Perioperative pain management after scapular tip free flap harvesting for head and neck reconstruction using mini-catheters to inject the local anesthetic.

PURPOSE: Although functional and esthetic results after the use of a scapular tip free flap (STFF) in head and neck reconstruction, and the related donor-site morbidity, have been extensively described, data regarding acute postoperative donor-site pain management are lacking. Purpose of this study is to explore the use of mini-catheters to administer local anesthetics for donor-site pain management after reconstruction using STFF. METHODS: Patients who underwent head and neck reconstruction using a STFF were prospectively enrolled and, through a perineural catheter placed in the donor site during the surgical procedure, a bolus of chirochaine was injected before the patient regained consciousness and at 8, 16, and 24 h postoperatively. Before and 40 min after each dose administration, donor-site pain on a numerical rating scale (NRS; 0-10) was evaluated. RESULTS: Study population consisted of 20 patients (40-88 years). At 8 h, the pain scores before and after the injection were 0-10 (mean 3.35) and 0-5 (mean 1.25), respectively. At 16 h, the pain scores before and after the injection were 0-8 (mean 2.55) and 0-4 (mean 0.55), respectively. At 24 h, the pain scores before and after the injection were 0-8 (mean 1.30) and 0-4 (mean 0.30), respectively. CONCLUSION: Statistical analysis confirmed a significant difference between the pain scores before and after administration at 8, 16, and 24 h (p < 0.001, p < 0.001, and p = 0.003, respectively). Mini-catheters for local anesthetic administration represent an effective strategy for pain control after STFF harvesting for head and neck reconstruction.

Intratumor genetic heterogeneity and head and neck cancer relapse.

BACKGROUND: Head and neck squamous cell carcinomas are treated by surgery, radiotherapy (RT), chemoradiotherapy (CRT) or combinations thereof, but locoregional recurrences (LRs) occur in 30-40% of treated patients. We have previously shown that in approximately half of the LRs after CRT, cancer driver mutations are not shared with the index tumor. AIM: To investigate two possible explanations for these genetically unrelated relapses, treatment-induced genetic changes and intratumor genetic heterogeneity. METHODS: To investigate treatment-induced clonal DNA changes, we compared copy number alterations (CNAs) and mutations between primary and recurrent xenografted tumors after treatment with (C)RT. Intratumor genetic heterogeneity was studied by multi-region sequencing on DNA from 31 biopsies of 11 surgically treated tumors. RESULTS: Induction of clonal DNA changes by (C)RT was not observed in the xenograft models. Multi-region sequencing demonstrated variations in CNA profiles between paired biopsies of individual tumors, with copy number heterogeneity scores varying from 0.027 to 0.333. In total, 32 cancer driver mutations could be identified and were shared in all biopsies of each tumor. Remarkably, multi-clonal mutations in these same cancer driver genes were observed in 6 of 11 tumors. Genetically distinct heterogeneous cell cultures could also be established from single tumors, with different biomarker profiles and drug sensitivities. CONCLUSION: Intratumor genetic heterogeneity at the level of the cancer driver mutations might explain the discordant mutational profiles in LRs after CRT, while there are no indications in xenograft models that these changes are induced by CRT.

The submental island flap: pedicle elongation and indications in head and neck reconstruction.

BACKGROUND: The submental island flap is an axial pattern skin flap first described by Martin et al. in 1993. When used to reconstruct skin defects it matches the recipient site in terms of colour, texture and thickness. One of the main limitations to its application is the arc of the pedicle allowing coverage of only the lower two thirds of the face. METHODS: A retrospective review was performed of all patients who had had a submental island flap reconstruction at the Operative Unit of Maxillo-Facial Surgery of the University Hospital of Parma, Italy, between 2001 and 2011. The Authors focused on the surgical technique adopted, the clinical indications and the results obtained. They analysed the different ways to elongate the pedicle and discuss their thoughts on the choice of reconstruction. A flowchart was created to help in the decisional process. RESULTS: Between 2001 and 2011 the submental island flap was used to reconstruct head and neck defects in 22 patients. Thirteen patients had defects of the oral cavity; the remaining 9 patients had skin defects involving the pre-auricular region, the temporal area and the peri-nasal cheek skin. No major complications occurred and in one case a partial necrosis of the distal portion of the flap was observed. Five patients underwent surgical revision involving intraoral flap debulking 6-10 months after the primary procedure. DISCUSSION AND CONCLUSIONS: The techniques to elongate the pedicle used and described were: additional dissection of the pedicle, Y-V procedure, reverse flow flap, section of facial vein and microvascular anastomosis. Their choice is mainly conditioned by the site of the defect.

Rehabilitation with endosseous implants in fibula free-flap mandibular reconstruction: a case series of up to 10 years.

PURPOSE: To evaluate the clinical outcome and the aesthetic and functional results of implant rehabilitation of fibula free-flap reconstructed mandibles. MATERIALS AND METHODS: The charts of patients who underwent mandibular reconstruction with fibula free flap and implant prosthodontic rehabilitation between 1998 and 2008 at the Operative Unit of Maxillofacial Surgery of Parma, Italy, were reviewed. In the study the estimated survival rates of implants placed in reconstructed mandibles we identified the prognostic factors and evaluated the functional outcomes. RESULTS: Fourteen patients with a mean age of 50 years (range 15-63 years), were included in the study. A total of 62 implants were positioned. Complications occurred in 7 cases, an improvement in function and aesthetics was reported by the majority of patients. CONCLUSIONS: A high survival rate for implants placed in fibula free-flap reconstructed mandibles was observed. Although different factors were believed to be associated with a poorer prognosis (radiotherapy, composite defects, etc.) no statistically significance was found, showing no absolute contraindications to implant placement.

Free flaps in elderly patients: outcomes and complications in head and neck reconstruction after oncological resection.

INTRODUCTION: Free flaps represent the first reconstructive option for many head and neck defects. The increasing life expectancy of the population results in increasing numbers of ageing patients facing complex reconstructive surgery. In this study we evaluated our experience with free-flap transfers in older patients, analysing the post-operative reconstructive and systemic complications. MATERIALS AND METHODS: Between 2000 and 2009, 360 patients underwent free flap reconstruction of defects resulting from the treatment of head and neck tumours at the Operative Unit of Maxillofacial Surgery, University - Hospital of Parma, Italy. Fifty-five patients (15.3%) were more than 75 years old at the time of treatment. RESULTS: At the end of the follow-up successful free-flap transfer was achieved in 360 of the 373 flaps harvested (96.5%). The overall reconstructive complication rate was 31.4%, (31.8% in the younger group and 29.1% in the remaining patients). Medical complications were observed in 29.2% of cases (less than 75 years: 28.8%; more than 75 years: 30.9%). The ASA status was associated with a statistically significantly higher incidence of complications within patients less than 75 years old (p < 0.0001). DISCUSSION AND CONCLUSIONS: The results of this study, in agreement with previous studies, provide evidence that free-tissue transfer may be performed in ageing patients with a high degree of technical success. The chronologic age cannot be considered an appropriate criterion in the reconstructive decision. On the contrary, a careful selection of the patients based on comorbidities and general conditions (ASA status) is of primary importance in reducing post-operative complications and to improving the results of surgery.

Mid-IR fiber-optic reflectance spectroscopy for identifying the finish on wooden furniture.

Mid-IR fiber-optic reflectance spectroscopy (FORS) is a totally noninvasive infrared analytical technique allowing the investigation of artworks without the need for any sampling. The development and optimization of this analytical methodology can provide a tool that is capable of supporting conservators during the first steps of their interventions, yielding fast results and dramatically reducing the number of samples needed to identify the materials involved. Furthermore, since reflection IR spectra suffer from important spectral anomalies that complicate accurate spectral interpretation, it is important to characterize known reference materials and substrates in advance. This work aims to verify the possibility of investigating and identifying the most widely used wood finishes by means of fiber-optic (chalcogenide and metal halides) mid-infrared spectroscopy. Two historically widely employed wood finishes (beeswax, shellac) and two modern ones (a hydrogenated hydrocarbon resin and a microcrystalline wax) were investigated in an extended IR range (from 1000 to 6000 cm(-1)) with reflectance spectroscopy and with FORS. The broad spectral response of the MCT detector was exploited in order to include overtones and combination bands from the NIR spectral range in the investigation. The reflectance spectra were compared with those collected in transmission mode in order to highlight modifications to shapes and intensities, to assign absorptions, and finally to select "marker" bands indicating the presence of certain finishing materials, even when applied onto a substrate such as wood, which shows many absorptions in the mid-infrared region. After the characterization, the different products were applied to samples of aged pear wood and investigated with the same techniques in order to check the ability of mid-IR FORS to reveal the presence and composition of the product on the wooden substrate.

Microcystic adnexal carcinoma of the centrofacial region: a case report.

Microcystic adnexal carcinoma is a rare, locally aggressive neoplasm with both eccrine and follicular differentiation and a high probability of perineural invasion of the centrofacial region. Given the histopathological features of this tumour, early diagnosis is essential for adequate management. This report refers to a case of microcystic adnexal carcinoma of the nasogenial region, with infiltration of the deep planes extending to the anterior wall of the maxillary sinus. Surgical treatment involved wide demolition of the centrofacial region followed by reconstruction using four locoregional flaps: an Indian flap and a Mustardé flap were used for cutaneous reconstruction; a septal flap to support the maxillogenial region; a mucosal flap to separate the nasal cavities.

Joint practice guidelines for radionuclide lymphoscintigraphy for sentinel node localization in oral/oropharyngeal squamous cell carcinoma.

Involvement of the cervical lymph nodes is the most important prognostic factor for patients with oral/oropharyngeal squamous cell carcinoma (OSCC), and the decision of whether to electively treat patients with clinically negative necks remains a controversial topic. Sentinel node biopsy (SNB) provides a minimally invasive method for determining the disease status of the cervical node basin, without the need for a formal neck dissection. This technique potentially improves the accuracy of histologic nodal staging and avoids overtreating three-quarters of this patient population, minimizing associated morbidity. The technique has been validated for patients with OSCC, and larger-scale studies are in progress to determine its exact role in the management of this patient population. This document is designed to outline the current best practice guidelines for the provision of SNB in patients with early-stage OSCC, and to provide a framework for the currently evolving recommendations for its use. Preparation of this guideline was carried out by a multidisciplinary surgical/nuclear medicine/pathology expert panel under the joint auspices of the European Association of Nuclear Medicine (EANM) Oncology Committee and the Sentinel European Node Trial (SENT) Committee.

Free and locoregional flap associations in the reconstruction of extensive head and neck defects.

Head and neck surgical defects after oncological resection of advanced carcinoma involving the oral cavity are often composite and involve bone, mucosa, soft tissues and skin. For the most extensive defects, the simultaneous association of two free flaps is the best choice to improve the function of the preserved structures. This procedure is difficult and involves prolonged surgery, therefore it is only possible in selected patients. In some composite head and neck defects the association of free and locoregional flaps seems to be indicated. This study, discusses the use of free and locoregional flap association, focusing on its aesthetic advantages and functional results. From January 1995 to December 2006, 30 patients received simultaneous locoregional and free flap transfer for closure of post-ablative oral cavity defects. Microvascular tissue transfer included the radial forearm, anterolateral thigh, rectus abdominis, and fibula and iliac crest free flaps. Locoregional flaps included the cervicofacial, cervicopectoral, deltopectoral, pectoralis major, latissimus dorsi and posterior scalp flaps. Based on the good functional and aesthetic outcome and low rate of complications, the association of free and locoregional flaps represents a good reconstructive option for patients with extensive post-oncological composite head and neck defects.

[Surgical management of orbital malignant melanoma: our experience and a report of three cases]. / Chirurgische Behandlung des malignen Orbita-Melanoms: unsere Erfahrung und ein Bericht über drei Fälle.

PURPOSE: The aim of this study is to illustrate our personal experience concerning the diagnostic and therapeutic management of primary and secondary orbital melanomas. PATIENTS AND METHODS: Nine patients (five men and four women) with a histological diagnosis of orbital malignant melanoma were surgically treated in our department during the last 10 years (1995 - 2005). RESULTS: All the patients had a unilateral orbital malignant melanoma. A primary tumour was diagnosed in one case. There was metastatic orbital localisation of a cutaneous malignant melanoma in two cases. In six cases, a secondary melanoma originated from the uveal tract (three cases), conjunctiva (two cases), or paranasal sinuses (one case). All the patients underwent surgical treatment of the tumour (exenteration in 5 cases; subtotal exenteration in one case; subtotal excision in two cases; and craniofacial resection in one case) combined with immunotherapy in one case. The median age at surgery was 66 years, with a mean postoperative follow-up of 17 +/- 14 months. Four patients died of widespread dissemination of the melanoma after a mean time of 13 +/- 7 months. Two more patients died of causes other than melanoma. Three patients were still living at 9, 33 and 45 months after surgery. None of the patients presented with a local relapse of the melanoma during follow-up. CONCLUSION: Although different approaches have been proposed, the prognosis of orbital melanoma remains poor. In our experience too, the patients with longest survival were those whose tumours were exenterated.

Oromandibular reconstruction with simultaneous free flaps: experience on 10 cases.

Composite defects resulting from surgery for advanced oral cancer represent a difficult reconstructive problem and, in some cases, tissutal defects are extensive requiring multiple free flaps. Personal experience is reported with double free-flap technique in the reconstruction of large complex defects in 10 patients treated for T4 oral squamous-cell carcinoma. Fibula osteo-cutaneous free flap was used in association with forearm free flap in 5 cases, fibula osseous-forearm in 3 cases, fibula osseous-rectus abdominis in 1 case, iliac crest-forearm in 1 case. Forearm free flap was used for intra-oral reconstruction in all cases. Total flap survival is 100% and all patients regained adequate oral diet. At the time of evaluation (February 2001), 40% of patients are alive and mean survival rate is 36 months. In conclusion, simultaneous free flap reconstruction, in massive oro-mandibular defects, represents in some selected patients, a good choice to achieve satisfactory aesthetic and functional results.

Role of intra-operative sentinel lymph node biopsy in oral cavity and oropharynx squamous cell carcinoma: preliminary data.

In patients with squamous cell carcinoma of the oral cavity and oropharynx, the presence of latero-cervical lymph node metastases was found to be the most important of the better known prognostic factors. Still, today, the most reliable technique by which to detect the presence of lymph node metastases is surgery aimed at the dissection of the latero-cervical space; albeit, this surgical procedure has been shown to be an over-treatment in a large percentage of patients presenting squamous cell carcinoma, clinically, radiologically and histologically negative, at neck level. The technique of intra-operative biopsy of sentinel lymph node, routinely used in the staging and treatment of tumours with elective lymphatic involvement such as carcinoma of the breast and malignant cutaneous melanoma, has progressively caught the attention of head and neck surgeons in the most important referral centres in the world, and, indeed, its role has been hypothesised in the treatment of patients with squamous cell carcinoma of the oral cavity and oropharynx with clinically N0 neck. Preliminary results are reported, concerning the use of this intraoperative sentinel lymph node biopsy technique with double tracer in patients presenting squamous cell carcinoma originating in the mucosa of the upper air-digestive tract, clinically and radiologically free from disease at latero-cervical level.

Effect of fluorinated groups on photooxidative stability of polymeric protectives applied on marble.

Some new protective copolymers and a commercial one have been tested on Candoglia marble, a very low porosity stone. Two of the polymers contained a partially fluorinated methacrylic monomer, 2,2,2 trifluoro ethyl methacrylate (TFEMA), in combination with either an acrylic, methyl acrylate (MA) or a vinyl ether, n-butyl vinyl ether (n-BVE) unit. Two copolymers, ethyl methacrylate/n-butyl vinyl ether and ethyl methacrylate (EMA)/methyl acrylate (Paraloid B72), were non-fluorinated and similar in compositions and molar ratio. The aim of the work is to test the copolymers and compare the performances of fluorinated new polymers with the non fluorinated one and with the largely used commercial product. The results obtained demonstrate that the introduction, even in limited amounts, of fluorine atoms in the side ester groups of methacrylic type polymers really improves their protective effect and the durability of the stone treatments. The best results were obtained with the copolymer TFEM/MA which is the fluorinated homologous of Paraloid B72.

[Primary reconstruction of lateral oro-mandibular defects using titanium plates (Thorp) and revascularized non-osseous flaps: a personal experience]. / Ricostruzione primaria di difetti oro-mandibolari laterali con placche in titanio (thorp) e lembi rivascolarizzati non-ossei: nostra esperienza.

Reconstruction of a particular defect is an highly complex problem, that is reflected in the number and variety of techniques proposed. This is particularly true for reconstruction of mandibular segment defects usually together with the need to repair oro-pharnygeal soft tissues defects of various size. The high rate of successes that can be obtained today using microvascular reconstruction techniques explains the reason why bone free flaps have progressively become the "gold standard" used as benchmark for all other forms of primary mandibular reconstruction. However, for selected patients (elderly patients or individuals in poor general health; the presence of lateral oro-mandibular defects or soft tissue defects significantly exceeding the bone defect) the association of non-osseous microvascular free flaps (such as forearm skin flaps or miocutaneous free flaps of the abdominal rectus muscle) with a titanium mandibular reconstruction plate (THORP) can prove a valid alternative. Indeed, in these cases reconstruction of choice would be the association of two free flaps, one osseous and the other non osseous. The use of THORP-type mandibular reconstruction plates in repairing lateral defects increases the overall risk of complications related to the reconstruction technique which is already hindered by the risks associated with the use of microvascular free flaps. The present work starts with a retrospective evaluation of 5 years series of primary mandibular reconstruction for lateral oro-mandibular defects following oncological surgery. The role of THORP-type titanium mandibular plates, used in combination with non-osseous free flaps in the treatment of selected patients, is then described and discussed.

Diethylaminoethanol action in the arthritis with Freund adjuvant, in rats.

The authors have studied the action of diethylaminoethanol on Freund adjuvant arthritis, induced in female Lewis rats. They worked on 3 groups, each one including 14 rats, weighing 110-130 g: group I = control; group II = rats injected intracutaneous with 0.1 ml Freund adjuvant; group III = rats injected with Freund adjuvant and treated with diethylaminoethanol i.m. (10 mg/kg body weight), and gel application (2.5%) on paws and tail, daily. During the experiment clinical observations and measurements were made and when the animals were killed, blood was sampled for haematological and immunological assays (CD4, CD8, CD25 T cells and NK cells, antinuclear autoantibody and immune complexes). While in all the rats from group II (without treatment) inflammatory processes developed at the level of the peripheral joints, in group III (diethylaminoethanol treated), these ones were present in only 64% of the rats and by much more reduced forms, followed by a short period of involution. The paw volume, measured with an electronic plethysmometer, was more reduced in the treated rats (7.1-14.2%) than in the non treated ones (27.7-29.3%). The haematologic examination showed an increased number of neutrophiles in both groups with FA injecting. The immunological investigations revealed: a decrease of CD4 cells and an increase of CD8 T cells and NK cells in both groups, a much more decreased level (13.2%) of circulatory immune complexes in treated rats, as compared to the non-treated ones (71.7%). No differences were found regarding the CD25 cells and antinuclear antibodies. The histo-pathological examination showed that the intensity and the extension area of the joint lesions (granulation tissue with fibrous change, cartilage invasion and dilaceration, bone atrophy) were much more reduced in the treated rats. The authors put forward the hypothesis that these effects might be due to diethylaminoethanol antiinflammatory properties.

Risk of venous thromboembolism and stroke associated with oral contraceptives. Role of congenital thrombophilias.

To assess the risk of thromboembolism in women using oral contraceptives (OCs), we identified through computer search in the hospitals of the province of Parma, Italy, all women aged 15-44 who were resident in the province and had a documented thromboembolic event in the years 1989-93. The number of users and nonusers of OCs was estimated by the drug sale data for the province and by the demographic statistics. In cases with venous thromboembolism (VT) the prevalence of concomitant deficiency of antithrombin III, protein C, protein S, and of factor V gene mutation Arg506GIn was evaluated. The incidence rate of VT was 37/59,603 woman-years in users (0.62 per 1000) and 13/303,954 woman-years in nonusers (0.042 per 1000), for a relative risk (RR) of 14.5 (95% confidence interval: 7.8-27.1; P < 0.001); the rate of stroke per 1000 woman-years was 0.17 in users and 0.036 in nonusers (RR = 4.6; 2.9-10.7; P < 0.01). A congenital thrombophilia involving the protein C anticoagulant system was documented in about 25% of young women developing venous thromboembolism while on OCs.

An acquired hemorrhagic disorder of fibrin crosslinking due to IgG antibodies to FXIII, successfully treated with FXIII replacement and cyclophosphamide.

We report a new case of severe bleeding diathesis due to an acquired inhibitor of fibrin crosslinking. The patient, an 80-year-old woman, was admitted to the hospital for a massive subcutaneous hematoma, with severe anemia requiring red cell transfusion; a subsequent retroperitoneal hematoma developed 2 weeks later. Coagulation studies were normal except for a thromboelastographic pattern suggestive of FXIII deficiency. Clot solubility test was abnormal even after 1:1 mix with normal plasma. Immunochemical studies confirmed the presence of a monoclonal IgG lambda inhibitor directed against FXIII activity (type II FXIII inhibitor). The patient IgG fraction selectively inhibited FXIII transamidating activity but did not inhibit the thrombin-mediated activation of FXIII. The patient was treated with high doses of FXIII concentrate to overcome the inhibitor and immunosuppressive therapy with cyclophosphamide and discharged in good conditions. High doses of commercially available FXIII appear to be a safe and effective method of controlling acute episodes of bleeding in patients with acquired FXIII deficiency.

Low molecular weight heparin versus warfarin in the prevention of recurrences after deep vein thrombosis.

To evaluate the role of low-molecular weight heparin (LMWH) as an alternative to oral anticoagulants in the prevention of recurrent venous thromboembolism, we compared in a randomized trial conventional warfarin treatment with a three-month course of enoxaparin 4000 anti-Xa units once a day subcutaneously. 187 patients with symptomatic deep-vein thrombosis (DVT), diagnosed by strain-gauge plethysmography plus D-dimer latex assay and confirmed by venography in most cases, were treated with full-dose subcutaneous heparin for ten days and then randomized to secondary prophylaxis. During the 3-month treatment period, 6 of the 93 patients who received LMWH (6%) and 4 of the 94 patients on warfarin (4%) had symptomatic recurrence of venous thromboembolism confirmed by objective testing (p = 0.5; 95% confidence interval [CI] for the difference, -3% to 7%). Four patients in the LMWH group had bleeding complications as compared with 12 in the warfarin group (p = 0.04; 95% CI for the difference, 4% to 14%). In the 9-month follow-up period, during which 34 patients on warfarin prolonged treatment for other 3 months and 14 up to one year, 10 patients in the enoxaparin group and 4 patients in the warfarin group suffered a documented recurrence of venous thromboembolism. Of these 14 late recurrences, just one occurred in patients with postoperative DVT. After one year there were 16 recurrences (17%) in the LMWH group and 8 (9%) in the warfarin group (p = 0.07; 95% CI for the difference, 1% to 16%).(ABSTRACT TRUNCATED AT 250 WORDS)

Subcutaneous vs intravenous heparin in the treatment of deep venous thrombosis--a randomized clinical trial.

271 patients with acute symptomatic deep venous thrombosis of lower limbs, confirmed by strain-gauge plethysmography and/or venography, were randomly assigned to receive intermittent subcutaneous heparin calcium or heparin sodium by continuous intravenous infusion for 6-10 days. Heparin dosage was adjusted to maintain activated partial thromboplastin time values (Thrombofax reagent) at 1.3-1.9 times the basal ones. Strain-gauge plethysmography was repeated at the end of heparin treatment, and evaluation of therapy was performed by comparing the indexes of venous hemodynamics and by assessing the incidence of pulmonary embolism and of bleeding complications. In the intravenous group, Maximal Venous Outflow (MVO) increased from 20.8 +/- 12.8 to 28.4 +/- 17.5 ml/min per 100 ml of tissue and Venous Capacitance (VC) from 1.39 +/- 0.92 to 1.94 +/- 1.0 ml/100 ml of tissue (mean +/- SD). In the subcutaneous group, MVO increased from 21.0 +/- 12.7 to 27.5 +/- 18.1 and VC from 1.60 +/- 0.86 to 2.06 +/- 1.0. The median improvement of MVO and VC were 22% and 36% respectively in the IV group and 20% and 24% in the SC group. Clinical pulmonary embolism occurred in 2 patients in the intravenous group (1 fatal) and in 4 in the subcutaneous group (1 fatal). 9 major bleeding complications occurred in the intravenous group (1 fatal) and 5 in the subcutaneous group (1 fatal). The differences were not significant at the statistical analysis. The results suggest that subcutaneous intermittent heparin has a comparable efficacy to continuous intravenous heparin in the treatment of deep venous thrombosis. To the same conclusion points an overview of the seven randomized trials which compared these treatment modalities.