antisense construct targeting Bcl-2 or a Bcl-2–specific inhibitor was able to sensitize resistant SCLC cells to RAD001. Moreover, SCLC tumor growth in vivo was significantly inhibited by RAD001. Conclusion: Together, our data show that inhibiting mTOR signaling with RAD001 potently disrupts growth and survival signaling in human SCLC cells.

To evaluate the usefulness of positron emission tomography with 18-fluorodeoxyglucose (18FDG-PET) in locating residual or relapsed gestational trophoblastic neoplasia (GTN).The Charing Cross GTN database was screened, and 11 patients who had undergone 18FDG-PET were identified. A retrospective analysis was conducted to determine the value of this investigation as compared with other imaging modalities in clinical care.All patients had elevated beta-human chorionic gonadotropin (beta-hCG) at the time of the investigation; none were false positive. In 7 patients the 18FDG-PET scans correctly confirmed the presence (4 of 7 cases) or absence (3 of 7 cases) of disease sites defined by other imaging investigations. In 2 patients positive PET-guided appropriate surgical resection of lung lesions that appeared of equivocal significance on computed tomography (CT) resulted in -hCG normalization. One patient had a pulmonary metastasis on CT not considered positive on 18FDG-PET (false negative). One patient with enlarged mediastinal lymph nodes on CT that were 18FDG-PET positive also had a vascular uterus on magnetic resonance imaging/Dopper ultrasound that was negative on PET (false negative). Hysterectomy led to hCG normalization and cure. The mediastinal lymph nodes were positive on CT and PET due to sarcoidosis (false positive). Patients with serum hCG levels10 IU/L could have positive PET scans; that can contribute to patient care.18FDG-PET can aid in identifying residual disease sites in women relapsing from previously treated GTN. However, careful evaluation in combination with other imaging modalities is required to reduce the risk of false positive and negative results.

The established International Prognostic Index for lymphomas has not included patients with systemic AIDS-related non-Hodgkin lymphoma.To establish the most appropriate prognostic index for use in patients with systemic AIDS-related non-Hodgkin lymphoma.A prospective study involving univariate and multivariable analyses of patients with AIDS-related non-Hodgkin lymphoma whose data were used to examine standard and new criteria for survival after diagnosis.The Chelsea and Westminster cohort of HIV-1-infected persons.9621 HIV-positive patients, 111 in whom AIDS-related non-Hodgkin lymphoma was treated after 1996, in the era of highly active antiretroviral therapy (HAART).Cox proportional hazards regression analysis to determine the prognostic significance of multiple clinicopathologic variables.Survival of patients with AIDS-related non-Hodgkin lymphoma has increased in the HAART era (log-rank chi-square, 9.23; P = 0.002). Univariate analyses using the established International Prognostic Index factors of age, tumor stage, lactate dehydrogenase level, Eastern Cooperative Oncology Group performance status, and number of extranodal sites were confirmed to be significant variables. Regression modeling for patients in whom disease was diagnosed after 1996 revealed only 2 independent predictors of death: International Prognostic Index risk group and CD4 cell count. These predictors yielded 4 internally validated risk strata with predicted 1-year survival rates of 82%, 47%, 20%, and 15% (P0.001). Prognostic risk scores in the highest quartile yielded a likelihood ratio for death of 7.90 (hazard ratio, 1.0), whereas a prognostic score less than 1.0 yielded a likelihood ratio of 0.23 (hazard ratio, 0.15 [95% CI, 0.06 to 0.33]).The sample was small, and different HAART regimens were used.For patients with AIDS-related non-Hodgkin lymphoma that was diagnosed in the era of HAART, application of the International Prognostic Index remains useful. The addition of CD4 cell count provides further independent prognostic information. Patients who present with AIDS-related non-Hodgkin lymphoma and a low CD4 cell count have a poor prognosis; this information can be used to guide therapeutic options.

Purpose A proportion of patients with HIV infection who subsequently receive highly active antiretroviral therapy (HAART) exhibit a deterioration in their clinical status, despite control of virologic and immunologic parameters. This clinical response, known as the immune reconstitution inflammatory syndrome (IRIS), occurs secondary to an immune response against previously diagnosed pathogens. Patients and Methods From our cohort of 5,832 patients treated in the HAART era, we identified 150 therapy-naive patients with a first presentation of Kaposi's sarcoma (KS). Their clinicopathologic features and progress were recorded prospectively. Results After commencing HAART, ten patients (6.6%) developed progressive KS, which we identify as IRIS-associated KS. In a comparison of these individuals with those whose KS did not progress, we found that IRIS-KS occurred in patients with higher CD4 counts (P = .03), KS-associated edema (P = .01), and therapy with both protease inhibitors and non-nucleosides together (P = .03). Time to treatment failure was similar for both groups, although the CD4 count declined more rapidly at first, in those patients with IRIS-associated KS. Despite this initial decline, in our clinical experience HAART could be successfully continued in those with IRIS-associated KS. Conclusion We have identified IRIS-KS in a cohort of HIV patients with KS who start HAART.

Treatment options are limited for patients with advanced acquired immunodeficiency syndrome-related Kaposi’s sarcoma (AIDS-KS). The management of early stage cutaneous AIDS-KS has been revolutionized by the introduction of highly active antiretroviral therapy and for most patients highly active antiretroviral therapy alone will control early stage AIDS-KS. However, patients with advanced stage Kaposi’s sarcoma with visceral disease, tumor-associated edema or extensive oral disease require systemic chemotherapy in addition to antiretrovirals. The standard first-line therapy for these affected individuals is a liposomal anthracycline, and response rates of around 70% are usually achieved. For patients with refractory or recurrent AIDS-KS, treatment algorithms are less well defined. The use of paclitaxel in these circumstances is reviewed.

To assess whether a complete hydatidiform mole (CHM) carries an increased risk of later requiring chemotherapy in pregnancies continued to term.The Charing Cross gestational trophoblastic neoplasia (GTN) database was screened between 1973 and 2002 to identify registered singleton CHMs with a known gestational age at the time of evacuation. Of the 8,313 cases 2,800 were centrally histopathologically reviewed by us and confirmed as CHM. The proportion of patients requiring chemotherapyfor both total registered and centrally reviewed patients was analyzed by trimester of evacuation (13, 13-24,24 weeks). Statistical significance was assessed by the chi2 test.For the total population, including non-centrally reviewed patients, evacuation occurring in the first, second or third trimester was associated with a treatment rate of 13.9% (601 of 4,333), 10.8% (412 of 3,803) and 5.1% (9 of 177), respectively. In patientsfor whom a central pathologic review had been performed to confirm the diagnosis, the treatment rates were 27.7% (525 of 1,897), 27% (241 of 893) and 20% (2 of 10). The higher apparent treatment rates reflect an error in the denominator as we do not review all nontreated cases. In the total population, evacuation in the third trimester correlated with a reduction in risk of subsequent treatment (P.001). Most of these late deliveries were induced (before adequate ultrasound), whereas the earlier pregnancies were mostly terminated via suction dilatation and curettage.There is no evidence that delayed evacuation/delivery of singleton CHM increases the risk of subsequently requiring chemotherapy.

9530 Background: The established International Prognostic Index (IPI) for lymphomas has not included patients with systemic AIDS-related non Hodgkin’s lymphoma (ARL). As this remains an important c...

5109 Background: GTTs including invasive mole and choriocarcinoma are usually cured with chemotherapy assessed by a normalisation of the pregnancy hormone hCG. Relapses detected by a rising hCG can...

5086 Background: Elevated serum beta human chronic gonadotrophin (β-hCG) not due to pregnancy can occur as a consequence of (1) gestational trophoblastic disease (GTD) (2) non-gestational trophoblastic tumours, (3) false positive, often associated with heterophilic antibodies, (4) during the menopause, and (5) it may represent a high normal level. The accurate differentiation between these causes is vital to avoid potentially inappropriate investigations and therapies which may induce infertility or other serious adverse events. Here we report the United Kingdom experience of patients with an elevated β-hCG where the cause was initially uncertain and provide a clinical algorithm for the management of such cases. Method: The Charing Cross and Sheffield GTD database was screened between 1981–2004 to identify patients referred with an elevated β-hCG in the absence of a previous diagnosis of GTD and who were not pregnant. Results: Between 1981–2004 fourteen women were referred with persistently raised serum β...

Editor—Peter et al say that bisphosphonates can be used as prophylaxis against metastatic bone cancer1; this statement is incorrect. Although nitrogen containing bisphosphonates such as zoledronic acid can inhibit specific enzymes in the mevalonate pathway and thus affect tumour growth by inducing apoptosis,2 their use as adjuvant therapy against bone metastasis is controversial and is not currently accepted practice. To date, three randomised controlled trials have investigated the benefit of adjuvant bisphosphonates: all entailed giving clodronate for two to three years in women with early breast cancer.3-5 The study by Diel et al reported significant reduction in bone metastases and improved disease free and overall survival in the clodronate group.3 Powles et al found a reduction in the occurrence of bone metastases in women receiving clodronate that was significant only while clodronate was being administered, although mortality was significantly reduced.4 Conversely, Saaro et al found no benefit of adjuvant clodronate with regard to bone metastases5; moreover, they found a detrimental effect with a significantly higher incidence of non-osseous metastases as well as significantly worse disease free and overall survival in the clodronate group. Given these inconsistent results, adjuvant bisphosphonate use should be limited to clinical trials. Several such trials are ongoing, including the national surgical adjuvant breast and bowel project trial B34 and AZURE in the United Kingdom. These trials should define the clinical role, if any, of bisphosphonate in managing early breast cancer.