Is Old (Fludrabine/Busulfan/Cyclophosphamide/rAntiThymocyteGlobulin) Conditioning Still Gold for Allogeneic Transplants in Transfusion Dependent Beta-Thalassemia of All Risk Categories in 21st Century?

Allogeneic stem cell transplant (allo-SCT) is the only curative option for transfusion dependent thalassemia (TDT) until the gene therapy could bring paradigm shift. We analysed TDT allo-SCTs performed with Flu/Bu/Cy/rATG conditioning between October 2018 and April 2022 at our center. A retrospective analysis of 55 consecutive HLA matched alloSCT for TDT and was approved by hospital's Institutional Review Board. Median age was 7(2-13) years. On presentation, number of patients with Class I, II, III were 18 (32.7%), 14(25.4%) and 23(41.8%) respectively {ClassIIIA = 14(25.4%),ClassIIIB = 9(16.3%)}. After downstaging, Class I, II, III were 22(40%), 15(27.2%) and 18(32.7%) patients respectively {ClassIIIA = 15(27.2%),ClassIIIB = 3(5.4%)}. Graft was bone marrow in 53(96.4%) and peripheral blood stem cell in 2(3.6%) patients. Mean CD34 stem cell dose was 3.28(1.2-6.5) × 106/kg. Neutrophils and platelets engrafted at a median of 16(12-32) and 17(12-48) days. Median duration of follow-up was 20.7(1.8-43.9) months. There was no primary rejection. Although, mixed chimerism was common {17(30.9%)}, there was only one secondary rejection (1.8%). Venoocclusive disease was seen 12(21.8%) patients {mild = 9(75%), moderate = 2(16.6%) and severe = 1(8.3%)}. Acute and Chronic graft versus host disease was observed in 4(7.2%) and 4(7.2%) patients respectively. There was no treatment related mortality. Overall survival and Thalassemia Free Survival were 100% ± 0% and 98% ± 2% respectively. Flu/Bu/Cy/rATG conditioning with BM graft is a safe and effective regimen even in higher risk. It also highlights the importance of pretransplant downstaging of risk class in improving the outcomes.

Intracranial metastases in patients with squamous cell carcinoma of the head and neck.

BACKGROUND: Intracranial metastases are rarely clinically diagnosed in patients with head and neck squamous cell carcinoma. Only 7 patients with metastases to the cavernous sinus from head and neck squamous cell carcinomas have been reported. METHODS: A retrospective study revealed 13 patients with intracranial metastases of head and neck squamous cell carcinoma. In a 53-year-old woman a cavernous sinus metastasis of a laryngeal carcinoma was histologically diagnosed by using a CT-guided surgical navigation system and was treated with stereotactic radiotherapy. RESULTS: The mean survival was 4.3 months. Predictive factors for longer survival were absence of extracranial disease, age younger than 60 years, and treatment with radiotherapy. CONCLUSIONS: The prognosis for patients with intracranial disease is poor. The current development of computer-assisted stereotactic navigation and stereotactic radiotherapy may facilitate surgical diagnostic exploration and improve treatment, especially in patients without extracranial disease.

Advanced squamous cell carcinoma of the base of the tongue treated with surgery and post-operative radiotherapy.

BACKGROUND: Early stage squamous cell carcinoma of the base of the tongue has been successfully treated with radiotherapy and brachytherapy. However, the vast majority of these tumours seen in Western Europe are already at an advanced stage. Medical records of 79 patients with squamous cell carcinoma of the base of the tongue treated between 1980 and 1994 were examined. METHODS: Eighty-three per cent of the primary tumours were stage T3 or T4. Fifty-nine patients were treated with surgery and post-operative radiotherapy. Quality of life assessment amongst the survivors was performed by means of a questionnaire. RESULTS: Five year disease free survival in patients undergoing excision for T3-T4 tumours was 59%. Patients with T2-T3 tumours undergoing partial excision of the tongue base had a 3 year recurrence free survival rate of 68%. Distant metastasis occurred in 16%. Seventy-eight per cent of the patients judged their quality of life to be near normal. CONCLUSION: Surgery and post-operative radiotherapy offer a reasonably good survival in advanced carcinoma of the base of the tongue with preservation of quality of life.

The short and long term effects of intraoperative electron beam radiotherapy (IORT) on thoracic organs after pneumonectomy an experimental study in the canine model.

PURPOSE: The tolerance of mediastinal structures and thoracic organs to intraoperative radiotherapy (IORT) was investigated in the canine model. METHODS AND MATERIALS: Twenty-two adult beagles divided into three groups were subjected to a left pneumonectomy and IORT (10 MeV electrons) at doses of 20 Gy (n = 9), 25 Gy (n = 4), or 30 Gy (n = 9). Intraoperative electron beam radiotherapy was delivered through a 5 cm circular lucite cone encompassing a mediastinal field including the bronchial stump, aorta, esophagus, heart, phrenic nerve, contralateral hilar structures, and lung. Clinical monitoring was performed with regular chest X-ray, ECG, bronchoscopy, esofagoscopy, and fluoroscopy. From the different treatment dose groups, dogs were electively sacrificed at 1.5, 6, 12, and 72 months with complete autopsies. RESULTS: There was no bronchial stump dehiscence or acute morbidity. Four dogs developed radiation induced esophagitis (18%), one in the 20 Gy IORT group (11%) and three in the 30 Gy IORT group (33%). There were six IORT related mortalities (27.5%), one esophagoaortic fistula (4.5%) and five bronchovascular fistulas (23%): two in the 20 Gy IORT group (22%), two in the 25 Gy IORT group (50%) and two in the 30 Gy IORT group (22%). Histopathological findings in uncomplicated follow-up showed marked myointimal fibrosis in the muscular arteries, submucosal fibrosis of the esophagus, and interstitial fibrosis of bronchial and lung tissue, especially in the higher dose group. CONCLUSION: The mediastinal vascular, bronchial and esophageal structures are relatively sensitive to doses > 20Gy IORT. The IORT related morbidity found in this study may be lower when the current clinically used IORT doses of 10-15 Gy are applied. Further clinical application of IORT in the future treatment strategies for resectable nonsmall cell lung cancer may be worthwhile to investigate.

Malignant epithelial parotid gland tumours: analysis and results in 65 previously untreated patients.

BACKGROUND: Optimal management of malignant epithelial parotid tumours requires knowledge of the available therapeutic modalities and the different biological characteristics. The aim of the study was to review the characteristics of patients at presentation, histological classification, disease-free and overall survival rates, and the results of the applied treatment policy regarding the facial nerve and neck. METHODS: Between 1974 and 1995 a total of 65 patients was treated with curative intent for a previously untreated malignant epithelial parotid gland tumour. All patients underwent some type of parotidectomy, 20 of whom had an en bloc radical neck dissection. In selected cases the facial nerve or its branches were peeled off the tumour thus violating the objective of tumour-free margins and relying heavily on the efficacy of postoperative radiotherapy. In total 51 patients received postoperative radiotherapy. None of the patients was lost to follow-up. RESULTS: There were 12 locoregional failures (18 per cent). In only one of these 12 patients was salvage therapy successful; the remaining 11 patients died from the tumour. All but one of the eight patients with distant metastasis only died from the tumour. The estimated 5- and 10-year disease-free rates were 68 and 59 per cent respectively. The corresponding survival rates were 75 per cent and 67 per cent. A significant relationship could be observed between tumour stage and survival. The presence of lymph node metastases proved to be the strongest single prognostic factor. CONCLUSION: In selected cases a conservative approach towards the facial nerve is justified.

Intraoperative irradiation of the canine pancreas: short-term effects.

Intraoperative electron beam radiotherapy (IORT) is clinically used as a potential adjunctive treatment to surgery of locally advanced pancreatic and gastric cancer. The tolerance of the pancreas to IORT was studied in 15 adult beagles, divided in 3 groups of 5 beagles in which 25, 30 or 35 Gy IORT was delivered through a 6-7 cm circular lucite cone with 6-8 MeV electrons to the pancreas and medial wall of the duodenum. The dogs were followed for endocrine and exocrine pancreatic insufficiency. Two dogs (13%) developed radiation-induced morbidity which consisted of a common bile duct stenosis and an enterocolic fistula, as was confirmed at autopsy after 8 and 18 months, respectively. After a follow-up of 1 year, none of the dogs had developed pancreatitis, diabetes or exocrine insufficiency. There was a significant reduction in serum insulin levels and glucose clearance rates without overt diabetes for 30 Gy and 35 Gy (p < 0.05). No significant changes were found for 25 Gy. This study suggests that 25 Gy IORT to the pancreas may be used clinically, and that higher IORT doses may induce endocrine pancreatic insufficiency in the long-term.

Limb-sparing treatment with surgery and intraoperative radiotherapy (IORT) for a second local recurrence of myxoid liposarcoma in the popliteal region, after previous surgery and high-dose radiation.

A 46-year-old man with a second local recurrence of a myxoid liposarcoma in the fossa poplitea, after surgery and high-dose external beam radiotherapy, was successfully treated by a limb-sparing procedure combining marginal excision, intraoperative radiotherapy and reconstructive surgery. After a 48-month follow-up, there was no evidence of disease, and the function of the leg and knee was normal.

Open-label tolerability study of enteric-coated naproxen in the treatment of osteoarthritis and rheumatoid arthritis.

Two hundred and ninety-six patients were enrolled in a 6-month, open-label tolerability study of enteric-coated naproxen in patients with rheumatoid arthritis (n = 174) and osteoarthritis (n = 122). Thirty percent of the patients were greater than 65 years of age. Under standard clinical prescribing conditions, enteric-coated naproxen 500 mg twice daily and 375 mg twice daily demonstrated an acceptable tolerability profile that was not different from what one would expect with standard naproxen.

The extended Hartmann operation as an elective procedure for rectal cancer. A forgotten operation.

The authors describe their experience with the extended Hartmann procedure as the elective and definitive operation in a selected group of 36 patients having primary adenocarcinoma of the rectum. The operations were carried out between 1st January 1978 and 31st December 1989. The average age of the patients was 70 years (range 37 to 84 years). Ten patients had preoperative radiotherapy because of deep infiltration and (or) fixation of the tumor. In this series the Hartmann procedure was chosen because abdomino-perineal excision was not needed and low anterior resection could not warrant acceptable continence. With a Hartmann procedure the risks of a low colorectal or colo-anal anastomosis were avoided while the perineal excision was abandoned. Eight patients had hepatic metastases. The Dukes' classification of the remaining patients was A in two, B in nine and C in 17 patients. Postoperative morbidity was within acceptable limits for this particular patient group. There was no hospital mortality. Twenty patients had a potentially curative resection prior to 31st December 1987, thus making them available for follow-up of at least 2 years. Ten of these patients have been in follow-up without evidence of disease for an average of 76 months (mean 65 months, range 28-123 months). The authors conclude that the procedure is safe and that the remaining rectal stump does not generate morbidity or discomfort. Considering the fact that only two of the 36 patients had a Dukes' A tumor, the low recurrence rate shows that the Hartmann procedure yields satisfactory pelvic radicality.

[Treatment strategy and results in primary inoperable rectal cancer]. / Behandlungsstrategie und Ergebnisse beim primär inoperablen Rectumcarcinom.

The authors report their experience with laparotomy in patients with rectal carcinoma to identify those patients with locally non-resectable primary cancer of the rectum who may be treated initially by high-dose radiotherapy. The goal of this so-called "staging laparotomy" is to assess mobility and tumor size by means of bimanual palpation, to stage the abdominal cavity and to create total fecal diversion by performing an endcolostomy in order to condition these patients for maximum tolerance during the protracted radiotherapy course (greater than 50 Gy/5-6 weeks). The formation of an endcolostomy seems to avoid severe morbidity and even mortality of high-dose radiotherapy without delay of further surgery. Twenty-two patients with locally advanced rectal carcinoma were treated in this way. The tumor was resectable in 18 of the 20 patients who underwent relaparotomy after high-dose radiotherapy. Six out of the 13 patients with a radical resection died with evidence of disease during the follow-up (2 with local disease). One patient died with no evidence of disease after 5 years and 6 patients are still alive without disease after an average of 37 months (15-67 months).

Local tumor control by intra-operative radiotherapy (IORT): a pilot experience.

Patients with locally advanced disease, considered incurable by conventional therapeutic options, were treated, if possible, with surgical resection, and intra-operative radiotherapy (IORT) with or without external beam radiotherapy (EBRT), with the aim of improving local control of disease. Twelve patients were selected for IORT and eight patients were subsequently submitted to IORT in order to achieve local control. There were no IORT related complications, and local tumor control was achieved in all cases with a median follow-up of 22 months. IORT is a new and experimental treatment modality with a potential advantage over conventional radiotherapy.

Local control in T3 laryngeal cancer treated with radical radiotherapy, time dose relationship: the concept of nominal standard dose and linear quadratic model.

In a retrospective study of the Dutch cooperative head and neck group 104 evaluable patients with T3NxMO squamous cell carcinoma of the larynx were treated primarily with a full course of radiotherapy. The results of treatment are presented in terms of locoregional control. The actuarial 3-year local control rate was 53%. Regional control was 77% for node positive patients and 96% for N0 patients (p = 0.01). Surgical salvage was successful in 53% of cases with a local recurrence and in 3/8 regional recurrences, resulting in an ultimate locoregional control rate of 83% for N0 patients and 68% for N+ patients. A uni- and multivariate analysis of local control rate versus total dose, nominal standard dose, and extrapolated response dose has been done. To calculate extrapolated response dose the linear quadratic equation was used, assuming an a/b of 10 and a potential doubling time of clonogenic cells of 3, 5, and 7 days. In multivariate analysis the extrapolated response dose with a potential doubling time of 5 days was the only independent prognostic factor for local control (p = 0.069) and ultimate locoregional control (p = 0.0015). Nominal standard dose showed no dose-response relationship. Based on the S-shaped dose response curve, using the LQ model, several therapeutical options are discussed.

Effect of selective elimination of the oral flora on mucositis in irradiated head and neck cancer patients.

Recently it has been reported that chlorhexidine 0.1% rinsing was not successful in eradication of gram-negative bacilli in patients who have head and neck cancer. These bacilli could play a role in irradiation mucositis. This study reports the effect of lozenges containing 2 mg polymyxin E, 1.8 mg tobramycin, and 10 mg amphotericin B qid on the oropharyngeal flora in 15 irradiated head and neck cancer patients. The results were compared with those of a previous study in two groups of 15 patients comparing chlorhexidine rinsing with placebo. In all patients using lozenges, eradication of gram-negative bacilli and yeasts was achieved within 3 weeks. A significant increase of enterococci was found. Mucositis was significantly reduced compared with the previous two groups. All patients showed erythema only, whereas 80% of both the placebo and chlorhexidine rinsing patients suffered from severe mucositis, with signs of pseudomembranes developing from the third week of conventional irradiation protocol. The effect of selective elimination of gram-negative bacilli from the oropharynx and the prevention of severe mucositis may be explained by the eradication of these bacteria and/or neutralization of salivary endotoxin, released by gram-negative bacilli, mediating the inflammatory processes.

Advanced rectal cancer in the female: reduction of pelvic recurrence by rectal resection en bloc with hysterectomy and/or posterior vaginal wall excision.

The authors report their experience with 20 female patients with advanced rectal cancer in whom rectal excision was combined with concomitant excision of the uterus and/or posterior vaginal wall. Six patients presented with a malignant fistula between the rectum and the genital tract; 10 had pre-operative radiotherapy, with a total dose of 50 Gy in seven patients and 30 Gy in three. The resection was judged as radical in 18 patients; the specimen was staged as a Dukes' B in eight and a Dukes' C in 10 cases. Three patients died within the follow-up period, due to intercurrent disease, without evidence of recurrence. Seven patients have been followed without evidence of disease for an average of 91 months (range 39-143 months). One patient is alive 5 years after surgery with a pelvic recurrence. Seven patients succumbed to distant metastases alone (n = 4) or to a combination of haematogenous metastases and pelvic recurrence (n = 3). The authors make a plea for local radicality in advanced rectal cancer in female patients, to preserve quality of life in most patients and a cure in some.

Evaluation of results of temporal bone resection.

The results of 16 cases of temporal bone resection were evaluated. The resections, 12 of which were total and 4 partial, had mostly been performed for squamous cell carcinoma invading the temporal bone. Five patients in whom the intervention was considered radical and not followed by irradiation, were alive and well 9 years or more later. The significance of postoperative radiotherapy was demonstrated in 3 patients who were alive and in good health 9 years or more later, although histological examination of resection margins showed residual tumour. Eight patients died 10 months to 5 1/3 years after operation, 6 of whom from recurrence, one from radiation necrosis of the temporal lobe of the brain, and one from cerebrovascular occlusion. Histologically, squamous cell carcinoma was found significantly more among the patients who died from recurrence than among those still living.

Mucositis prevention by selective elimination of oral flora in irradiated head and neck cancer patients.

Mucositis induced by irradiation is the reactive inflammatory-like process of the oropharyngeal mucous membranes following irradiation. Bacteria colonizing the oral tissues are thought to contribute to this inflammatory process. The eradication of Gram-negative bacilli (selective elimination of oral flora) in fifteen comparably irradiated head and neck cancer patients was found to be associated with a significant reduction in mucositis compared with two groups of 15 patients receiving either placebo or chlorhexidine rinsing. Criteria used were the extent of local mucositis signs (mucositis score), as well as generalized side-effects such as the need of nasogastric tube feedings following severe feeding problems. Mucositis signs were confined to erythema only in all selectively decontaminated patients. No pseudomembranes were observed and artificial feeding was completely prevented. These promising results need further confirmation in larger (multicenter) studies.

The short- and long-term effect of single high-dose intra-operative electron beam irradiation of retroperitoneal structures--an experimental study in dogs.

Intra-operative electron beam radiotherapy is a new treatment modality. The abdomen is the area of greatest potential applicability of IORT and therefore its effect on retroperitoneal structures was investigated in a canine model. The retroperitoneal structures tolerate 30 to 40 Gy well, with the exception of the radiation-sensitive ureter which showed fibrosis. Twenty to 25 Gy is within the safe dose limits for the clinical application of IORT.

Is adjuvant intra-operative radiotherapy (IORT) for resectable and unresectable pancreatic carcinoma worthwhile?

The hitherto limited experience with IORT has demonstrated that the combined treatment modality of surgery and IORT with or without EBRT is feasible in resectable and unresectable pancreatic cancer. IORT in combination with EBRT has not significantly improved median or overall survival, but local tumor control and pain control rates have increased. The major complication of IORT in unresectable pancreatic cancer is hemorrhage from the upper gastrointestinal tract in 20% of the patients. Hence, prophylactic by-passes should be performed after IORT treatment. The exact value of IORT in the treatment of pancreatic cancer is still to be defined. A prospective randomized phase III trial is necessary to evaluate the true value of IORT in the treatment of pancreatic cancer.