Pneumorrhachis Secondary to a Locally Advanced Rectal Cancer with Pre-Sacral Abscess-Case Report and Review.

The occurrence of pneumorrhachis (PR), defined as the presence of air within the spinal canal, presents a complex clinical picture with diverse etiological factors. We report an exceedingly rare case of PR arising from locally advanced rectal cancer accompanied by a pre-sacral abscess. This report aims to enhance awareness and understanding of rare causes of PR within the medical community, particularly among surgeons engaged in emergency procedures. The patient survived the acute phase of the disease through multiple surgical interventions and admission to the intensive care unit, but succumbed to cardiovascular complications three weeks later. We also offer a brief review of the literature concerning PR originating from the colorectal lumen.

Exploring the Influence of Age, Gender and Body Mass Index on Colorectal Cancer Location.

Background and objectives: The global burden of non-communicable diseases like obesity and cancer, particularly colorectal cancer (CRC), is increasing. The present study aimed to investigate the association between CRC location (proximal vs. distal) and patient demographic factors including age, sex, and BMI, as well as cancer stage at diagnosis. Materials and Methods: In this cross-sectional study, data from 830 patients diagnosed with CRC were analyzed. The variables included age, sex, weight, height, BMI, cancer location, and cancer stage at diagnosis. Patients were stratified into three age groups and three BMI categories, and we analyzed the association between cancer location and these variables using Chi-squared tests and multivariate logistic regression. Results: The rectum and ascending colon were the most common locations of malignant neoplasms. No statistically significant differences in cancer location across age groups were observed. Significant differences were found in the BMI across age groups, particularly in the normal weight and overweight categories. Normal weight and obese patients had a higher proportion of Stage 3 and Stage 4 cancers. Obesity emerged as a significant predictor for rectal cancer in a multivariate logistic regression analysis, with an odds ratio of 1.56. However, no significant associations were found between cancer location and other factors like age, gender, or cancer stage. Conclusions: Our study revealed that normal weight and obese patients had a higher proportion of Stage 3 and Stage 4 cancers, with obesity emerging as a significant predictor for rectal cancer. It is important to note that while obesity was found to be a significant predictor for rectal cancer, the development and location of colorectal cancer is likely influenced by various factors beyond those studied here. Therefore, further research is needed to investigate the roles of other potential risk factors, like loss of SIRT6 and adipose tissue homeostasis. Additionally, inflammation associated with microbiota in the colorectal mucosa, systemic gene expression, and visceral obesity may also play important roles in the development and progression of colorectal cancer. Understanding these intricate relationships is crucial for better screening, disease prognosis, and management strategies.

Discovery of a putative blood-based protein signature associated with response to ALK tyrosine kinase inhibition.

BACKGROUND: ALK tyrosine kinase inhibition has become a mainstay in the clinical management of ALK fusion positive NSCLC patients. Although ALK mutations can reliably predict the likelihood of response to ALK tyrosine kinase inhibitors (TKIs) such as crizotinib, they cannot reliably predict response duration or intrinsic/extrinsic therapeutic resistance. To further refine the application of personalized medicine in this indication, this study aimed to identify prognostic proteomic biomarkers in ALK fusion positive NSCLC patients to crizotinib. METHODS: Twenty-four patients with advanced NSCLC harboring ALK fusion were administered crizotinib in a phase IV trial which included blood sampling prior to treatment. Targeted proteomics of 327 proteins using MRM-MS was used to measure plasma levels at baseline (including pre-treatment and early treatment blood samples) and assess potential clinical association. RESULTS: Patients were categorized by duration of response: long-term responders [PFS ≥ 24 months (n = 7)], normal responders [3 < PFS < 24 months (n = 10)] and poor responders [PFS ≤ 3 months (n = 5)]. Several proteins were identified as differentially expressed between long-term responders and poor responders, including DPP4, KIT and LUM. Next, using machine learning algorithms, we evaluated the classification potential of 40 proteins. Finally, by integrating the different analytic methods, we selected 22 proteins as potential candidates for a blood-based prognostic signature of response to crizotinib in NSCLC patients harboring ALK fusion. CONCLUSION: In conjunction with ALK mutation, the expression of this proteomic signature may represent a liquid biopsy-based marker of long-term response to crizotinib in NSCLC. Expanding the utility of prognostic biomarkers of response duration could influence choice of therapy, therapeutic sequencing, and potentially the need for alternative or combination therapy.Trial registration ClinicalTrials.gov, NCT02041468. Registered 22 January 2014, https://clinicaltrials.gov/ct2/show/NCT02041468?term=NCT02041468&rank=1.

What Is the Comparative Efficacy of Surgical, Endoscopic, Transanal Resection, and Radiotherapy Modalities in the Treatment of Rectal Cancer?

BACKGROUND: Rectal cancer is a significant healthcare burden, and effective treatment is crucial. This research aims to compare the effectiveness of surgical and endoscopic resection, transanal resection, and radiotherapy. METHODS: A literature analysis was conducted in order to identify relevant studies, by comparing the different surgical approaches and variables affecting treatment decisions. The findings were analyzed and synthesized to provide a comprehensive overview. RESULTS: Surgical treatment, particularly TME (total mesorectal excision), proved consistent efficacy in achieving complete tumor resection and improving long-term survival. Endoscopic treatment and transanal resection techniques were promising for early-stage tumors but were associated with higher local recurrence rates. Radiotherapy, especially in combination with chemotherapy, played a crucial role in locally advanced cases, improving local control and reducing recurrence risk. Patient data, tumor characteristics, and healthcare system factors were identified as important factors in treatment modality selection. CONCLUSION: Surgical treatment, specifically TME, remains the recommended standard approach for rectal cancer, providing excellent oncological outcomes. Endoscopic treatment and transanal resection techniques can be considered for selected early-stage cases, while radiotherapy is beneficial for locally advanced tumors. Treatment decisions should be personalized based on patient and tumor characteristics, considering the available resources and expertise within the healthcare system.

The Challenges of Colorectal Cancer Surgery during the COVID-19 Pandemic in Romania: A Three-Year Retrospective Study.

The predictions on the influence of the SARS-CoV-2 pandemic on access to medical services in Romania predicted a 35% drop in oncological hospitalizations in 2020 compared to the previous decade, raising the hypothesis that patients with colorectal cancer can become indirect victims of the ongoing pandemic. Therefore, the aim of the current research was to observe how the COVID-19 pandemic influenced colorectal cancer surgery in Romania, to determine the level of addressability towards specialized care, to compare the cancer staging between the pandemic and pre-pandemic periods, and to observe the risk factors for disease progression. This retrospective study was spread over three years, respectively, from March 2019 to March 2022, and included a total of 198 patients with a history of colorectal cancer surgery. It was decided to perform a parallel comparison of 2019, 2020, and 2021 to observe any significant changes during the pandemic. Our clinic encountered a significant decrease in all interventions during the pandemic; although the number of CRC surgeries remained constant, the cases were more difficult, with significantly more patients presenting in emergency situations, from 31.3% in 2019 to 50.0% in 2020 and 57.1% in 2021. Thus, the number of elective surgeries decreased significantly. The proportion of TNM (tumor-node-metastasis) staging was, however, statistically significant between the pre-pandemic and pandemic period. In 2019, 13.3% of patients had stage IIa, compared with 28.8% in 2020 and 13.1% in 2021. Similarly, the proportion of very advanced colorectal cancer was higher during the pandemic period of 2020 and 2021 (12.0% in 2019 vs. 12.5% in 2020 and 25.0% in 2021), which was represented by a significantly higher proportion of patients with bowel perforation. Patients with an advanced TNM stage had a 6.28-fold increased risk of disease progression, followed by lymphovascular invasion (HR = 5.19). However, the COVID-19 pandemic, represented by admission years 2020 and 2021, did not pose a significant risk for disease progression and mortality. In-hospital mortality during the pandemic also did not change significantly. After the pandemic restrictions have been lifted, it would be advisable to conduct a widespread colorectal cancer screening campaign in order to identify any instances of the disease that went undetected during the SARS-CoV-2 pandemic.

Opportunistic Colonoscopy Cancer Screening Pays off in Romania-A Single-Centre Study.

Colorectal cancer (CRC) is the third most diagnosed cancer in men (after prostate and lung cancers) and in women (after breast and lung cancer). It is the second cause of cancer death in men (after lung cancer) and the third one in women (after breast and lung cancers). It is estimated that, in EU-27 countries in 2020, colorectal cancer accounted for 12.7% of all new cancer diagnoses and 12.4% of all deaths due to cancer. Our study aims to assess the opportunistic colorectal cancer screening by colonoscopy in a private hospital. A secondary objective of this study is to analyse the adenoma detection rate (ADR), polyp detection rate (PDR), and colorectal cancer (CRC) detection rate. We designed a retrospective single-centre study in the Gastroenterology Department of Saint Mary Hospital. The study population includes all individuals who performed colonoscopies in 2 years, January 2019-December 2020, addressed to our department by their family physician or came by themselves for a colonoscopy. One thousand seven hundred seventy-eight asymptomatic subjects underwent a colonoscopy for the first time. The mean age was 59.0 ± 10.9, 59.5% female. Eight hundred seventy-three polyps were found in 525 patients. Five hundred and twenty-five had at least one polyp, 185 patients had two polyps, 87 had three polyps, and 40 patients had more than three polyps. The PDR was 49.1%, ADR 39.0%, advanced adenomas in 7.9%, and carcinomas were found in 5.4% of patients. In a country without any colorectal cancer screening policy, polyps were found in almost half of the 1778 asymptomatic patients evaluated in a single private center, 39% of cases adenomas, and 5.4% colorectal cancer. Our study suggests starting screening colonoscopy at the age of 45. A poor bowel preparation significantly impacted the adenoma detection rate.

Analysis of the Genomic Landscape in ALK+ NSCLC Patients Identifies Novel Aberrations Associated with Clinical Outcomes.

Rearrangements in the anaplastic lymphoma kinase (ALK) gene are found in approximately 5% of non-small cell lung carcinoma (NSCLC). Here, we present a comprehensive genomic landscape of 11 patients with ALK+ NSCLC and investigate its relationship with response to crizotinib. Using whole-exome sequencing and RNAseq data, we identified four rare ALK fusion partners (HIP1, GCC2, ERC1, and SLC16A7) and one novel partner (CEP55). At the mutation level, TP53 was the most frequently mutated gene and was only observed in patients with the shortest progression-free survival (PFS). Of note, only 4% of the genes carrying mutations are present in more than 1 patient. Analysis of somatic copy number aberrations (SCNA) demonstrated that a gain in EML4 was associated with longer PFS, and a loss of ALK or gain in EGFR was associated with shorter PFS. This study is the first to report a comprehensive view of the ALK+ NSCLC copy number landscape and to identify SCNA regions associated with clinical outcome. Our data show the presence of TP53 mutation as a strong prognostic indication of poor clinical response in ALK+ NSCLC. Furthermore, new and rare ALK fusion partners were observed in this cohort, expanding our knowledge in ALK+ NSCLC.

Adoptive immunotherapy against allogeneic kidney grafts in dogs with stable hematopoietic trichimerism.

Dogs given nonmyeloablative conditioning and marrow grafts from 2 dog leukocyte antigen (DLA)-identical littermate donors developed stable trichimerism and stably accepted a subsequent kidney graft from one of the marrow donors without the need for immunosuppression. In this study, we used trichimeras to evaluate strategies for adoptive immunotherapy to solid tumors, using the kidney as a tumor surrogate. Three DLA-identical trichimeric recipients were established by simultaneously infusing marrow from 2 DLA-identical donor dogs into a DLA-identical recipient conditioned with 2 Gy of total body irradiation (TBI) and given a short course of postgraft immunosuppression. After stable hematopoietic engraftment was confirmed, a kidney was transplanted from 1 of the 2 marrow donors into each respective trichimeric recipient. Peripheral blood lymphocytes from each kidney donor were then used to sensitize the alternate marrow donor. The trichimeric recipients were given donor lymphocyte infusions (DLIs) from the sensitized dogs and monitored for chimerism, graft-versus-host disease (GVHD), and kidney rejection. After DLI, we observed both prompt rejection of the transplanted marrow and donor kidney and disappearance of corresponding hematopoietic chimerism. Presumably due to shared minor histocompatibility antigens, host chimerism also disappeared, and GVHD in skin, gut, and liver developed. The native kidneys, although exhibiting lymphocytic infiltration, remained functionally normal. This study demonstrates that under certain experimental conditions, the kidney--an organ ordinarily not involved in graft-versus-host reactions--can be targeted by sensitized donor lymphocytes.

Intensified postgrafting immunosuppression failed to assure long-term engraftment of dog leukocyte antigen-identical canine marrow grafts after 1 gray total body irradiation.

BACKGROUND: Late graft rejection after conditioning with 1 Gy of total body irradiation (TBI) was consistently seen in historical dogs given two postgrafting immunosuppressive drugs. METHODS: Here, 16 dogs were given four different three-drug combinations of cyclosporine, mycophenolate mofetil, sirolimus, or methotrexate after 1 Gy TBI and dog leukocyte antigen-identical marrow grafts. In addition, we assessed the effects of TBI doses of 0.5, 1.0, 2.0, or 3.0 Gy, respectively, on immune functions in six dogs not given marrow grafts. RESULTS: All dogs showed initial engraftment, 13 rejected, and three had sustained grafts beyond 26 weeks. The dogs with durable grafts had received greater median numbers of nucleated marrow cells compared with the 13 dogs that rejected their grafts (6.14 vs. 3.6 x 10(8) per kg; P=0.03). In a Cox proportional hazard model, which included data from 16 historical dogs, each increase in transplanted marrow cell numbers by 1 x 10(8) per kg decreased the hazard ratio of rejection by 0.5. Decreasing percents of remaining CD3, CD4, and CD8 cells in peripheral blood and lymph nodes were observed with increasing TBI doses. Further, greater suppressions of B-cell- and T-cell-dependent production of IgM and IgG antibodies in response to sheep red blood cell injections were observed after 2 Gy compared with 1 Gy TBI. CONCLUSION: Overall, triple postgrafting immunosuppression after 1 Gy TBI was well tolerated but failed to prevent graft rejection in this model. In vivo radiation studies have shown higher numbers of remaining host lymphocytes and better T-cell-dependent antibody production after 1 Gy compared with 2 Gy TBI.

Graft-versus-tumor effects after allogeneic hematopoietic cell transplantation with nonmyeloablative conditioning.

PURPOSE: We have used a nonmyeloablative conditioning regimen consisting of total-body irradiation (2 Gy) with or without fludarabine (30 mg/m(2)/d for 3 days) for related and unrelated hematopoietic cell transplantation (HCT) in patients with hematologic malignancies who were not candidates for conventional HCT because of age, medical comorbidities, or preceding high-dose HCT. This approach relied on graft-versus-tumor (GVT) effects for control of malignancy. PATIENTS AND METHODS: We analyzed GVT effects in 322 patients given grafts from HLA-matched related (n = 192) or unrelated donors (n = 130). RESULTS: Of the 221 patients with measurable disease at HCT, 126 (57%) achieved complete (n = 98) or partial (n = 28) remissions. In multivariate analysis, there was a higher probability trend of achieving complete remissions in patients with chronic extensive graft-versus-host disease (GVHD; P = .07). One hundred eight patients (34%) relapsed or progressed. In multivariate analysis, achievement of full donor chimerism was associated with a decreased risk of relapse or progression (P = .002). Grade 2 to 4 acute GVHD had no significant impact on the risk of relapse or progression but was associated with increased risk of nonrelapse mortality and decreased probability of progression-free survival (PFS). Conversely, extensive chronic GVHD was associated with decreased risk of relapse or progression (P = .006) and increased probability of PFS (P = .003). CONCLUSION: New approaches aimed at reducing the incidence of grade 2 to 4 acute GVHD might improve survival after allogeneic HCT after nonmyeloablative conditioning.

Comparison of ARF after myeloablative and nonmyeloablative hematopoietic cell transplantation.

BACKGROUND: Acute renal failure (ARF) occurs with significant frequency after myeloablative and nonmyeloablative allogeneic hematopoietic cell transplantation (HCT). Myeloablative (conventional) HCT is the standard of care for cure of various malignant disorders. The newer modality of nonmyeloablative ("mini-allo") HCT is reserved for patients with advanced age and comorbidities who are ineligible for myeloablative HCT. The present study compares the incidence of ARF between patients undergoing concurrent myeloablative and nonmyeloablative HCT in the same period at the same institution. METHODS: This retrospective cohort study from 1997 to 2003 compares 140 myeloablative and 129 nonmyeloablative patients from the Fred Hutchinson Cancer Research Center. Severity of ARF was classified into 4 grades based on the increase in serum creatinine levels in the first 100 days after HCT. Mortality was studied at 100 days and 1 year. RESULTS: Nonmyeloablative patients were significantly older and had greater pretransplantation comorbidity at baseline. Despite this, patients undergoing myeloablative HCT had a greater incidence of severe ARF (grades 2 and 3, 73% versus 47%; P < 0.001). The incidence of dialysis also was 4-fold greater (12% versus 3%; P < 0.001) in the myeloablative than nonmyeloablative group. On multivariate analysis after controlling for baseline characteristics, myeloablative HCT was associated with a 4.8-fold greater incidence of ARF compared with nonmyeloablative HCT. Nonrelapse mortality also was greater in the myeloablative group at 100 days and 1 year. CONCLUSION: The incidence and severity of ARF, as well as nonrelapse mortality, occurring after nonmyeloablative HCT is significantly lower compared with myeloablative HCT.

Allogeneic hematopoietic cell transplantation: from experimental biology to clinical care.

PURPOSE: For more than half a century, researchers have explored myeloablative, high-dose chemo/radiotherapy followed by allogeneic hematopoietic stem cell transplantation (HCT) for therapy of malignant and nonmalignant hematological diseases. Continuous advances in the field have changed this approach from one that was initially thought to be fraught by insurmountable complications to one that is now considered standard therapy for many diseases. METHODS: In order to extend allogeneic HCT to include elderly patients, who represent the main population affected by hematological malignancies, and to those who are medically unfit to undergo conventional HCT, novel non-myeloablative approaches have been developed. These approaches rely on graft-vs-tumor effects for tumor eradication rather than high-dose chemoradiotherapy, and, accordingly, have lower toxicities than conventional regimens. RESULTS: Results with non-myeloablative regimens have been gratifying, and this may change the future of allogeneic HCT. Advances could not have been possible without basic research and studies in pre-clinical animal models. CONCLUSION: Further work is focused on improving graft-vs-tumor effects while achieving better control of graft-vs-host disease.

Prevalence of anemia and iron deficiency in Romanian patients with inflammatory bowel disease: a prospective multicenter study.

BACKGROUND AND AIMS: Anemia is the most frequent systemic complication in inflammatory bowel diseases. It affects the quality of life and can interact with working capacity. Our objectives were to identify the prevalence of anemia, its main causes and its management in patients with inflammatory bowel disease from Romania. METHODS: We conducted a multicenter prospective study from March 2013 to August 2014. We enrolled 291 patients from three referral centers: 115 (39.52%) with Crohn's disease (CD) and 176 (60.48%) with ulcerative colitis (UC). We defined anemia according to the WHO criteria. RESULTS: Median age of the patients was 41 years and the median time period since diagnosis was 3 years (0.75-7). The median activity index for UC (UCAI) was 4 and the median CD activity index (CDAI) was 96. More patients with CD were on antiTNFα therapy (p < 0.01), corticosteroids (p =0.18) or azathioprine (p=0.05) and required surgery for their underlying disease at study enrollment (p < 0.01). Anemia was present in 31.27% of the patients, more often in those with CD (35.65%) than with UC (28.41%) (not statistically significant); 53.26% of the patients had iron deficiency while 4.12% had folic acid and 8.59% vitamin B12 deficiency; 9.62% of the patients had received anti-anemic therapy at inclusion in the study or in the last three months prior to study enrollment. CONCLUSIONS: About one in three Romanian patients with inflammatory bowel disease has anemia, which is frequently associated with iron deficiency. About 30% of the patients with anemia are under therapy and the most frequent route for iron supplementation is the oral one. This might contribute to the high prevalence of iron deficiency and the low level of compliance.

Treatment delays in non-small cell lung cancer and their prognostic implications.

INTRODUCTION: The impact of treatment delays on survival of patients with non-small cell lung cancer (NSCLC) is uncertain. Although later treatment could negatively affect psychological well-being, the maximum acceptable waiting time has not been determined. METHODS: We analyzed consecutive patients with NSCLC between January 2005 and May 2007 in our center. Treatment delay was calculated from the first abnormal radiographic study. Cox proportional hazards analysis was used to identify predictive factors and log-rank tests to compare survival. RESULTS: Four hundred ninety-five cases were identified; shorter treatment delays were associated with a poor prognosis. Conversely, for every week that the treatment could be delayed, the hazard ratio was improved at 0.97 (p = 0.05). Standard treatment was given to 319 of these patients who were separated in localized, regional, and advanced stages. The median treatment delay was 73 days and distributed as follows: 85, 94, and 50 days for localized, regional, and advanced stages, respectively (p < 0.01). For localized or regional stages, the association between treatment delay and survival was inconclusive. In the advanced group, each week of treatment delay had a hazard ratio of 0.93 (p = 0.009). Survival of advanced patients who began treatment earlier versus later than the group median was 6.8 versus 11.6 months (p = 0.027). CONCLUSIONS: For patients with advanced NSCLC receiving equivalent chemotherapy regimens, shorter treatment delays were associated with shorter survival. We hypothesize that urgent treatment carried a negative prognostic meaning, as this was preferentially offered to patients presenting with a higher symptom burden, which conferred them a worse outcome.

Stable trichimerism after marrow grafting from 2 DLA-identical canine donors and nonmyeloablative conditioning.

Although hematopoietic cell transplantation (HCT) is generally accomplished using a single donor, multiple donors have been used to enhance the speed of engraftment, particularly in the case of umbilical cord blood grafts. Here we posed the question in the canine HCT model whether stable dual-donor chimerism could be established using 2 DLA-identical donors. We identified 8 DLA-identical littermate triplets in which the marrow recipients received 2 Gy total body irradiation followed by marrow infusions from 2 donors and postgrafting immunosuppression. All 8 dogs showed initial "trichimerism," which was sustained in 5 dogs, while 2 dogs rejected one of the allografts and remained mixed chimeras, and 1 dog rejected both allografts. Immune function in one trichimeric dog, as tested by mixed leukocyte culture response and antibody response to sheep red blood cells, was found to be normal. Five dogs received kidney grafts from one of their respective marrow donors at least 6 months after HCT without immunosuppressive drugs, and grafts in 4 dogs are surviving without rejection. In summary, following nonmyeloablative conditioning, simultaneous administration of marrow grafts from 2 DLA-identical littermates could result in sustained trichimerism, and immunologic tolerance could include a kidney graft from one of the marrow donors.

What role is there for antithymocyte globulin in allogeneic nonmyeloablative canine hematopoietic cell transplantation?

We investigated whether pretransplantation immunosuppression with canine-specific rabbit antithymocyte globulin (ATG), combined with a suboptimal dose of 1 Gy of total body irradiation (TBI), would permit engraftment of canine dog leukocyte antigen-identical marrow. Cumulative ATG doses of 2 to 5 mg/kg produced a T-cell depletion of 1 log in the peripheral blood and 50% in the lymph nodes. Serum levels of ATG peaked on days 4 to 6 after initiation of therapy and became undetectable by day 13 as a result of canine antibody responses to ATG. ATG prolonged allogeneic skin graft survival to 14 days (n = 5), compared with 8 days in control dogs (P = .0003). Five dogs were given marrow transplants after ATG (3.5-5 mg/kg) and 1 Gy of TBI. Posttransplantation immunosuppression consisted of mycophenolate mofetil and cyclosporine. All dogs showed initial engraftment, with maximum donor chimerism levels of 25%. However, only 1 dog achieved sustained engraftment, and 4 rejected their grafts. The duration of engraftment ranged from 8 to > or = 36 weeks (median, 11 weeks), and this is comparable to that in 6 historical controls not given ATG (range, 3-12 weeks; median, 10 weeks; P = .20). The total nucleated cell doses in the marrow grafts had the highest correlation coefficient with the duration of engraftment: 0.82 (P = .09). We concluded that administering ATG before an otherwise suboptimal conditioning dose of 1 Gy of TBI failed to secure uniform stable hematopoietic engraftment.

Prognostic relevance of 'early-onset' graft-versus-host disease following non-myeloablative haematopoietic cell transplantation.

We retrospectively analysed outcomes among 395 patients with haematologic malignancies who underwent non-myeloablative haematopoietic cell transplantation (HCT) from human leucocyte antigen (HLA)-matched related (n = 297) or unrelated donors (n = 98) in order to identify a possible correlation between the time of onset of graft-versus-host disease (GVHD) and survival. The non-myeloablative regimen consisted of 2 Gy total body irradiation with or without fludarabine, followed by postgrafting immunosuppression with mycophenolate mofetil and cyclosporine. The cumulative incidences of grades II-IV acute GVHD and extensive chronic GVHD were 45% and 47%, respectively, with related donors, and 68% and 68%, respectively, with unrelated donors. High-dose corticosteroid treatment for acute or chronic GVHD was started at a median of 79 (range, 8-799) days and 30 (range, 5-333) days after transplantation from related and unrelated donors respectively. With related donors, the cumulative incidence of non-relapse mortality among patients with GVHD was 55% at 4 years when prednisone was started before day 50 (n = 72), compared with 29% when treatment was started after day 50 (n = 115) (P < 0.001). With unrelated donors, time to onset of treatment for GVHD was not associated with survival. Patients with early-onset GVHD after non-myeloablative HCT from HLA-identical related donors might benefit from intensified primary immunosuppressive treatment.

Postgrafting immunosuppression with sirolimus and cyclosporine facilitates stable mixed hematopoietic chimerism in dogs given sublethal total body irradiation before marrow transplantation from DLA-identical littermates.

We studied the value of postgrafting immunosuppression with sirolimus (SRL) and cyclosporine (CSP) in enhancing engraftment of dog leukocyte antigen-identical littermate marrow after nonmyeloablative conditioning in a canine model. Dogs received either 2 Gy (n=7) or 1 Gy (n=5) total body irradiation (TBI), followed by postgrafting immunosuppression with SRL and CSP. In the first cohort, all 7 dogs showed rapid initial engraftment. One engrafted dog died on day 21 due to hemorrhagic pneumonitis. Durable engraftment was seen in 5 of 6 remaining dogs, with a median follow-up of >48 (range, >32 to >56) weeks. The sixth dog rejected the marrow graft (as assessed by variable number of tandem repeats) at 11 weeks; however, a subsequent skin graft from the same marrow donor did not undergo acute cellular rejection, suggesting donor-specific tolerance. In the second cohort, all 5 dogs rejected the marrow graft at a median of 9 weeks (range, 3-11 weeks). We conclude that SRL/CSP is as effective as a previously studied combination of mycophenolate mofetil and CSP at establishing durable marrow engraftment after sublethal conditioning.

Morbidity and mortality with nonmyeloablative compared with myeloablative conditioning before hematopoietic cell transplantation from HLA-matched related donors.

Nonmyeloablative regimens for allogeneic hematopoietic cell transplantation (HCT) have been developed for patients ineligible for myeloablative conditioning. We compared regimen-related toxicities (RRTs) and nonrelapse mortality (NRM) in 73 nonmyeloablative and 73 myeloablative recipients of HLA-matched related donor HCT, using the National Cancer Institute (NCI) Common Toxicity Criteria. Nonmyeloablative regimens were 2 Gy total body irradiation (TBI), either alone (n = 40) or combined with fludarabine, 30 mg/m(2)/d for 3 days (n = 33). Posttransplantation immunosuppression included mycophenolate mofetil and cyclosporine. Myeloablative regimens consisted mostly of cyclophosphamide + TBI or busulfan + cyclophosphamide, followed by posttransplantation methotrexate and cyclosporine. Nonmyeloablative patients were at higher risk than ablative patients because of greater age, longer time from diagnosis to HCT, more frequent preceding high-dose HCT, and higher pretransplantation Charlson comorbidity scores. Nevertheless, they experienced significantly less severe toxicities in 7 organs/systems: hematologic, gastrointestinal, hepatic, hemorrhage, infection, metabolic, and pulmonary. This translated into less NRM at day 100 (3% versus 23%, P = 10(-4)) and 1 year (16% versus 30%, P =.04). In multivariate analysis, the strongest factor predicting lessened RRT and NRM was nonmyeloablative conditioning, whereas high pretransplantation comorbidity scores predicted higher NRM. In conclusion, nonmyeloablative regimens had lower RRT and NRM and could be considered for comparative studies, including younger patients with more favorable Charlson comorbidity scores.

Comparing morbidity and mortality of HLA-matched unrelated donor hematopoietic cell transplantation after nonmyeloablative and myeloablative conditioning: influence of pretransplantation comorbidities.

We have carried out HLA-matched unrelated donor hematopoietic cell transplantation (HCT) after nonmyeloablative conditioning in patients with hematologic malignancies who were ineligible for conventional transplantations because of age, comorbidities, or both. The nonmyeloablative regimen consisted of 90 mg/m2 fludarabine and 2 Gy total body irradiation given before and mycophenolate mofetil and cyclosporine given after HCT. This report compares, retrospectively, morbidity and mortality among 60 consecutive patients given nonmyeloablative conditioning (nonablative patients) to those among 74 concurrent and consecutive patients given myeloablative conditioning (ablative patients) before unrelated HCT. The Charlson Comorbidity Index was used to assess pretransplantation comorbidities. Even though nonablative patients had significantly higher pretransplantation comorbidity scores, were older, and had more often failed preceding ablative transplantations and cytotoxic therapies, they experienced fewer grades III to IV toxicities than ablative patients. Further, the incidence of grades III to IV acute graft-versus-host disease (GVHD) was significantly lower in nonablative patients. Both patient groups had comparable 1-year probabilities of chronic GVHD. The 1-year nonrelapse mortality rate was 20% in nonablative patients compared to 32% in ablative patients (hazard ratio=1.4). After adjustment for pretransplantation differences between the 2 patient groups, the hazard ratio was 3.0 (P=.04). Multivariate analyses showed higher pretransplantation comorbidity scores to result in increased toxicity and mortality.