Pelvic Bone Marrow Research Articles

Haematological toxicity in cancer cervix patients treated with concurrent chemoradiation by conventional technique- correlation with bone marrow radiation dose

Introduction: The standard of care for treatment of cancer cervix is concurrent chemoradiation followed by brachytherapy in the majority of cases. Conventional radiotherapy with chemotherapy causes haematological toxicities which may be related to radiation to pelvic bone marrow. The present study aims to study the haematological toxicities and correlate with the mean dose to the bone marrow. Material and Methods: Retrospective data of cancer patients treated in the institute in the year 2019 was retrieved. Haematological toxicities were analyzed in terms of CTCAE criteria. Mean dose to bone marrow was calculated after the delineation in the CT scan. The correlation between haematological toxicity and mean bone marrow was done using a paired t-test for statistical significance. Results: The data of 20 patients were retrieved. Anaemia Grade, I and Grade II-IV was seen in 65% and 35% respectively. Leukopenia Grade I and Grade II-IV were seen in 85% and 15% respectively and Lymphopenia Grade I and Grade II-Iv were seen in 55% and 45% respectively. The mean dose to bone marrow did not show any statistical significance with the severity of haematological toxicity. There was no Grade II-IV toxicity of neutropenia and thrombocytopenia. Conclusion: Conventional radiotherapy can safely be practice for patients with cancer cervix with acceptable haematological toxicities.

Chitosan channels with stuffed mesenchyme originated stem/progenitor cells for renovate axonal regeneration in complete spinal cord transection

AIM To examine the implantation of chitosan channels stuffed with mesenchyme-originated stem/progenitor cells (MSPCs) derived from adult rats in a spinal cord transection model. The level of axonal regeneration, the effect of chitosan channels on the survival of MSPCs, and the functional recovery results were also evaluated. MATERIAL AND METHODS Chitosan channels stuffed with MSPCs were implanted at the level of T8 in a transected rat spinal cord. MSPCs were harvested from the pelvic bone marrow of adult rats, and the MSPC?chitosan channel group was compared with three control groups. The axonal regeneration capacity, the effect of chitosan channels on the survival of MSPCs, and the functional recovery results were compared among four groups. The survival of MSPCs was evaluated using histopathological techniques and electron microscopy, axonal regeneration/germination was evaluated by confocal microscopy, and locomotor function was assessed for 4 weeks using the Basso, Beattie, and Bresnahan locomotor score. RESULTS The MSPC-chitosan channel group exhibited enhanced survival of transplanted MSPCs compared with MSPCs transplanted directly into the lesion cavity, although no significant difference was detected in locomotor function between the treatment and control groups. The MSPC-chitosan channel group demonstrated thicker myelination of axons than the other groups. CONCLUSION Chitosan channels promoted the survival of transplanted MSPCs and created a tissue bridge after complete spinal cord transection. They also induced axonal regeneration and germination. No significant improvement in functional recovery was found between the groups.

Association of pre-surgery to pre-radiotherapy lymphocyte counts ratio with disease-free survival in rectal cancer patients receiving neoadjuvant concurrent chemoradiotherapy

BackgroundColorectal cancer is the fourth most common cancer globally and neoadjuvant concurrent chemoradiotherapy (nCRT) and surgery are the standard treatments for locally advanced colorectal carcinoma. This study investigated the association between dynamic changes in absolute lymphocyte counts (ALCs) and disease-free survival (DFS) in rectal cancer patients receiving nCRT and identified factors associated with these changes.MethodsWe retrospectively examined 34 patients with locally advanced rectal cancer who received nCRT followed by surgery and adjuvant chemotherapy. The association between ALCs and DFS and that between ALCs and downstaging were analyzed and potential clinical- and treatment-related factors related to dynamic changes in ALCs were subsequently evaluated. The patient eligibility criteria were as follows: pathologically confirmed rectal adenocarcinoma, clinical stages II–III, ≥ 18 years of age, and so on. Pre-RTL was defined as ALCs obtained before the initiation of nCRT and pre-SL was defined as ALCs obtained before surgery. We measured pre-SL to pre-RTL ratio (pre-SLR), DFS, and ALCs.ResultsThe median ALC declined significantly during nCRT. A lower pre-SLR was associated with poorer DFS with statistical significance in Kaplan–Meier (p = 0.007), univariate regression (hazard ratio [HR] = 6.287, 95% confidence interval [CI] 1.374–28.781, p = 0.018), and multivariable regression (HR = 7.347, 95% CI 1.595–33.850, p = 0.011) analyses. Neither patient characteristics nor treatment-related factors were related to downstaging. The pelvic bone marrow (PBM) volume receiving at least 30 Gy (V30) was significantly associated with pre-SLR in the univariate (HR = 5.760, 95% CI 1.317–25.187, p = 0.020) and multivariable (HR = 5.760, 95% CI 1.317–25.187, p = 0.020) regression analyses.LimitationsOur study had several limitations. The sample size was small and the study was performed in a selected population, which may limit the generalization of the findings.ConclusionsRadiotherapy had a profound impact on the change in ALCs. A lower pre-SLR was significantly associated with poorer DFS in rectal cancer patients receiving nCRT. The V30 of PBM was a predictor of pre-SLR.

Local Field Radiotherapy Induced Therapy Related Myeloid Neoplasms and Bone Marrow Suppression

Introduction: Different cytotoxic agents have been implicated in development of therapy related myeloid neoplasm (t-MN). These include alkylating agents, topoisomerase II inhibitors, antimetabolites, and ionizing field radiation given to large field including active bone marrow (BM) (Swerdlow, 2016). This report highlight the impact of local field radiotherapy on BM through discussing few patients diagnosed in our center who showed profound BM hypocellularity or developed t-MN following exposure to local field radiotherapy without chemotherapy. Local field Radiotherapy as a causative agent for t-MN: A result of retrospective study performed in our center through (2012-2018), a total of 20 patients of t-MN out of 232 total AML patients (8.6%) were detected. Two patients out of 20 (10%) in our cohort had developed t-MN following exposure to local field radiotherapy. Patient (1): 50-year old Asian male diagnosed as Vocal cord tumor, received local field radiotherapy for 2 months with no chemotherapy. 15.8 months later, he presented to with two days history of gum bleeding associated with pancytopenia (WBCx10^3/µl:2.3, Hb g/dl:6.7, Platelets x10^3/µl:100). Peripheral blood smear showed infiltration with many leukaemic promyelocytes and diagnosed as Acute promyelocytic leukemia (APL). The diagnosis was confirmed by BM examination and detection of PML RARA classic rearrangement fusion indicating PML/RARA, t(15;17) in 88.5% cells. Reticulin stain shows increased reticulin fibrosis (1-2/ 3). The patient was stratified as intermediate risk and started on ATRA followed by PETHEMA protocol with complete remission. Patient (2): A 62-year old Egyptian lady with background of hepatitis C and previous stroke, diagnosed as Endometrioid Endometrial Cancer FIGO grade I. The patient received Brachytherapy 21 Gy dose to vaginal vault, in 3 fractions (7 Gy each) without complications. 22 months later, she developed progressive neutropenia and diagnosed as high grade myelodysplastic syndrome (MDS-EB-2) with complex karyotype and P53 somatic mutation, managed by palliative therapy. Discussion: Generally laryngeal cancers radiotherapy is directed to confined area and secondary cancers are more common in the area of close proximity to radiation field. Brachytherapy is a limited source of radiation placed into a cylinder and inserted within the prostate or the vagina for treatment of cancer prostate or endometrial carcinoma respectively. Compared to external radiotherapy (RT), the limited field radiotherapy (including external beam RT and brachytherapy), the doses received by BM is very low and hence the risk of secondary leukaemia is expected to be significantly lower. Although local field RT appears to be associated with a small increase in the incidence of solid cancers, only a few studies have evaluated the risk of developing myeloid malignancies after limited field radiotherapy. Numerous cases of (t-APL) have been reported in the literature mostly following TOPO isomerase II inhibitors. However, up to our knowledge no previous reports of t-MN with recurrent genetic translocations (including t-APL) following local field radiotherapy. Local field radiotherapy induced bone marrow suppression: Two male patients with previous history of cancer prostate and limited field radiotherapy. BM examination for both patients revealed profound hypocellularity (<5-5%) with suppressed trilineage hematopoiesis. Patient (3): A 66 year-old male diagnosed as cancer prostate, subjected to radical prostatectomy, followed by salvage radiotherapy. Two months later, the patient was referred for persistent cytopenia (WBC 2.9 x10^3/uL, Hemoglobin 12.8 gm/dL and platelets (92 x10^3/uL). Follow-up revealed persistent thrombocytopenia. No follow-up BM was performed. Patient (4): A 73-year old male patient with previous history of marginal zone lymphoma and cancer prostate treated by brachytherapy. He underwent BM examination for lymphoma staging. Discussion: For patients who have received adjuvant, salvage or radical RT, a significant portion of the pelvic BM receives a substantial dose of RT. To our knowledge, there are no significant published data assessing the impact of limited field radiotherapy on BM particularly radiation induced BM suppression. Larger studies are required in order to accurately assess the actual effect of local field radiotherapy on hematopoiesis and its genetic profiling. Disclosures No relevant conflicts of interest to declare.

Mid-term (4-7 years) Results of Matrix-Associated Stem Cell Transplantation (MAST) in Chondral Defects of the First Metatarsophalangeal Joint

Category:Midfoot/ForefootIntroduction/Purpose:Matrix-associated stem cell transplantation (MAST) has shown good short-term results for treatment of chondral defects at first metatarsophalangeal joint (MTP1). The aim of the study was to assess mid-term results (=4-year-follow- up).Methods:In a prospective consecutive non-controlled clinical follow-up study, 61 patients with 81 chondral defects at MTP1 that were treated with MAST from October 1, 2011 to October 31, 2014 were analysed. Degree of osteoarthritis, range of motion (ROM), size and location of the chondral defects, pedographic parameters, and the Visual Analogue Scale Foot and Ankle (VAS FA) before treatment and at follow-up were registered and analysed. Bone marrow aspirate was harvested from the ipsilateral pelvic bone marrow and centrifuged (10 minutes, 1,500 RPM). The supernatant was used to impregnate a collagen I/III matrix (Chondro-Guide). The matrix was fixed into the chondral defect with fibrin glue.Results:Following mean (range) values were registered at time of surgery: age 44 (35-72) years, VAS FA 49.4 (12.3-82.3), ROM 20.4/0/8.4° (dorsiflexion/plantarflexion), degree of osteoarthritis 1.9 (1-3). The 81 chondral defects were located as follows, dorsal metatarsal head, n=28 (35%), plantar metatarsal head, n=12 (15%); dorsal & plantar, n=21 (26%); medial sesamoid, n=14 (17%); lateral sesamoid, n=6 (7%)(two defects, n=14, three defects, n=3). The defect size was 0.9 (.5 - 3.0) cm2. Fifty-six patients (92%) completed follow-up at 62 (48-84) months. VAS FA increased to 82.5 (45.6-100; t-test, p<.01). ROM increased to 30.2/0/15.4 (p=.05). Degree of osteoarthritis decreased to 1.1 (0-3, p=.04)Conclusion:The surgical treatment of chondral defects at MTP1 including MAST led to improved clinical scores, ROM and degree of osteoarthritis after 4-7 years. No adverse effects of MAST were registered. Even though a control group is missing, we conclude that MAST is an effective method for the treatment of chondral defects at MTP1.

Response of FDG avid pelvic bone marrow to concurrent chemoradiation for anal cancer

Background and purposeTo determine if suppression of active bone marrow, as defined on FDG PETCT, is seen in on-treatment imaging of anal cancer patients receiving concurrent chemoradiation. Methods and materialsScans from 26 patients participating in the ART trial (full title: Anal squamous cell carcinoma: Investigation of functional imaging during chemoRadioTherapy), a single center observational study with FDG PETCT prior to radiotherapy and at fraction 8–10 of concurrent chemoradiation were analysed. Active bone marrow was contoured in both the pelvis and un-irradiated thoracic spine. SUV and volume of active bone marrow after 8–10 fractions of treatment were compared to baseline. Dose metrics to pelvic active bone marrow were extracted and compared to reduction in SUV/active bone marrow volume and to blood count nadir using linear regression. ResultsSuppression of active bone marrow is seen in the pelvis by a reduction in mean SUV and volume of active bone marrow after 8–10 fractions of treatment. Suppression is not seen in un-irradiated thoracic spine. Dose metrics were associated with reduced SUV and reduced volume of active bone marrow. Volume of active bone marrow receiving <20 Gy was associated with WCC/ANC nadir. 20 Gy was identified as the most likely clinically meaningful dose threshold for toxicity. Volume of active bone marrow receiving <20 Gy correlated to WCC and ANC with an increase of 100 cc being associated with an increase of 0.4 and 0.3 respectively. ConclusionThe effect of concurrent chemoradiation in suppression of active bone marrow is seen in on-treatment FDG PETCT scans. Chemotherapy appears well tolerated after 2 weeks of treatment.

Effect of Pelvic Bone Marrow-Sparing on Acute Hematologic Toxicity in Rectal Cancer Patients Undergoing Chemoradiotherapy

To investigate whether pelvic bone marrow sparing (PBMS) could reduce the incidence of acute hematologic toxicity in rectal cancer patients undergoing chemo-radiotherapy. 84 rectal cancer patients were selected and divided into the IMRT Group (42 cases) and the PBMS-IMRT Group (42 cases). All patients underwent concurrent chemo-radiotherapy. The PTV was prescribed with a total dose of 50∼50.4Gy in 1.8∼2Gy fractions. Capecitabine combined was administered concurrently with pelvic radiation. The pelvic bone was contoured both for the PBMS-IMRT and IMRT groups. Only the pelvic bone in PBMS-IMRT group was prescribed by:V10≤85%,V20≤65%,V30≤45%.The mean dose (Dmean) and the volume of each organ at risk (OAR) with dose range from 5 to 50Gy (e.g., V 5, V10, V15, V20, V25, V30, V35, V40, V45, andV50) was calculated for all the patients from the two groups. The patient acute hematologic toxicity (e.g. patient with symptoms of leukopenia, neutropenia, anemia, or thrombocytopenia) was recorded according to RTOG scoring scale. Independent sample t test were applied for the dose-volume parameters, and card square analysis for clinical parameters. In terms of the OAR dose-volume parameters, the V5∼V35 and Dmean for the pelvic bone, left femoral head and the right femoral head significantly (p<0.05) decreased for the PBMS-IMRT Group compared with the IMRT group. There was no significant difference in any dose-volume parameters for the bladder. As for PTV dose distribution, there was a significant (p=0.001) improvement of the target conformity in the PBMS-IMRT group. In addition, the dose homogeneity was also improved by 14.5% for this group, although not significantly (P=0.108). For the following acute hematologic toxicity observation, the numbers of the patients with grade 0, 1, 2, 3, 4 were 12, 6, 14, 10, and 0 respectively for the IMRT group. Meanwhile the corresponding numbers were 10, 19, 12, 1, and 0 for PBMS-IMRT group. The incidence of grade 2 or upper acute hematologic toxicity in the PBMS-IMRT group was significantly reduced (31%, 13/42 vs. 57.1%, 24/42, p=0.027). There was no incidence of grade 2 or upper acute cystitis in both of the two groups. The marrow-sparing of the pelvic bone significantly reduces its dosage as well as the left and right femoral head. Patients with pelvic bone marrow-sparing had lower incidence of the grade 2 or upper acute hematologic toxicity compared with those without marrow-paring. Pelvic bone marrow-sparing can benefit patients with rectal cancer undergoing chemo-radiotherapy.

Definitive hyperfractionated, accelerated proton reirradiation for patients with pelvic malignancies

IntroductionPelvic reirradiation (re-RT) presents challenges due to concerns for late toxicity to tissues-at-risk including pelvic bone marrow (PBM). We routinely utilize a hyperfractionated, accelerated re-RT for recurrent rectal or anal cancer in the setting of prior radiation. We hypothesized that proton beam radiation (PBR) is uniquely suited to limit doses to pelvic non-target tissues better than photon-based approaches. Materials and methodsAll patients who received hyperfractionated, accelerated PBR re-RT to the pelvis from 2007 to 2017 were identified. Re-RT was delivered twice daily with a 6 h minimum interfraction interval at 1.5 Gray Relative Biological Effectiveness (Gy(RBE)) per fraction to a total dose of 39–45 Gy(RBE). Concurrent chemotherapy was given to all patients. Comparison photon plans were generated for dosimetric analysis. Dosimetric parameters compared using a matched-pair analysis and the Wilcoxon signed-rank test. Survival analysis was performed Kaplan Meier curves. ResultsFifteen patients were identified, with a median prior pelvic RT dose of 50.4 Gy (range 25–80 Gy). Median time between the initial RT and PBRT re-RT was 4.7 years (range 1.0–36.1 years). In comparison to corresponding photon re-RT plans, PBR re-RT plans had lower mean PBM dose, and lower volume of PBM getting 5 Gy, 10 Gy, 20 Gy, and 30 Gy (p < 0.001, p < 0.001, p < 0.001, and p = 0.033, respectively).With median 13.9 months follow-up after PBR re-RT, five patients had developed local recurrences, and four patients had developed distant metastases. One-year overall survival following PBR re-RT was 67.5% and one-year progression free survival was 58.7%. No patients developed acute or late Grade 4 toxicity. ConclusionPBR re-RT affords improved sparing of PBM compared with photon-based re-RT. Clinically, PBR re-RT is well-tolerated. However, given modest control rates with definitive re-RT without subsequent surgical resection, a multidisciplinary approach should be favored in this setting when feasible.

A study of dynamic contrast-enhanced MR imaging features and influence factors of pelvic bone marrow in adult females.

To investigate the effect of menstrual status and age on the perfusion of pelvic bone marrow in adult females using quantitative dynamic contrast-enhanced MRI (DCE-MRI). In total, 96 adult females who underwent DCE-MRI between September 2017 and December 2017 were included. All the subjects' quantitative DCE-MRI parameters of pelvic bone marrow were measured and retrospectively analyzed, including Ktrans (volume transfer constant), Kep (efflux rate constant), and Ve (interstitial volume). According to their menstrual status, the subjects were divided into a premenopausal group (n = 39) and a postmenopausal group (n = 57), and the two groups were then divided into four subgroups according to age. The intraobserver reliability was assessed by the intraclass correlation coefficient (ICC). The parameters were compared between different menstrual status groups and age subgroups by Mann-Whitney test, and Spearman correlation analysis was used to evaluate the correlation between the age and the quantitative parameters. The ICCs of the Ktrans, Kep, and Ve values were 0.989, 0.974, and 0.920, respectively. Ktrans, Kep, and Ve of the premenopausal group were significantly higher than those of the postmenopausal group (P < 0.05). The overall age was negatively correlated with Ktrans, Kep, and Ve (r = - 0.590, - 0.357, and - 0.381, respectively, P < 0.05). In the premenopausal group, Ktrans and Ve were significantly higher in subgroup 1 (≤ 40years) compared with subgroup 2 (> 40years) (P < 0.05), and age showed a negative correlation with Ktrans and Ve (r = - 0.344 and - 0.334, respectively, P < 0.05). In the postmenopausal group, Ktrans and Kep were significantly higher in subgroup 3 (≤ 60years) compared with subgroup 4 (> 60years) (P < 0.05), and age showed a negative correlation with Ktrans and Kep (r = - 0.460 and - 0.303, respectively, P < 0.05). Menstrual status and age have significant effects on the perfusion of the pelvic bone marrow microenvironment in adult females and that the microenvironment of the pelvic bone marrow displays different changes at different age stages. Quantitative DCE-MRI has contributed to the interpretation of the pelvic bone marrow perfusion status.

Correlation between pelvic bone marrow radiation dose and acute hematological toxicity in cervical cancer patients treated with concurrent chemoradiation.

PurposeTo evaluate the association between pelvic bone marrow (BM) dose volume parameters and probability of acute hematological toxicity (HT), a cohort of cervical cancer patients receiving definitive chemoradiation (CRT) was assessed.Materials and methodsMedical records of patients treated by CRT (45 Gy in 25 fractions, without dose constraints applied to the BM) were reviewed. Baseline and weekly hematological parameters were collected. BM was retrospectively delineated and divided into sub-sites: iliac crests, lower pelvis, lumbosacral region. BM volumes (V) receiving 5, 10, 20, 30, 40 Gy (V5, V10, V20, V30, V40, respectively) and mean dose (Dm) were calculated. Logistic regression was used to analyze associations between HT and dose-volume histograms parameters.Results114 patients were included. 75.4% were treated with 3D radiation therapy and 24.6% were receiving intensity modulated radiation therapy (IMRT). Neither age, chemotherapy regimen (cisplatin vs carboplatin), number of chemotherapy cycles, performance status, body mass index, or para-aortic irradiation were associated with HT. In univariate analysis, more frequent grade 3+ leukopenia was found in the IMRT group (odds ratio [OR]: 3.5; 95% CI, 1.4–9.1; p=0.007). In multivariate analysis, grade 4 HT was associated with lower pelvis V5>95% (OR 4.1; 95% CI, 1.6–14. p=0.02), lower pelvis V20>45% (OR 3.5; 95% CI, 1.1–13.4; p=0.05), total pelvic bone V20>65%, and iliac crests Dm >31 Gy (OR 4.5; 95% CI, 1.4–14.7; p=0.02).ConclusionThe following dose constraints could be proposed to decrease acute HT risk: lower pelvis V5<95%, lower pelvis V20≤45%, total pelvic bone V20<65%, and iliac crests Dm <31 Gy.

Dosimetric Comparison of Pelvic Bone Marrow Preservation between Volumetric-Modulated Arc Therapy and Intensity-Modulated Radiotherapy in Radical Radiotherapy of High-Risk Prostate Cancer

Background: Pelvic bone marrow (PBM) preservation is one of the factors that should be taken into consideration while choosing a technique for radiotherapy of pelvic malignancies. Aim: To dosimetrically compare between volumetric-modulated arc therapy (VMAT) and intensity-modulated radiotherapy (IMRT) in PBM preservation in radical treatment of high-risk prostate cancer. Methods: In 26 patients with high-risk prostatic carcinoma, dual arc VMAT and 7 fields IMRT plans were generated. In every patient, two targets were defined, clinical target volume (CTV) including the prostate and seminal vesicles (CTV-PSV) and CTV including pelvic lymph nodes (CTV-LN). The organs at risk delineated were the rectum, urinary bladder, small intestine, bulb of the penis, femoral heads bilaterally and PBM. The dose prescribed to the CTV-PSV was 76 Gy in 38 fractions given over 7.5 weeks and the dose to CTV-LN was 54 Gy in 38 fractions given over 7.5 weeks. Planning target volume (PTV) was created from the CTV with a margin of 5 mm in all direction. For assessment of PBM dose, V10, V20, V30, V40, V50 and mean dose were calculated. The dose volume histogram of PTV and PBM for both techniques was compared. Results: The mean dose of PTV 54 Gy was achieved in both techniques adequately with better sparing of organs at risk with the VAMT technique. The mean dose for PBM in the VMAT technique was significantly less than that in the IMRT (21.7 Gy vs. 25.8 Gy, respectively; p < 0.001). The significant differences in PBM doses were in the range of 20 Gy to 40 Gy. Conclusion: In radical treatment of prostate cancer, VMAT technique can offer comparable conformality to IMRT with better PBM preservation. Awareness of PBM delineation and reduction of its doses using VMAT can help to decrease the hematological toxicity.

Mid-term (4–7 years) results of matrix-associated stem cell transplantation (MAST) in chondral defects of the first metatarsophalangeal joint

Matrix-associated stem cell transplantation (MAST) has shown good short-term results for treatment of chondral defects at first metatarsophalangeal joint (MTP1). The aim of the study was to assess mid-term results (≥4-year-follow-up). In a prospective consecutive non-controlled clinical follow-up study, 61 patients with 81 chondral defects at MTP1 that were treated with MAST from October 1, 2011 to October 31, 2014 were analysed. Degree of osteoarthritis, range of motion (ROM), size and location of the chondral defects, pedographic parameters, and the Visual Analogue Scale Foot and Ankle (VAS FA) before treatment and at follow-up were registered and analysed. Bone marrow aspirate was harvested from the ipsilateral pelvic bone marrow and centrifuged (10 min, 1500 RPM). The supernatant was used to impregnate a collagen I/III matrix (Chondro-Guide, Geistlich, Wollhusen, Switzerland). The matrix was fixed into the chondral defect with fibrin glue. Following mean (range) values were registered at time of surgery: age 44 (35–72) years, VAS FA 49.4 (12.3–82.3), ROM 20.4/0/8.4° (dorsiflexion/plantarflexion), degree of osteoarthritis 1.9 (1–3). The 81 chondral defects were located as follows, dorsal metatarsal head, n = 28 (35%), plantar metatarsal head, n = 12 (15%); dorsal & plantar, n = 21 (26%); medial sesamoid, n = 14 (17%); lateral sesamoid, n = 6 (7%) (two defects, n = 14, three defects, n = 3). The defect size was 0.9 (.5–3.0) cm2. Fifty-six patients (92%) completed follow-up at 62 (48–84) months. VAS FA increased to 82.5 (45.6–100; t-test, p < .01). ROM increased to 30.2/0/15.4 (p = .05). Degree of osteoarthritis decreased to 1.1 (0–3, p = .04). The surgical treatment of chondral defects at MTP1 including MAST led to improved clinical scores, ROM and degree of osteoarthritis after 4–7 years. No adverse effects of MAST were registered. Even though a control group is missing, we conclude that MAST is an effective method for the treatment of chondral defects at MTP1. Die Matrix-Assoziierte Stammzelltransplantation (MAST) hat gute kurzfristige Ergebnisse bei der Therapie von Knorpeldefekten am Großzehengrundgelenk (MTP1) gezeigt. Ziel dieser Studie war die Analyse von mittelfristigen Ergebnissen (≥4-Jahre-Nachuntersuchung). In einer prospektiven konsekutiven unkontrollierten Nachuntersuchungsstudie wurden 61 Patienten mit 81 Knorpeldefekten an MTP1, die mit MAST von 01.10.2011 bis 31.10.2014 behandelt wurden, analysiert. Arthrosegrad, Bewegungsumfang (ROM), Größe und Lokalisation des Knorpeldefekts, pedographische Parameter und Visual Analog Skala Fuß und Sprunggelenk (VASFA) wurden präoperativ und bei der Nachuntersuchung registriert und analysiert. Knochenmarkpunktat wurde am gleichseitigen Beckenkamm gewonnen und zentrifugiert (10 Minuten mit 1.500 Umdrehungen/Minute). Mit dem zellreichen Überstand wurde eine Kollagen-I/III-Matrix (Chondro-Gide) imprägniert. Diese Matrix wurde mit Fibrinkleber und die Knorpeldefekte eingeklebt. Zum OP-Zeitpunkt wurden folgende Mittelwerte (Spannweite) registriert: Alter 44 (35-72) Jahre, VAS FA 49,4 (12,3-82,3), ROM 20,4/0/8,4° (Dorsalextension/Plantarflektion), Arthrosegrad 1.9 (1-3). Die 81 Knorpeldefekte waren wie folgt lokalisiert: Metatarsalekopf dorsal, n = 28 (35%); Metatarsalekopf plantar, n = 12 (15%); dorsal & plantar, n = 21 (26%), mediales Sesambein, n = 14 (17%), laterales Sesambein, n = 6 (7%) (zwei Defekte, n = 14; drei Defekte, n = 3). Die Defektgröße betrug 0,9 (0,5-3,0) cm2. Sechsundfünfzig Patienten (92%) wurden nach 62 (48-84) Monaten nachuntersucht. VAS FA stieg auf 82.5 (45.6-100; t-test, p<.01). ROM stieg auf 30.2/0/15.4 (p=.05). Der Arthrosegrad verringerte sich auf 1.1 (0-3, p=.04). Die operative Behandlung von Knorpeldefekten and MTP1 mit MAST führte zu verbesserten Scores, ROM und Arthrosegrad nach 4-7 Jahren. Unerwünschte Ereignisse wurden nicht registriert. Auch unter Berücksichtigung der fehlenden Kontrollgruppe schlussfolgern wir, dass MAST eine effektive Methode für die Therapie von Knorpeldefekten an MTP1 darstellt.

Management for locally advanced cervical cancer: new trends and controversial issues.

This article reviewed new trends and controversial issues, including the intensification of chemotherapy and recent brachytherapy (BT) advances, and also reviewed recent consensuses from different societies on the management of locally advanced cervical cancer (LACC). Intensive chemotherapy during and after radiation therapy (RT) was not recommended as a standard treatment due to severe toxicities reported by several studies. The use of positron emission tomography-computed tomography (PET-CT) and magnetic resonance imaging (MRI) for pelvic RT planning has increased the clinical utilization of intensity-modulated radiation therapy (IMRT) for the evaluation of pelvic lymph node metastasis and pelvic bone marrow. Recent RT techniques for LACC patients mainly aim to minimize toxicities by sparing the normal bladder and rectum tissues and shortening the overall treatment time by administering a simultaneous integrated boost for metastatic pelvic lymph node in pelvic IMRT followed by MRI-based image guided adaptive BT.

Impact of pelvic bone marrow irradiation on the hematological toxicity of subsequent chemotherapy in rectal cancer

Preoperative radio(chemo)therapy in rectal cancer may irreversibly damage pelvic bone marrow (PBM) and impair the tolerance of subsequent chemotherapy. The aim of the study was to assess the relationship between the irradiated volume of PBM and the toxicity of subsequent 5-fluorouracil, oxaliplatin, leucovorin (FOLFOX-4) in rectal cancer. We included consecutive rectal cancer patients who received FOLFOX-4 postoperatively or due to cancer relapse. The PBM was divided into iliac (IM), lumbosacral (LSM), and lower pelvic (LPM) marrow. We assessed mean dose, and percentage of volume receiving 10%-90% (V10%-V90%) of the prescribed dose for PBM, IM, LSM, and LPM. Generalized linear model for repeated measures (GLM) was used to test an influence of dose-volumes distribution on toxicities grade 2 or higher (TOX2) and grade 3 or higher (TOX3). The two-sided t-test was used to evaluate the difference in mean dose, mean V20%, and mean V40% between patients who experienced TOX2 or TOX3 and those who did not. 39 patients met eligibility criteria. Because of the low occurrence of TOX3 (n=3), related analyses were abandoned. We found no influence of dose-volume distribution on TOX2 in GLM and no significant differences in mean dose, mean V20%, and mean V40% for PBM, IBM, LSM, and LPM between patients who experienced TOX2 and those who did not. To conclude, no relationship between doses received by PBM in preoperative radio(chemo)therapy in rectal cancer and hematological tolerance of subsequent FOLFOX-4 chemotherapy was found.

114. Pelvic bone marrow dosimetric parameters analysis relating to hematologic toxicity in gynecological tumors patients treated with volumetric modulated arc therapy

Purpose To test the hypothesis that the volume of pelvic bone marrow (PBM) receiving 10–20-30–40 Gy (V10-V20-V30-V40) and median dose is associated with hematologic toxicity (HT) in gynecological cancer patients treated with concurrent chemoradiotherapy. Methods and materials We analyzed 29 consecutive gynecological cancer patients (21 only RT and 8 with concurrent chemotherapy) and volumetric-modulated-arc radiation therapy at the Varese Hospital between 2013 and 2015. The median radiation dose prescribed was 50.4 Gy (1,8 Gy daily fractions). The external contour of the PBM was delineated on the planning CT using bone windows was defined as the region extending from the iliac crests to the ischial tuberosities, including the os coxae, lumbosacral spine and proximal femora, and the relative dose volume histogram (DVHs) were calculated. HT was graded according to CTCAE and endpoints included the white blood cell count, absolute neutrophil count, hemoglobin, and platelet count nadirs. Results Non-parametric test for independent samples (Mann–Whitney test) show that the difference between the two groups was not significant for any Vx (p = 0.49). The Table 1 shows the mean values referred all patients in relation to the dose constraints used in the treatment planning. We identified only one patient associated with acute HT G3 (Table 1). Conclusion Techniques to limit PBM irradiation may reduce HT in cervical cancer patients. Only one patient developed acute HT G3, however, the values of DVH(Vx) related to pelvic bone structures are within the dose constraints. V40 results the most critical volume, this value is above the limit in 58.6% of patients, but none of them has developed acute HT. The Vx proposed by the scientific community are valid and safe for HT. We’re working on calculating cumulative DVH area-equivalent using the Lymann algorithm in order to evaluate if this parameter is capable of describing toxicity better than usual indexes like V10-V40.

Changes in Pelvic Active Bone Marrow seen on FDG-PET in Patients Receiving Concurrent Chemoradiation for Anal Cancer

Radical concurrent chemoradiation (CRT) for locally advanced anal cancer is associated with suppression of active bone marrow. We seek to determine the degree of suppression seen in FDG-PET imaging attributable to chemotherapy and attributable to chemoradiation. Anal cancer patients undergoing CRT had FDG PET scans prior to treatment (baseline scan) and at radiotherapy fraction 8-10 (wk2 scan) as part of the ART Trial (Anal squamous cell carcinoma: Investigation of functional imaging during CRT NCT02145416). RT was delivered in 28 fractions; 53.2/50.4 Gy to tumor and involved nodes, 40 Gy to elective nodes. Chemotherapy consisted of 12 mg/m2 Mitomycin D1 and 825 mg/m2 Capecitabine D1-D28 radiotherapy days only. PET scans were taken on GE Discovery scanner after 60 min (75 min on average) FDG uptake time. Whole bone was used to define bone marrow. Average SUV values were extracted from static scans for irradiated whole pelvic bone marrow (PBM), PBM substructures (iliac BM, lower pelvic BM, and lumbosacral BM) and non-irradiated thoracic spine (T9-11) using a treatment planning system. Median SUV in whole PBM was compared using Wilcoxon signed-rank test. Of the 29 patients recruited to ART, 12 had PET scans at both time points. Of these, two patients received 61.6 Gy in 28 and one 41.4 Gy in 23. All other patients received standard radiotherapy of 50.4 Gy (3 patients total) or 53.2 Gy (6 patients total). RT plan PBM V10 exceeded 60% for all patients and V20 exceeded 47%, equating to >2.9 Gy and 5.7 Gy, respectively, at the time of wk2 scan. A summary of SUV values is seen in the Table below.Abstract SU_4_2038; Table 1PBMIliac BMLower Pelvis BMLumbosacral BMT9-11Baseline Median1.131.171.001.331.66 Max1.631.691.402.072.70 Min0.830.900.730.901.28Wk2 Median0.991.090.851.161.67 Max1.231.331.091.432.37 Min0.740.740.640.790.45 Open table in a new tab There was a statistically significant reduction in the median SUV in the PBM from baseline to wk2 scan (median difference -0.20 (95% CI: -0.29, -0.04), p=0.006). A decrease was seen in all substructures with the largest decrease seen in lumbosacral (-0.22, -0.41, -0.07) and roughly equal reduction in iliac (-0.16, -0.31, 0.01) and lower pelvis (-0.16, -0.27, -0.01). A reduction was not observed in the non-irradiated thoracic spine (0.05, -0.25, 0.19)). The impact of concurrent chemoradiation on PBM is seen in reduced SUV values at wk2 compared to baseline. The effect of chemo only on SUV appears non-significant at wk2. Suppression of active bone marrow in CRT for anal cancer is therefore likely the combined toxicity of chemoradiation with chemotherapy in isolation relatively well tolerated at wk2 of treatment. Larger scale studies are required. The Oxford C REC ethically approved the trial. The trial was sponsored by the University of Oxford, funded by the CRUK & EPSRC Cancer Imaging Centre Oxford, and managed by the Oxford Clinical Trials and Research Unit. Oversight was provided by the Radiotherapy and Imaging Oversight Committee.

Intensity-Modulated Proton Therapy (IMPT) Reduces Dose to Pelvic Bone Marrow and Normal Pelvic Organs when Compared to Volumetric-Modulated Arc Therapy (VMAT) for patients with Anal Cancer

Anal squamous cell carcinoma (SCCa) has high cure rates with concurrent chemoradiotherapy (CRT), but acute toxicity rates are high. Severe lymphopenia, resulting from low absolute lymphocyte count (ALC), has been correlated with worse overall survival in several cancer types. We hypothesized that decreased dose to the pelvic bone marrow (PBM) correlates with decreased ALC nadir. In this work, we compared doses to the PBM and other organs-at-risk for patients treated with IMPT and VMAT. We also evaluated ALC, white blood cell counts (WBC) and absolute neutrophil counts (ANC) values and correlated these values with PBM doses. We analyzed 16 consecutive stages I-III anal SCCa patients treated between 1/1/2017 and 1/1/2018 with cisplatin and 5-fluorouracil-based CRT using VMAT. WBC, ANC, and ALC values were obtained weekly during treatment. The nadirs were identified and compared with various dosimetric parameters for PBM using the Pearson correlation. Ten consecutive patients treated with either VMAT (N = 8) or IMPT (N = 2) had both VMAT and IMPT plans generated and 6 patients had only VMAT plans. IMPT plans were generated using two posterior oblique beams for posterior pelvic targets (hinge angle ranged between 40 and 70 degrees with respect to each other) and anterior beam for inguinal nodal targets. Field specific targets were created for each beam, and plan was robustly optimized with Isocenter-shift of 0.5 cm and 3.5% range uncertainty in combination (12 perturbations). Dosimetric parameters for the PBM, bowel bag, bladder and external genitalia were compared with the Wilcoxon signed-rank test. For the 16 patients, the WBC, ANC, and ALC nadirs (mean ± SD) were 3.2 ± 1.0 K/uL, 2.2 ± 1.3 K/uL and 0.32 ± 0.17 K/uL, respectively. Increased volume of PBM receiving 10 Gy or more (V10) significantly correlated with decreased ALC nadir (R2 = 0.25, p = 0.049). There were no significant differences between PBM parameters and WBC or ANC nadirs. For the 10 patients for whom VMAT and IMPT plans were generated, IMPT was associated with lower doses to the PBM, bladder and genitalia but a higher maximum dose to the bowel (Table). Decreased V10 of the PBM is associated with decreased ALC nadirs in patients undergoing CRT for anal SCCa. IMPT is able to spare unnecessary dose to the PBM as well as the bladder and genitalia compared with VMAT. Clinical studies are needed to see whether these dosimetric benefits yield meaningful reductions in acute or long-term hematologic or non-hematologic toxicity.Abstract SU_2_2013; Table 1IMPT; mean±SDVMAT; mean±SDWilcoxon P-valueMean Pelvic BM21±4 Gy(RBE)29±3 Gy.004Pelvic BM V10 (%)65±1393±5.004Pelvic BM V20 (%)51±1276±8.004Pelvic BM V30 (%)37±748±7.004Pelvic BM V40 (%)20±425±5.016Bowel Bag Dmax52±3 Gy(RBE)42±21.010Bowel Bag V45 (cm3)178±120176±131.193Bladder V40 (%)28±1542±18.002Genitalia V30 (%)10±827±15.008 Open table in a new tab

Association Between Bone Marrow Dosimetric Parameters and Acute Hematologic Toxicity in Locally Advanced Rectal Cancer Patients Treated with Concurrent Weekly Irinotecan in Combination with Capecitabine-Based Chemoradiotherapy and Neoadjuvant IMRT

To test the hypothesis that increased pelvic bone marrow (BM) irradiation is associated with increased hematologic toxicity (HT) in locally advanced rectal cancer (LARC) patients undergoing weekly irinotecan in combination with capecitabine-based neoadjuvant chemoradiotherapy. We analyzed 95 patients with clinical stage T3-4, N0-2 who were eligible for preoperative chemoradiotherapy and UGT1A1*28 6/6 genotype in Fudan University Shanghai Cancer Centre (FUSCC) from November 2015 to January 2018. The dose of weekly irinotecan was 80 mg/m2 for UGT1A1*28 6/6 genotype patients, whereas the dose of capecitabine was fixed at 625 mg/m2. Intensity-modulated radiation therapy (IMRT) was applied to the whole pelvis with total dose of 50 Gy in 25 fractions. Pelvic bone marrow (BM) was delineated as ilium (IL), lumbosacral (LS), lower pelvis (LP), and the relative DVHs were calculated. All patients underwent blood cell counts twice a week. The endpoint for hematologic toxicity was grade≥3 (HT3+) leukopenia, neutropenia, anemia or thrombocytopenia according to CTCAE V4.03. Logistic regression was used to analyze correlation between dosimetric parameters and grade≥3 hematologic toxicity. Linear regression models were used to test for correlation to nadir blood counts. Thirty of 95 (31.6%) patients achieved pathological complete response (PCR). Twenty of 95 (21.1%) patients experienced grade≥3 hematologic toxicity. On univariate and multivariate logistic regression, the dosimetric parameter V10 Gy to the lower pelvic BM (LP V10) was associated with grade≥3 hematologic toxicity. Increased LP V10 was associated with an increased grade≥3 hematologic toxicity (p=0.015). Patients with LP V10 ≥90% had higher rates of grade ≥3 hematologic toxicity than did patients with LP V10 <90% (33.3%, 14/42 vs. 11.3%, 6/53, p=0.01). Linear regression analysis showed iliac and lower pelvic BM dose metrics to associate with reduced nadir ANC and WCC. On multivariate analysis, only LP V10 remained associated with nadir ANC (p=0.022). These findings support the hypothesis that HT increases with increasing pelvic BM volume irradiated. Efforts to maintain LP V10 <90% may reduce grade ≥3 hematologic toxicity in LARC patients undergoing concurrent capecitabine combined with weekly irinotecan and pelvic intensity-modulated radiation therapy (IMRT).

Total Body Quantification of Active Bone Marrow Response to Chemoradiation Therapy Using FLT PET Images in Pelvic Cancer Patients

To quantify bone marrow radiation dose response using total body bone marrow (TBBM) quantification analysis of sequentially obtained FLT PET images prior to, during, and after chemoradiation therapy in pelvic cancer patients. A total of 33 pelvic cancer patients were enrolled in IRB approved protocols to obtain FLT PET images prior to, during, and after chemoradiation therapy. Pre-therapy images were used as a control for pelvic bone marrow FLT uptake change. Time series FLT PET images were acquired after 1 week (5 fractions) and 2 weeks (10 fractions) during therapy and 30 days and 1 year after therapy was complete. Weekly low dose (20 mAs) attenuation correction CTs (AC CTs) were co-registered to the FLT PET images. All FLT images were resampled according to the voxel size of the AC CT. The region of interest (ROI) was defined as 5cm above the auditory canal to 10cm below the greater trochanter using a threshold value of 300 HU on each AC CT. The resampled FLT images were used to calculate the voxel by voxel FLT uptake value as a surrogate for marrow activity. A TBBM value was calculated by summing each FLT voxel value and normalizing by the number of voxels with the ROI. The results for each subject were averaged over each time point, but all subjects did not complete all time points. TBBM voxel by voxel analysis of bone marrow activity was calculated as a single normalized value for each time point with all available subject data sets: Week 0 (N = 33), Week 1 (N = 31), Week 2 (N = 28), 30 Day (N = 26), and 1 Year (N = 18). The average TBBM activity values using the 300 HU threshold were 1626 ± 434, 1438 ± 334, 1244 ± 294, 1644 ± 341, and 1613 ± 445 for Week 0, Week 1, Week 2, 30 Day, and 1 Year time points respectively. On average, Week 1 TBBM activity was 88% of Week 0 activity and Week 2 TBBM activity was 76% of Week 0 activity. TBBM recovered to within 1% of Week 0 activity 30 days and 1 year after therapy. TBBM variation was relatively high with a coefficient of variation (CV) of 27%, 23%, 24%, 21%, and 28% for Week 0, Week 1, Week 2, 30 Day and 1 Year time points respectively, which is likely due to individual patient variation. Other HU thresholds were used to identify bone, which results in higher or lower absolute values of TBBM activity. However, the relative change was within 1% and the CV was within 5%. This indicates that identifying the boney ROI for TBBM calculation is relatively insensitive to the HU threshold value even with a low quality, low dose CT. This study shows the potential of an image analysis tool that quantifies TBBM activity for pelvic cancer patients before, during, and after chemoradiation therapy. This metric accounts for both bone marrow depletion and compensatory effects. Correlating an individual patient TBBM value to systemic changes in CBCs could enable patient specific therapy that maximizes therapeutic effect while minimizing toxicity.

Research progress in effect of pelvic bone marrow-sparing intensity-modulated radiotherapy on hematologic toxicity in pelvic tumor patients after concurrent chemoradiotherapy

Concurrent chemoradiotherapy can improve the survival rate in patients with advanced pelvic tumors. However, it also increases the incidence of hematologic toxicity and other adverse events. Patients cannot tolerate these adverse events and discontinue the therapy. Pelvic bone marrow-sparing intensity-modulated radiotherapy (PBMS-IMRT) possesses obvious advantages in reducing the radiation dose and volume of the pelvic bone marrow. In this article, comparison between PBMS-IMRT and other irradiation therapies, correlation between dosimetric parameters and hematologic toxicity and imaging methods with precise delineation of the active bone marrow were reviewed. Key words: Pelvic neoplasm/pelvic bone marrow-sparing intensity-modulated radiotherapy; Hematologic toxicity; Dosimetric parameters