PDGRFA-mutant gastrointestinal stromal tumours (GISTs) in Eastern England: clinicopathological features and outcomes of 50 patients diagnosed between 2008-2021

Background PDGRFA-mutant gastrointestinal tumours (GISTs) comprise approximately 10% of GISTs and are mostly gastric. Targeted therapies against these tumours have historically been limited by tyrosine kinase inhibitor (TKI)-resistance. We reviewed the characteristics and outcome of all PDGRFA-mutant patients seen at our centre over the last 13 years. Methods All PDGRFA-mutant patients seen at the Cambridge University Hospitals NHS Foundation Trust GIST clinic from July 2008-July 2021 were retrospectively reviewed and followed up. Results: 50 PDGRFA-mutant GIST patients were diagnosed during the 13-year period. 60% were male. Median tumour size was 5 cm and the majority were epithelioid (44%) or mixed (36%) type. Commonest primary location was the gastric body (52%). In non-metastatic patients the low-risk modified AFIP risk group was the most common (65.2%). PDGFRA exon 18 (86%) were the most common PDGFRA mutations, most being imatinib resistant. None harboured a KIT mutation. 38% of cases had high KIT expression (immunohistochemistry), whilst 48% had patchy expression and 14% were negative. Most were positive for DOG1 (94%). CD34 was highly expressed in 48% of cases. 13% developed metastases during the 13-year follow-up period: liver (80%) being the commonest site. 76% of all patients underwent radical resection. 14% received TKI therapy. After a median follow-up of 55.1 months, 82% remained alive: 6 patients died from metastatic GIST; 3 from other causes. Median time to metastatic disease was 30.1 months, and median time from metastatic diagnosis to death was 18.5 months. Patients who presented with metastatic disease had the poorest survival outcome (p=0.001) Conclusion To date this is the largest single-centre European PDGRFA-mutant GIST cohort. Results highlight the generally indolent nature of PDGRFA-mutant disease (contrasted to the poor outcome of those who present with metastatic disease), male and gastric preponderance (unlike KIT-mutant GISTs), and variable KIT expression.

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Gastrointestinal stromal tumors (GISTs) of the esophagus and gastroesophageal junction (GEJ).

Journal of Clinical Oncology ◽

10.1200/jco.2017.35.4_suppl.179 ◽

2017 ◽

Vol 35 (4_suppl) ◽

pp. 179-179

Author(s):

Andrew M. Briggler ◽

Rondell P Graham ◽

Gustavo Figueiredo Marcondes Westin ◽

Andrew Folpe ◽

Dawn E. Jaroszewski ◽

...

Keyword(s):

Median Time ◽

Mutational Analysis ◽

Gastroesophageal Junction ◽

Tumor Location ◽

Tnm Staging ◽

Low Grade ◽

Anastomotic Site ◽

Adjuvant Imatinib ◽

Kit Mutation

179 Background: GISTs arise from interstitial cells of Cajal anywhere within the gastrointestinal tract, but those of the esophagus and GEJ are exceedingly rare ( < 1% of cases). Our aim was to characterize clinicopathological features and outcomes of esophageal and GEJ GISTs and compare survival with a population-based registry (SEER). Methods: 28 cases were identified using the Mayo Clinic Cancer Registry from 1997 to 2016, and 378 cases from the SEER 18 registry from 2000 to 2013. Mayo cases were re-reviewed by Mayo pathologists. We analyzed patient characteristics, tumor location, TNM staging, mitotic index, molecular diagnostics, IHC staining, and histomorphology. JMP software was used to calculate time to recurrence (TTR) and overall survival (OS) utilizing Kaplan-Meier and log-rank. Results: At Mayo, 60% of tumors arose in the distal esophagus. Mean tumor size was 5.73 cm. 42% of cases were low grade. None had nodal involvement. Five cases were metastatic at diagnosis, all to the liver. 86.7% had spindle cell morphology. IHC staining was positive for KIT in 92%, followed by CD34 (52%), DOG-1 (24%), and actin (16%). Mutational analysis was done on 10 cases and KIT mutation was found in 8 cases; 2 were wild-type. Two-thirds of patients underwent surgery, mostly esophagectomy. 14 patients received adjuvant imatinib. Median time to diagnosis from symptom onset was 2 months; median time to surgery from diagnosis was 1 month. Of 10 patients with complete follow-up, 2 had recurrences: 1at the anastomotic site and 1 in the liver. Median TTR from surgery was 36.5 months. Median follow-up time was 31.5 months. Median OS from diagnosis for the Mayo cohort was 129.5 months (95% CI 55.7-x). SEER cohort median OS was 81 months (95% CI 63-101), and females had superior OS compared to males (HR 0.67; 95% CI 0.48-0.93, p = 0.016). Conclusions: Patients undergoing surgical resection for esophageal and GEJ GISTs had a favorable prognosis, but recurrences occurred. The superior OS seen in the Mayo cohort suggests early resection and adjuvant imatinib may improve outcomes.

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Ipilimumab and nivolumab (I+N) as first-line treatment of metastatic renal cell carcinoma (mRCC): A real-world review in North West of England, United Kingdom.

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.6_suppl.295 ◽

2021 ◽

Vol 39 (6_suppl) ◽

pp. 295-295

Author(s):

Jennifer Allison ◽

Richard Griffiths ◽

Tom Waddell ◽

Manon Rhys Pillai

Keyword(s):

Median Time ◽

Metastatic Disease ◽

Survival Data ◽

Single Agent ◽

Comparable Efficacy ◽

Line Treatment ◽

First Line ◽

Disease Response ◽

North West

295 Background: Ipilimumab and Nivolumab (I+N) is now an established first line option for patients with advanced RCC of intermediate (I) or poor (P) IMDC risk score. In this retrospective review, we review our experience of this combination in two cancer centres in North West England with a focus on immune related adverse events (irAEs) and their impact on the patient pathway. Methods: Treatment naïve mRCC patients starting I+N between May 2019 and July 2020 were identified. Primary outcomes of interest include overall response rate (ORR), the management of irAEs and early survival observations. Results: A total of 69 patients were identified. Median age was 60yr (19-82yr), 77% had clear cell histology. The IMDC risk was 72% I and 28% P. Median follow-up was 11.0 mo (1-22mo). ORR was 45% (CR 9%, PR 36%, SD 28%, PD 23%, NE 4%) Median time to first response was 2.9mo. (1.8- 15.5mo). 10% of patients experienced pseudoprogression. Median PFS and OS are not yet reached with 86% of patients still alive at the time of data cut-off. The majority (75%) of patients completed all 4 doses of I+N. Of the 10% receiving less than 4 doses due to toxicity, 14% continued on single agent N. Overall, 15% discontinued therapy due to toxicity and 28% experienced at least one treatment delay. Any grade irAEs were seen in 74% of patients (G3 35%) with no treatment related deaths. The commonest irAEs were: rash/pruritis 39%; endocrinopathies 30%(G3 7%); diarrhoea 29% (G3 14%); hepatitis 22% (G3 6%); and nephritis 3% (G3 3%). Of the patients developing irAEs, 71% received steroids with 16% requiring additional immunosuppression including infliximab (6%) and mycophenolate mofetil (8%). A third of all patients required admission for irAE management with a total of 37 inpatient episodes across the cohort with a median length of 7 days (1-24). 7% of patients proceeded to surgery for either primary or metastatic disease, which contributed to ongoing disease response in these patients. At the time of data cut-off, 45% of patients were no longer on treatment due to PD (29%), toxicity (15%) or unrelated death (1%). Of those who stopped due to toxicity, 50% subsequently progressed with a median time to progression of 4mo (3-6 mo) and 50% remain on active surveillance with a median follow-up of 7.5mo (1-10). 62% of patients with PD received second line treatment; most frequently, cabozantinib (83%). Conclusions: Our experience of I+N shows comparable efficacy and toxicity profiles to available reports. irAEs requiring intervention are frequent and may be associated with prolonged hospital admission, and patients should be counselled appropriately. Data within mirrors published reports of ongoing responses in a subset of patients who stop treatment due to toxicity and also suggests a possible role for resection of residual or metastatic disease in disease control. Updated survival data will be presented.

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Novel Tyrosine Kinase Inhibitor Therapy Before Allogeneic Stem Cell Transplantation in Patients with Chronic Myeloid Leukemia.

Blood ◽

10.1182/blood.v112.11.2154.2154 ◽

2008 ◽

Vol 112 (11) ◽

pp. 2154-2154

Author(s):

Leandro de Padua Silva ◽

Jorge Cortes ◽

Elias Jabbour ◽

Sergio Giralt ◽

Partow Kebriaei ◽

...

Keyword(s):

Stem Cell ◽

Stem Cell Transplantation ◽

Tyrosine Kinase ◽

Cord Blood ◽

Tyrosine Kinase Inhibitor ◽

Median Time ◽

Graft Failure ◽

Kinase Inhibitor ◽

Cytogenetic Response

Abstract Background: A significant proportion of patients undergoing allogeneic hematopoietic stem cell transplantation (HSCT) for CML will have received a novel tyrosine kinase inhibitor (NTKI) after failing imatinib mesylate. It is unclear, however, if these drug will influence HSCT outcomes by changing the toxicity profile of transplantation. Aims: To describe outcomes of patients that received a NTKI prior to HSCT. Methods: We retrospectively analyzed the outcome of 30 patients (pts) with CML [8 chronic phase (CP), 9 accelerated phase (AP), and 13 in blastic phase (BP)] that were so treated. All pts failed imatinib, and then received a second TKI {dasatinib (n=14), nilotinib (n=13), bosutinib (n=3)}, or a third TKI {dasatinib (n=2), nilotinib (n=1), or INNO-406 (n=1)} prior to HSCT. Preparative regimens were intravenous busulfan-based in 24 pts and fludarabine and melphalan in 6. Graft-versus-host disease (GVHD) prophylaxis consisted of tacrolimus and mini-methotrexate 5 mg/m2 on days 1, 3, 6, and 11 after HSCT. Donors were match related (MRD) in 12, match unrelated (MUD) in 14, haplo-identical in 1, 1-antigen mismatched related in 1, and unrelated cord blood in 2 cases. Results: Median age at HSCT was 42 years (range, 22–63). The median time on NTKI treatment was 27 weeks (range, 2–86), and the median time from the end of NTKI therapy to HSCT was 10 weeks (range, 1–32). At the time of start of second TKI, 8 were in CP, 9 in AP, and 13 in BP. At the time of start of 3rd TKI, 2 were in AP, and 2 in BP. Twenty-one pts (70%) responded to 2nd TKI; this included: 2 partial hematologic response (PHR; 1 AP, 1 BP), 5 complete hematologic response (CHR; 2 CP, 3 BP), 5 minor cytogenetic response (minor cytogenetic response (mCyR): 1 CP, 2 AP, 2 BP), 2 partial cytogenetic response (PCyR; 1 CP, 1 AP), and 7 complete cytogenetic response (CCyR; 2 CP, 2 AP, 3 BP). Two pts responded to third TKI: 1 PHR and 1 CCyR. Eight of the responders (38%) maintained their response till the HSCT. At the time of HSCT, 9 pts were in CP, 8 were in second CP, 6 were in AP, and 7 in BP. Twenty-eight pts (93%) engrafted neutrophils within a median of 12 days (range, 5–20). Both pts with primary graft failure received cord blood transplants: one was rescued with autologous stem cells and the second received a haplo-identical transplant. Two pts had secondary graft failure 2 and 6 months from the first HSCT, respectively, and were rescued with a related 1-antigen mismatched donor transplant and same MUD transplant, respectively. Acute GVHD was observed in 19 pts (Grade I in 11, Grade II/III in 6, Grade IV in 2). Chronic GVHD was observed in 10 pts (extensive in 5). Of the 28 evaluable pts for response, 5 achieved a complete cytogenetic response (CCyR), 20 achieved a complete molecular response (CMR); 3 did not respond and had disease progression by day 30 post HSCT. Eight (4 CCyR, 4 CMR) patients relapsed within a median of 4 months (range, 3–7) from HSCT. After a median follow-up of 20 months (range, 5–44), 17 patients were alive: 12 in CMR, 2 in CCyR, and 3 with active disease; 13 patients died (2 and 8 within 3 and 12 mos post HSCT, respectively), 8 of disease progression, 4 of GVHD, and one of uncontrollable infection. The estimated 2-year survival was 51%. Conclusion: Previous treatment with NTKI did not increase early transplant-related morbidity/mortality in this preliminary experience. These drugs may “downstage’ CML prior to HSCT, and this effect may be beneficial. Further follow-up and larger number of patients will be necessary to expand these observations.

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Novel Tyrosine Kinase Inhibitor Therapy (NTKI) Prior to Allogeneic Stem Cell Transplantation (ASCT) in Patients with Chronic Myeloid Leukemia (CML): No Evidence for Increased Transplant-Related Toxicity.

Blood ◽

10.1182/blood.v108.11.5262.5262 ◽

2006 ◽

Vol 108 (11) ◽

pp. 5262-5262

Author(s):

Elias Jabbour ◽

Jorge Cortes ◽

Hagop Kantarjian ◽

Sergio Giralt ◽

Francis Giles ◽

...

Keyword(s):

Stem Cell ◽

Disease Progression ◽

Median Time ◽

Kinase Inhibitor ◽

Chronic Gvhd ◽

Chronic Phase ◽

Unrelated Donor ◽

Molecular Response ◽

Number Of Patients

Introduction: Patients undergoing ASCT for CML are increasingly likely to have received a NTKI after failing imatinib mesylate. It is unknown whether the use of these NTKIs prior to ASCT increases transplant-related toxicity. Methods: We retrospectively analyzed the outcome of 12 patients with CML (1 in chronic phase, 6 in accelerated phase, and 5 in blastic phase) who received dasatinib (n=2), nilotinib (n=7), or both (n=3) prior to ASCT. Results: Median age was 41 years (range, 18–59 years). The median time on treatment was 134 days (range, 30–285 days), and the median time from the end of NTKI therapy to ASCT was 34 days (range, 7–130 days). Preparative regimen was ablative in 8 patients and non-ablative in 4. Stem cell source was a matched related donor in 7 patients, a matched unrelated donor in 3, a haplo-identical donor in 1, and unrelated cord blood in 1. All patients engrafted within 13 days. There was no significant early transplant-related toxicity: gastro-intestinal toxicities of grade 3 were encountered in 2 patients. One patient had secondary graft failure 6 months after the first ASCT that required a second ASCT. Acute graft-versus-host disease (GVHD) of grade 2 was observed in 7 patients (58%) and chronic GVHD in 6 (50%). Nine patients achieved a molecular response: four complete and five major (Q-PCR< 0.05%). Three patients had disease progression by day 30 post ASCT. Two patients have relapsed after 6 and 18 months. After a median follow-up of 10 months (range, 3–22 months), 7 patients are alive in molecular response and 5 patients died, 4 of disease progression and one of extensive chronic GVHD. Conclusion: Previous treatment with NTKI did not increase transplant-related toxicity in this preliminary experience. Further follow-up and larger number of patients will be necessary to confirm these observations.

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Long Term Follow-up of Ph+ CML Patients Achieving Complete Cytogenetic Response (CCgR) with Interferon Based Therapy - GIMEMA Protocol CML0509

Blood ◽

10.1182/blood.v118.21.786.786 ◽

2011 ◽

Vol 118 (21) ◽

pp. 786-786

Author(s):

Domenico Russo ◽

Giuliana Alimena ◽

Chiara Colombi ◽

Massimo Breccia ◽

Simona Soverini ◽

...

Keyword(s):

Overall Survival ◽

Median Time ◽

Kinase Inhibitor ◽

Progression Free Survival ◽

Cytogenetic Response ◽

Molecular Data ◽

Prolonged Survival ◽

Cooperative Study Group ◽

Biological Studies

Abstract Abstract 786 Interferon alpha (INFα) either alone or in combination with Ara-C was the frontline therapy of Ph+ chronic myeloid leukaemia (Ph+ CML) between 1980 and 2000. INFα prolonged survival as compared to conventional chemotherapy and it was the first drug able to induce complete cytogenetic responses (CCgRs). Patients achieving a CCgR by INFα ± Ara C were less than 10–15%, but they represent fascinating elite of patients who are the most likely candidates for prolonged survival and possibly for cure. The last update of the largest European cohort of 317 CML patients who had obtained a CCgR on IFNα was reported in 2001 (Bonifazi et al., Blood, 2001). Briefly, the median time to first CCgR was 19 months, the 10 year survival rate from first CCgR was 72% and the survival probability for patients with low Sokal risk was 84%. In this study, the contribution of the Italian Cooperative Study Group on CML was of 119 cases. Although INFα was used more than 20 years ago, obtaining information on this selected category of CCgR–INFα responding patients in the Imatinib era may be interesting both from the biological and clinical point of view. We report here the preliminary results of an observational study aimed to update the overall survival (OS), the progression free survival (PFS) to accelerated-blastic phase (ABP) and the CCgR duration in 92 Ph+ CML patients who were treated in Italy with an INFα based therapy between 1986 and 2001 and who obtained a CCgR at least once. In this selected cohort of patients, the median time to first CCgR was 24 months (range, 3–143), and the median duration of the first CCgR was 87 months (3-252). The overall survival (OS) calculated from diagnosis, from start of IFNα and from the time of the first CCgR was 185 months (range, 74–334), 179 months (range, 74–287) and 154 months (range, 51–274), respectively. This is the longest follow-up of Ph+ CML patients who obtained a CCgR with an IFNα-based therapy. Out of 92 patients in CCgR, 71 (77%) cases stopped IFNα and 21 (23%) continued to be treated with IFNα. Out of the 71 cases who stopped IFNα, 38 (53%) cases lost CCgR and 3 (4%) cases died because of progression to ABP; 15 (21%) maintained CCgR without any other therapy and 18 (25%) maintained CCgR but shifted to Imatinib. Among the latter 33 patients maintaining the CCgR, 4 cases died because of CML unrelated causes. Out of the 21 cases who continued to be treated with IFNα, 18 (86%) currently maintain the CCgR and are alive and well, while 3 lost CCgR and died (2 cases for ABP). These data show that there are at least 33/92 (36%) patients who are alive and well and are maintaining a CCgR, either with continued IFNa treament (18 cases) or after IFNα treatment discontinuation (15 cases) but who have never been treated with Imatinib or any other tyrosine kinase inhibitor (TKI). We are now analyzing molecular data and we are collecting peripheral blood and bone marrow samples for correlative biological studies aimed to characterize the peculiar genetic and epigenetic features of these patients Work supported by European LeukemiaNet and Cofin 2009 Disclosures: Castagnetti: Bristol Myers Squibb: Honoraria; Novartis: Honoraria. Rosti:Novartis: Consultancy; Bristol Myers Squibb: Consultancy; Novartis: Research Funding; Novartis: Honoraria; Bristol Myers Squibb: Honoraria. Baccarani:Novartis: Consultancy; Bristol Myers Squibb: Consultancy; Novartis: Honoraria; Bristol Myers Squibb: Honoraria; Pfizer: Honoraria; Ariad: Honoraria.

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Therapy-Related Myelodysplasia/Acute Myeloid Leukemia (t-MDS/AML) After Conventionally-Treated Breast Cancer: Impact of Cytogenetics on Outcome After Allogeneic Hematopoietic Cell Transplantation (HCT),

Blood ◽

10.1182/blood.v118.21.4149.4149 ◽

2011 ◽

Vol 118 (21) ◽

pp. 4149-4149

Author(s):

Rajinder S. Grover ◽

Vinod Pullarkat ◽

Can-Lan Sun ◽

Smita Bhatia ◽

Stephen J. Forman

Keyword(s):

Breast Cancer ◽

Overall Survival ◽

Median Time ◽

Metastatic Disease ◽

Combination Chemotherapy ◽

Poor Prognosis ◽

Early Stage ◽

Chromosome 5 ◽

Allogeneic Hct

Abstract 4149 Background: The outcome of early stage breast cancer has improved in recent years with use of effective combination chemotherapy, including cyclophosphamide, anthracyclines or taxanes. Patients who undergo lumpectomy also receive radiation therapy for locoregional control. t-MDS/AML are rare but serious consequences of these therapeutic exposures; historically with an overall poor prognosis. Translocations involving the mixed-lineage leukemia (MLL) gene on chromosome band 11q23, and core binding factor genes on 21q22 and 16q22, are hallmarks of t-MDS/AML resulting from treatment with topoisomerase II inhibitors (anthracyclines). Loss of part or whole of chromosomes 5 and/or 7 (5-/7- abnormality) are associated with t-MDS/AML after treatment with alkylating agents and radiation. Allogeneic HCT (sibling-related, unrelated or double-cord) offers the only curative option for some of these patients. However, the long-term outcome of post-breast cancer t-MDS/AML after allogeneic HCT has not been described, and subgroups with better or worse prognosis not identified. Methods: From 1997 to 2011, 28 patients with t-MDS/AML after treatment of breast cancer with conventional chemotherapy and/or radiation underwent allogeneic HCT at City of Hope. Overall survival defined from the time of allogeneic HCT to the last date of follow up or date of death, was estimated using Kaplan-Meier method. Cox regression techniques were utilized to understand predictors of overall survival. Results: Of the 28 patients, 16 had been treated for early-stage breast cancer (I/IIA), 11 had received treatment for locally advanced disease (IIB/ III) and 1 patient had metastatic disease. Twenty-five patients received combination chemotherapy as adjuvant therapy or for metastatic disease; this included cyclophosphamide (100%), doxorubicin (88%) and taxanes (52%). Details of chemotherapy are unknown for one patient. Twenty-one patients (75%) also received radiation (2 received radiation alone). Median age at time of diagnosis of t-MDS/AML was 56 years (range: 34–79); median time from diagnosis of breast cancer to diagnosis of t-MDS/AML was 2.4 years (range 1–12.3); median time from t-MDS/AML to allogeneic HCT was 0.55 year (range: 0.15–4.1). Ten patients presented with MDS and 18 with AML. Cytogenetic abnormalities included MLL - 11q23 abnormality (n=12), 5-/7- and/or complex abnormalities (n=9), t(15;17)(q22;q21.1) (n=1), t(8;21) (n=1), inv(16)(p13.1;q22) (n=2). Of the 28 patients, 27 were treated with induction therapy and 74% were in complete remission (CR) at the time of HCT. Fourteen patients (50%) received sibling-related HCT, 13 received matched unrelated donor (MUD) transplant and 1 received a double cord transplant. Two patients received second allogeneic HCT and one patient received donor lymphocyte infusion (DLI) for relapsed t-MDS/AML. Sixty-one percent received reduced-intensity conditioning with fludarabine/melphalan and others received full-intensity conditioning. Sixteen patients developed cGvHD after transplant. After a median follow up of 2.2 years, 8 patients had died (cause of death: t-MDS/AML [n=5], sepsis [n=1], GvHD [n=1], breast cancer [n=1]), with an overall survival of 78.2% at two years post-HCT for the entire cohort. The 2-year overall survival was 71.4% for sibling-related HCT and 84.4% for MUD (log-rank p=0.14). There was a difference in overall survival by the type of cytogenetic abnormalities. Thus, the 2-year survival rate for patients with 11q23 abnormality was 90.9% while that for patients with chromosome 5-/7- abnormalities or complex abnormalities was 62.5% (log rank p=0.27). Patients with cGvHD had better outcome compared with those without cGvHD (2 year survival 87.5% vs. 64.3%, log-rank p value=0.03). These findings were confirmed on multivariate regression analysis, which revealed chromosome 5-/7- or complex abnormalities to be associated with a significantly worse outcome (HR=6.9, p=0.035), while cGvHD was associated with a better outcome (HR=0.14, p=0.02) after adjustment for age at HCT. Conclusions: Although t-MDS/AML after conventional treatment of breast cancer has historically been shown to have a poor prognosis, allogeneic HCT in patients with available donors provides a chance of cure. Among patients undergoing allogeneic HCT, a superior outcome was observed in patients with 11q23 abnormalities and among those with cGvHD. Disclosures: No relevant conflicts of interest to declare.

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Clinical outcomes following laparoscopic management of pT3 renal masses: A large, multi-institutional cohort

Canadian Urological Association Journal ◽

10.5489/cuaj.2848 ◽

2015 ◽

Vol 9 (11-12) ◽

pp. 397 ◽

Cited By ~ 2

Author(s):

Jasmir G Nayak ◽

Premal Patel ◽

Jennifer Bjazevic ◽

Zhihui Lui ◽

Olli Saarela ◽

...

Keyword(s):

Metastatic Disease ◽

Tumour Size ◽

Clinical Stage ◽

Locally Advanced ◽

Progression Free Survival ◽

Renal Masses ◽

Laparoscopic Management ◽

Oncological Outcomes ◽

Kaplan Meier

Introduction: We described the clinical and oncological outcomes of patients treated by laparoscopic surgery for non-metastatic pT3 renal cell carcinoma (RCC).Methods: We queried a multi-institutional database for patients diagnosed with non-metastatic pathological T3 RCC from 13 Canadian centres treated laparoscopically (radical or partial nephrectomy) between 2008 and 2014. Clinical and pathological outcomes were evaluated. Progression was defined as the development of recurrence or metastatic disease. Log-rank testing and Kaplan-Meier statistical methods assessed for differences and estimated progression-free survival (PFS).Results: In total, 176 patients were identified with a median age of 64 years. The median tumour size was 7.0 cm. Pre-clinical stage was cT1 to cT4 in 39%, 28%, 30% and 3%, respectively. The median blood loss was 150 mL (range: 0–6000) and the median operative time was 124 minutes (range: 60–360). Most lesions were clear cell RCC (80%). After a median follow-up of 17.6 months (range: 0.2–75.0), disease progression occurred in 26% (46/176) of patients, consisting of local recurrence in 7% (3/46), and metastatic disease in 93% (43/46). The 3-year PFS was 67%, with a median PFS of 49 months. Of those who progressed, the median time to progression was 10.3 months.Conclusions: This study is the largest cohort of pT3 RCC patients treated laparoscopically in the literature and suggests that for properly selected patients, laparoscopic management of locally advanced renal masses yields acceptable short-term oncological outcomes.

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A Sensitive Replicate RQ-PCR of BCR ABL Transcripts Suggests That A Large Portion of Long Term Post Allogeneic SCT CML Patients Are in Deep MR and May Therefore Be Cured From Their Disease

Blood ◽

10.1182/blood.v120.21.1690.1690 ◽

2012 ◽

Vol 120 (21) ◽

pp. 1690-1690

Author(s):

Maya Koren-Michowitz ◽

Avichai Shimoni ◽

Filomena Daraio ◽

Francesca Crasto ◽

Roberta Lorenzatti ◽

...

Keyword(s):

Median Time ◽

Kinase Inhibitor ◽

Conflicts Of Interest ◽

Conditioning Regimen ◽

Chronic Phase ◽

Disease Status ◽

Molecular Response ◽

Transcript Levels

Abstract Abstract 1690 RQ-PCR has become the major method for the follow up of CML pts in the tyrosine kinase inhibitor (TKI) era. In CML pts undergoing allogeneic SCT (Allo-SCT) it has been shown that successive increase in quantitative BCR ABL transcript levels is in correlation with the clinical outcome and may serve as an early sign of disease relapse and an indication for a therapeutic intervention such as the addition of a TKI or DLI. However, the sensitivity of current RQ-PCR methods which is limited to approximately 10−4 in the majority of routine clinical laboratories, do not allow for the detection of very low BCR ABL transcript levels, and therefore RQ-PCR negativity cannot be regarded as CMR in the majority of pts. Studies of replicate RQ-PCR (rRQ-PCR) have shown that the number of measurement repetitions is relevant in the detection of rare transcripts and rRQ-PCR was found to be more sensitive than conventional RQ-PCR in TKI treated CML pts. We evaluated the role of rRQ-PCR in the detection of MRD in a cohort of long term post Allo-SCT CML patients. Samples from 12 CML pts (M=7, F=5), median age 43 y, at a median time of 85 months after SCT (range 28–136) were tested. SCT was myeloablative (n=6) or with RIC (n=6), from a matched sibling (n=7) or a MUD (n=5), in first chronic phase (CP1) (n=8) or at a later phase (n=4). rRQ-PCR was done in 82 replicates using the same conditions of conventional RQ-PCR. Results of rRQ-PCR are given in Table 1. 75% of the patients had negative RQ-PCR in all 82 wells, while 3 patients had positive results in 1 (1.2%), 2 (2.4%) and 6 (7.3%) wells, respectively, which was above the background determined in normal PB samples (6/901 positive wells, 0.66%). The sensitivity of rRQ-PCR was 10−5.5 or higher in all patients. Negative rRQ-PCR result was not related to the phase at SCT (CP1 vs. others), conditioning regimen (myeloablative vs. RIC), donor type (sibling vs. MUD) or the presence of GVHD. Median time from diagnosis to SCT was borderline longer in patients with positive rRQ-PCR results (61 vs. 25 months, p=0.08). Higher sensitivity RQ-PCR methods are able to further define subgroups of post BMT CML pts and allow for a more accurate follow up of MRD. We will present update clinical data at 1 year after rRQ-PCR determination. Table 1. Results of rRQ-PCR. Patient number Disease status at SCT Conditioning Time from diagnosis to SCT (months) Time from SCT to rRQ-PCR (months) rRQ-PCR result BCR ABL/ABL1 (IS) Total quantity of ABL transcripts Level of MR 1 AP RIC 97 57 0 575034.8 MR5.5 2 CP2 MA 6 30 0.0000862 705622.3 3 CP2 MA 273 48 0.0007393 563237.5 4 CP1 RIC 4 52 0 997521.8 MR6 5 CP1 MA 16 34 0 555768.9 MR5.5 6 CP1 MA 39 30 0 700630.1 MR5.5 7 CP1 MA 6 40 0 874247.9 MR5.5 8 CP1 RIC 61 68 0.0000484 1067353 9 CP1 RIC 33 46 0 938046.4 MR5.5 10 CP1 RIC 18 58 0 1467748 MR6 11 AP RIC 6 28 0 776271.9 MR5.5 12 CP2 MA 3 23 0 860350.6 MR5.5 RIC reduced intensity conditioning; MA myeloablative conditioning; MR molecular response. 1 Average result of positive wells normalized to the international standard. PCR positive in 12, 63 and 24 wells of 82 tested. Disclosures: No relevant conflicts of interest to declare.

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Novel tyrosine kinase inhibitor therapy (NTKI) prior to allogeneic stem cell transplantation (ASCT) in patients (pts) with chronic myeloid leukemia (CML): No evidence for increased transplant-related toxicity

Journal of Clinical Oncology ◽

10.1200/jco.2006.24.18_suppl.16515 ◽

2006 ◽

Vol 24 (18_suppl) ◽

pp. 16515-16515

Author(s):

M. J. De Lima ◽

E. Jabbour ◽

J. E. Cortes ◽

H. Kantarjian ◽

S. Giralt ◽

...

Keyword(s):

Stem Cell ◽

Median Time ◽

Myeloid Leukemia ◽

Kinase Inhibitor ◽

Previous Treatment ◽

Molecular Response ◽

Tyrosine Kinase Inhibitor Therapy ◽

Number Of Patients ◽

Preparative Regimen

16515 Background: Patients undergoing ASCT for CML are increasingly likely to have received a NTKI after failing imatinib mesylate. It is unknown whether the use of these NTKIs prior to ASCT increases transplant-related toxicity. Methods: We retrospectively analyzed the outcome of 8 patients with CML (1 chronic, 4 accelerated, and 3 in blastic) who received dasatinib (n = 2) or AMN-107 (n = 6) prior to ASCT. Results: The median time on treatment was 85 days, and the median time from the end of NTKI therapy to HSCT was 37 days. Preparative regimen was ablative in 5 patients and non-ablative in 3. All patients engrafted within 13 days. There was no significant early transplant-related toxicity. Five patients achieved a molecular response after a median follow-up of 8 months; three complete and two major (Q-PCR < 0.05%). Three patients relapsed within 3 months. Two patients died of disease progression, and extensive GVHD, respectively. Conclusions: Previous treatment with NTKI did not increase transplant-related toxicity in this preliminary experience. Further follow-up and larger number of patients will be necessary to confirm these observations. No significant financial relationships to disclose.

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Open-label, multicenter safety study of vemurafenib in patients with BRAFV600 mutation–positive metastatic melanoma.

Journal of Clinical Oncology ◽

10.1200/jco.2013.31.15_suppl.9046 ◽

2013 ◽

Vol 31 (15_suppl) ◽

pp. 9046-9046 ◽

Cited By ~ 3

Author(s):

James M. G. Larkin ◽

Michele Del Vecchio ◽

Paolo Antonio Ascierto ◽

Jacob Schachter ◽

Claus Garbe ◽

...

Keyword(s):

Metastatic Melanoma ◽

Median Time ◽

Kinase Inhibitor ◽

Very Elderly ◽

Open Label ◽

Safety Study ◽

First Line Therapy ◽

Prior Systemic Therapy ◽

Clinical Trial Information

9046 Background: Vemurafenib (VEM), a BRAF kinase inhibitor, has demonstrated high response rates and improved progression-free and overall survival in pts with BRAFV600mutation–positive metastatic melanoma (mM). We present interim results from predefined subgroups from a large multicenter, open-label safety study of VEM in pts with mM (NCT01307397). Methods: Pts with BRAFV600mutation–positive histologically confirmed mM received VEM (960 mg BID) as first-line therapy or subsequent to previous therapies. Assessments for safety and efficacy were made every 28 days. Results: As of Feb 29, 2012, 2,265 pts have received VEM. Pts had a median age of 54.0 (13-95) yrs and median time since diagnosis of mM of 6.2 (0-351.9) mos. 59% had received prior systemic therapy. Median time of exposure to VEM as of the cut-off date was 3 (0.03-11.24) mos for the overall population and majority of subgroups, and approximately 2.5 mos for pts with ECOG ≥2 and age ≥75 yrs. 1537 (68%) pts were still receiving VEM at the cut-off date. 728 (32%) pts discontinued, most frequently because of PD (538/728 pts; 74%). Adverse events (AEs) were reported for 87% of all patients, with arthralgia (32%) and rash (26%) the most frequent. The incidences of AEs in the subgroups are summarized (Table). Although efficacy analyses are limited by the short duration of follow-up, six-month OS rate was 76% (95% CI 72-79%) and median PFS was 4.1 mos (95% CI 3.9-4.5 mos). Postbaseline tumor assessments were available for 63% and 30% of pts at wk 8 and 16, respectively. At wk 8 CR: 2%, PR: 57%, SD: 30%, PD: 6%. At wk 16 CR: 3%, PR: 46%, SD: 31%, PD: 15%. Conclusions: Although the overall safety profile of VEM in this study was consistent with previous clinical data, interim analyses of subgroups suggest that very elderly pts may be at higher risk of G3 AEs. Clinical trial information: NCT01307397. [Table: see text]

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