Persistent port-a-cath®-related fistula and fibrosis in a breast cancer patient successfully treated with local ozone application

Vol. 43 No. 2 February 2012 Polly E. Kintzel, PharmD Department of PharmacySpectrum Health Fistula and Fibrosis in a Breast Grand Rapids, Michigan, USA Cancer Patient Successfully Treated John A. Mulder, MD With Local Ozone Application Medical AffairsFaith HospiceGrand Rapids, Michigan, USA Persistent and delayed healing of fistulae and local infection in previously irradiatedareas can increase the risk of systemic compli-cations and complicated clinical management.
Cancer patients have impaired immune sys- 1. Tremont-Lukats IW, Hutson PR, Backonja MM.
tems secondary to the tumor or oncology treat- A randomized, double-masked, placebo-controlled ments; this impairment decreases spontaneous pilot trial of extended IV lidocaine infusion for re- healing. Surgical options are often associated lief of ongoing neuropathic pain. Clin J Pain 2006; with adverse side effects together with an in- creased risk of further delay in wound healing.
2. Attal N, Rouaud J, Brasseur L, Chauvin M, Hyperbaric chambers have been used to treat Bouhassira D. Systemic lidocaine in pain due to pe- delayed wound healing and several radiation- ripheral nerve injury and predictors of response.
Neurology 2004;62:218e225.
induced side effects.However, this techniqueis cumbersome and with limited accessibility.
3. Ferrante FM, Paggioli J, Cherukuri S, Arthur GR.
Additionally, treatment and assessment of The analgesic response to intravenous lidocaine in radiation-induced subcutaneous fibrosis has the treatment of neuropathic pain. Anesth Analg1996;82:91e97.
had limited success. We describe a case of a per-sistent fistula in a previously irradiated area, 4. Viola V, Newnham HH, Simpson RW. Treatment which was refractory to treatment but which of intractable painful diabetic neuropathy with in- was successfully treated with local ozone appli- travenous lignocaine. J Diabet Complications 2006;20:34e39.
cations. The potential role of spectroscopyanalysis imaging for objective assessment of 5. Bach FW, Jensen TS, Kastrup J, Stigsby B, subcutaneous fibrosis was demonstrated.
Dejgard A. The effect of intravenous lidocaine onnociceptive processing in diabetic neuropathy. Pain1990;40:29e34.
6. Sharma S, Rajagopal MR, Palat G, et al. A phase A 46-year-old woman was admitted to our II pilot study to evaluate use of intravenous lido- hospital for evaluation of a persistent fistula caine for opioid-refractory pain in cancer patients.
and leakage secondary to a PORT-A-CATHÒ J Pain Symptom Manage 2009;37:85e93.
(Smiths Medical, St. Paul, MN) inserted in 7. Kvarnstrom A, Karlsten R, Quiding H, Gordh T.
a previously irradiated area. She had been The analgesic effect of intravenous ketamine and diagnosed three years earlier with right-sided, lidocaine on pain after spinal cord injury. Acta locally advanced, breast carcinoma (infiltrat- Anaesthesiol Scand 2004;48:498e506.
ing ductal carcinoma, T4bN1M0 Stage). She 8. Rowbotham MC, Reisner-Keller LA, Fields HL.
was treated with systemic chemotherapy (fluo- Both intravenous lidocaine and morphine reduce rouracil, epirubicin, cyclophosphamide, and the pain of postherpetic neuralgia. Neurology docetaxel). The tumor decrease was >50% (partial response). She underwent a modified 9. Bauer LA, Brown T, Gibaldi M, et al. Influence radical mastectomy followed by radiotherapy: of long-term infusions on lidocaine kinetics. ClinPharmacol Ther 1982;31:433e437.
Preliminary data from this study have been presented 10. Wallace MS, Ridgeway BM, Leung AY, Gerayli A, as invited lectures at the International Meeting of Yaksh TL. Concentration-effect relationship of intra- Ozone Therapy Schools, Royal Academy of Medi- venous lidocaine on the allodynia of complex regional cine, Madrid, Spain in June 2010 and the III Meeting pain syndromes types I and II. Anesthesiology 2000;92: of the World Federation of Oxygen-Ozone Therapy, Brescia, Italy in April 2011.

Vol. 43 No. 2 February 2012 54 Gy at 2 Gy/day on chest wall, axillar, supra- Pretreatment physical examination revealed and infraclavicular areas. Radiotherapy was a hyperpigmented fibrosis plaque in the right well tolerated, with some areas of dermatitis infraclavicular area, in the catheter bed.
Grade II. She proceeded on to hormonal Palpable subcutaneous induration measured therapy with tamoxifen. Local recurrence in 20  15 mm, with a fistulous cavity of 2 mm di- the chest wall occurred two years after the ini- ameter and 25 mm depth. Leakage persisted tial diagnosis. A PORT-A-CATHÒ for chemo- and needed to be swabbed several times per therapy administration was inserted in the day, every day (, upper left).
right infraclavicular area, which had received Informed consent was obtained before the the radiotherapy. Since insertion, the patient commencement of treatment. Ozone therapy presented with a persistent subcutaneous was done by insufflations of an O3/O2 gas peri-catheter fistula with continuous leakage, mixture (100 mg/ml) through the fistulous intermittently purulent. The catheter was cavity and multiple (four to six) infiltrations removed five months later when second-line distributed around the fibrous induration chemotherapy was concluded (13 cycles of (6e10 ml of O3/O2 gas mixture at 14 mg/ml paclitaxel, gemcitabine, and bevacizumab).
in each infiltration point). Ozone sessions Fistula and leakage continued uninterrupted included 15 minutes of soft vacuum on the during this period and persisted even after fibrosis area.
the PORT-A-CATHÒ was removed and several Spectroscopy analysis was performed using specific antibiotics were administered. The a tissue viability imaging system (TiVi) (TiVi600, patient reported progressive subcutaneous Wheels Bridge AB, Link€ oping, Sweden). It is fibrosis and a decrease in her quality of life based on linearly polarized white light, which secondary to these ongoing symptoms and is partly reflected by the upper layer of the skin moderate persistent local pain. She was and partly diffusely scattered in the deeper der- admitted to our hospital for evaluation of mal layers. This technique generates an image specific treatment four months after the that depends on red blood cell content in the catheter removal (nine months after the fis- dermal microvascular bed (depth of sampling tula was noticeable with its accompanying is about 400e500 mm)The TiVi device takes a standard photograph and automatically using linearly polarized light (right). Black areas are with higher red cell content in the dermal micro-vascularbed; in this case related to blood-flow stasis in the fibrosis area. Upper panel: before ozone therapy. Lower panel:after ozone therapy.
Vol. 43 No. 2 February 2012 performs a reproducible assessment according this problem should include block resection to the signal properties analyzed. TiVi imaging of the fibrotic area within the widely irradiated was performed pre- and post-treatment with area. Often the consequence is increased mor- bidity and potential risk of further delay in After two ozone insufflation treatments over wound healing.
two weeks, the fistulous cavity partially closed Our patient was referred to our hospital for and the leakage became intermittent. Follow- ozone therapy because of our previous experi- up treatment was subcutaneous infiltration in ence in treating side effects of oncology ther- the area of fibrosis alone. After the fifth session apy.We have described the effect of this at the end of five weeks, the leakage disap- technique in improving blood floand tissue peared and the fistulous cavity closed com- oxygenatioboth of which are decreased in pletely. The six initial sessions were one per radiation-induced fibrosis. Additionally, the week. The patient was living on another of antimicrobial properties of ozone augur well the Canary Islands and to save traveling time for complementary management of the docu- and costs, and because there was clear objec- mented infection associated with drained tive improvement, the seventh session was fluidBased on the mechanism of action of dif- two weeks later and the eighth session was ferent treatments proposed for radiation-related one month later. Hence, after eight ozone fistula/fibrosisother properties ascribed to sessions over 12 weeks, the treatment was con- ozone therapy can be of additional clinical value, cluded. Local pain and symptoms had notice- such as immunomodulation,anti-inflammatory ably decreased by the end of ozone therapy, effects through phospholipase A2 decrease, and an enhanced antioxidant system.
(10  15 mm) and more superficial than ini- In our patient, physical examination (palpa- tially (lower left).
tion) showed a decrease in the surface dimen- Objective quantification using TiVi imaging sion of fibrosis and the level of induration.
pre- and post-treatment showed a measurable However, these assessments often seem impre- decrease in blood flow stasis in the fibrosis area cise and subjective. TiVi , upper and lower (from 255  5 to 215  36 TiVi units, 19%; right) is noninvasive and highly reproducible.
P < 0.001), that is, blood flow in the skin in In our patient, changes measured with this tech- the fibrosis area was more similar to blood flow nique pre- and post-ozone treatment provided in skin areas without fibrosis. There was a simi- more objective assessment of the changes than lar decrease in the area of the fistulous cavity palpation, that is, decrease in thickness and di- 335  56 to 273  37 TiVi units; mensions of the induration/fibrosis area.
P < 0.001) (, upper and lower right).
In conclusion, management of refractory fis- tulae and fibrosis in previously irradiated areascan be difficult. Local treatment with ozone can be easy and effective especially when more Subcutaneous PORT-A-CATHÒs are widely standard treatments are unsuccessful or are used to facilitate chemotherapy administra- not available. Tissue viability imaging using tion. Anatomically, the placement is techni- linearly polarized light can be a very useful tool cally easier and with lower risk in the right for objective assessment and follow-up of rather than left infraclavicular area. However, irradiated areas have an increased risk of de-layed healing and morbidity after local invasive Bernardino Clavo, MD, PhD procedures. Often, it is not necessary to ad- Radiation Oncology DepartmentChronic Pain Unit, and minister special pharmacotherapeutic agents Experimental Surgery-Research Unit but, occasionally, delayed healing can be per- Dr. Negrin University Hospital sistent and debilitating. As with other refrac- Las Palmas, Spain tory radiation-related side effects, the most Canary Islands Institute for Cancer used nonsurgical approach is treatment with Las Palmas, Spain hyperbaric chambers.However, the accessibil- Grupo de Investigaci ity of the equipment is limited and was unavail- Oncologıa Radioterapica (GICOR) able in our center. The surgical approach for Vol. 43 No. 2 February 2012 Norberto Santana-Rodriguez, MD, PhD 4. Clavo B, Suarez G, Aguilar Y, et al. Syndrome of Experimental Surgery-Research Unit brain ischemia and hypometabolism treated by and Department of Thoracic Surgery ozone therapy. Forsch Komplementmed 2011; Dr. Negrin University Hospital Las Palmas, Spain 5. Clavo B, Catala L, Perez JL, Rodriguez V, opez-Silva, MSc, PhD Robaina F. Ozone therapy on cerebral blood flow: IMM-Instituto de Microelectr a preliminary report. Evid Based Complement Alter- de Madrid (CNM-CSIC) nat Med 2004;1:315e319.
6. Clavo B, Perez JL, Lopez L, et al. Effect of ozone Eugenio Dominguez, RN therapy on muscle oxygenation. J Altern Comple- Radiation Oncology Department ment Med 2003;9:251e256.
Dr. Negrin University Hospital 7. Valacchi G, Fortino V, Bocci V. The dual action Las Palmas, Spain of ozone on the skin. Br J Dermatol 2005;153: Medical Oncology DepartmentDr. Negrin University Hospital 8. Bocci V, Borrelli E, Travagli V, Zanardi I. The Las Palmas, Spain ozone paradox: ozone is a strong oxidant as wellas a medical drug. Med Res Rev 2009;29:646e682.
Dominga Gutierrez, RNRadiation Oncology Department 9. Delanian S, Lefaix JL. Current management for Dr. Negrin University Hospital late normal tissue injury: radiation-induced fibrosis Las Palmas, Spain and necrosis. Semin Radiat Oncol 2007;17:99e107.
Maria A. Hernandez, MD 10. Barber E, Menendez S, Leon OS, et al. Preven- Radiation Oncology Department tion of renal injury after induction of ozone toler- Dr. Negrin University Hospital Las Palmas, Spain Mediators Inflamm 1999;8:37e41.
Francisco Robaina, MD, PhDChronic Pain UnitDr. Negrin University HospitalLas Palmas, Spain Persistent Hiccups: An Unusual Presentation and Treatment Disclosures and Acknowledgments Hiccups are defined as sudden, involuntary, Research activity related to this work was sup- spasmodic contractions of the diaphragm and ported, in part, by the I3SNS Program from the external intercostal muscles that result in inspira- Instituto de Salud Carlos III (INT07/030 for BC tion that ends abruptly with the closure of the and INT 07/172 for NS), Madrid, Spain. The glottis. The innervation of the hiccup reflex in- ozone therapy device, Ozonosan Alpha-plusÒ, cludes an afferent pathway via the vagus, phrenic, was provided by Dr. H€ansler GmbH (Iffezheim, and sympathetic branches of T6eT12 and the ef- Germany). Editorial assistance was provided by ferent pathway via the phrenic nerve to the dia- Dr. Peter R. Turner of t-SciMed (Reus, Spain).
The authors declare no conflicts of interest.
muscles.1,2 Hiccups can result from direct injuryto the reflex arc or any underlying disease, in- cluding injury, irritation, or inflammation affect- 1. Pasquier D, Hoelscher T, Schmutz J, et al.
ing one of the nerves involved in the reflex arc.3 Hyperbaric oxygen therapy in the treatment of The sudden closure of the glottis results in the radio-induced lesions in normal tissues: a literature ‘‘hic' sound,4 and the upward-jerking motion review. Radiother Oncol 2004;72:1e13.
probably makes up the second part of the word.
2. Henricson J, Nilsson A, Tesselaar E, Nilsson G, Although hiccups do not seem to play a positive Sjoberg F. Tissue viability imaging: microvascular re-sponse to vasoactive drugs induced by iontophore- physiologic role, there are thousands of etiolo- sis. Microvasc Res 2009;78:199e205.
gies for hiccups reported in the literature and 3. Clavo B, Gutierrez D, Martin D, et al. Intravesical thousands of home and medical remedies to cure ozone therapy for progressive radiation-induced he- to them. The most commonly accepted causes maturia. J Altern Complement Med 2005;11:539e541.
for hiccups include distension of the esophagus


Appl Biochem Biotechnol (2013) 169:1727–1751DOI 10.1007/s12010-012-0079-9 2.45 GHz Microwave Irradiation-Induced OxidativeStress Affects Implantation or Pregnancy in Mice, Saba Shahin & Vineet Prakash Singh & Ritesh K. Shukla &Alok Dhawan & Ravi Kumar Gangwar &Surya Pal Singh & Chandra Mohini Chaturvedi Received: 17 August 2012 / Accepted: 27 December 2012 /Published online: 22 January 2013



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